Saunders, E.J.
Dadaev, T.
Brook, M.N.
Wakerell, S.
Govindasami, K.
Rageevakumar, R.
Hussain, N.
Osborne, A.
Keating, D.
Lophatananon, A.
Muir, K.R.
UKGPCS Collaborators,
Darst, B.F.
Conti, D.V.
Haiman, C.A.
Antoniou, A.C.
Eeles, R.A.
Kote-Jarai, Z.
(2024). Identification of Genes with Rare Loss of Function Variants Associated with Aggressive Prostate Cancer and Survival. Eur urol oncol,
Vol.7
(2),
pp. 248-257.
show abstract
full text
BACKGROUND: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less definitive for other genes. OBJECTIVE: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS). DESIGN, SETTING, AND PARTICIPANTS: We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score ≥8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival. RESULTS AND LIMITATIONS: We observed associations between PrCa aggressiveness and pLOF mutations in ATM, BRCA2, MSH2, and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 × 10-16) than noncarriers. CONCLUSIONS: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations. PATIENT SUMMARY: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa..
Sarig, K.
Oxley, S.
Kalra, A.
Sobocan, M.
Fierheller, C.T.
Sideris, M.
Gootzen, T.
Ferris, M.
Eeles, R.A.
Evans, D.G.
Quaife, S.L.
Manchanda, R.
(2024). BRCA awareness and testing experience in the UK Jewish population: a qualitative study. J med genet,
.
show abstract
BACKGROUND: 1 in 40 UK Jewish individuals carry a pathogenic variant in BRCA1/BRCA2. Traditional testing criteria miss half of carriers, and so population genetic testing is being piloted for Jewish people in England. There has been no qualitative research into the factors influencing BRCA awareness and testing experience in this group. This study aimed to explore these and inform improvements for the implementation of population genetic testing. METHODS: Qualitative study of UK Jewish adults who have undergone BRCA testing. We conducted one-to-one semistructured interviews via telephone or video call using a predefined topic guide, until sufficient information power was reached. Interviews were audio-recorded, transcribed verbatim and interpreted using applied thematic analysis. RESULTS: 32 individuals were interviewed (28 carriers, 4 non-carriers). We interpreted five themes intersecting across six time points of the testing pathway: (1) individual differences regarding personal/family history of cancer, demographics and personal attitudes/approach; (2) healthcare professionals' support; (3) pathway access and integration; (4) nature of family/partner relationships; and (5) Jewish community factors. Testing was largely triggered by connecting information to a personal/family history of cancer. No participants reported decision regret, although there was huge variation in satisfaction. Suggestions were given around increasing UK Jewish community awareness, making information and support services personally relevant and proactive case management of carriers. CONCLUSIONS: There is a need to improve UK Jewish community BRCA awareness and to highlight personal relevance of testing for individuals without a personal/family history of cancer. Traditional testing criteria caused multiple issues regarding test access and experience. Carriers want information and support services tailored to their individual circumstances..
Woodcock, D.J.
Sahli, A.
Teslo, R.
Bhandari, V.
Gruber, A.J.
Ziubroniewicz, A.
Gundem, G.
Xu, Y.
Butler, A.
Anokian, E.
Pope, B.J.
Jung, C.-.
Tarabichi, M.
Dentro, S.C.
Farmery, J.H.
CRUK ICGC Prostate Group,
Van Loo, P.
Warren, A.Y.
Gnanapragasam, V.
Hamdy, F.C.
Bova, G.S.
Foster, C.S.
Neal, D.E.
Lu, Y.-.
Kote-Jarai, Z.
Fraser, M.
Bristow, R.G.
Boutros, P.C.
Costello, A.J.
Corcoran, N.M.
Hovens, C.M.
Massie, C.E.
Lynch, A.G.
Brewer, D.S.
Eeles, R.A.
Cooper, C.S.
Wedge, D.C.
(2024). Genomic evolution shapes prostate cancer disease type. Cell genom,
Vol.4
(3),
p. 100511.
show abstract
full text
The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression..
James, N.D.
Tannock, I.
N'Dow, J.
Feng, F.
Gillessen, S.
Ali, S.A.
Trujillo, B.
Al-Lazikani, B.
Attard, G.
Bray, F.
Compérat, E.
Eeles, R.
Fatiregun, O.
Grist, E.
Halabi, S.
Haran, Á.
Herchenhorn, D.
Hofman, M.S.
Jalloh, M.
Loeb, S.
MacNair, A.
Mahal, B.
Mendes, L.
Moghul, M.
Moore, C.
Morgans, A.
Morris, M.
Murphy, D.
Murthy, V.
Nguyen, P.L.
Padhani, A.
Parker, C.
Rush, H.
Sculpher, M.
Soule, H.
Sydes, M.R.
Tilki, D.
Tunariu, N.
Villanti, P.
Xie, L.-.
(2024). The Lancet Commission on prostate cancer: planning for the surge in cases. Lancet,
Vol.403
(10437),
pp. 1683-1722.
Watts, E.L.
Gonzales, T.I.
Strain, T.
Saint-Maurice, P.F.
Bishop, D.T.
Chanock, S.J.
Johansson, M.
Keku, T.O.
Le Marchand, L.
Moreno, V.
Newcomb, P.A.
Newton, C.C.
Pai, R.K.
Purdue, M.P.
Ulrich, C.M.
Smith-Byrne, K.
Van Guelpen, B.
Eeles, R.A.
Haiman, C.A.
Kote-Jarai, Z.
Schumacher, F.R.
Benlloch, S.
Olama, A.A.
Muir, K.R.
Berndt, S.I.
Conti, D.V.
Wiklund, F.
Chanock, S.J.
Wang, Y.
Tangen, C.M.
Batra, J.
Clements, J.A.
Grönberg, H.
Pashayan, N.
Schleutker, J.
Albanes, D.
Weinstein, S.J.
Wolk, A.
West, C.M.
Mucci, L.A.
Cancel-Tassin, G.
Koutros, S.
Sørensen, K.D.
Grindedal, E.M.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Travis, R.C.
Hamilton, R.J.
Ingles, S.A.
Rosenstein, B.S.
Lu, Y.-.
Giles, G.G.
MacInnis, R.J.
Kibel, A.S.
Vega, A.
Kogevinas, M.
Penney, K.L.
Park, J.Y.
Stanford, J.L.
Cybulski, C.
Nordestgaard, B.G.
Nielsen, S.F.
Brenner, H.
Maier, C.
Kim, J.
John, E.M.
Teixeira, M.R.
Neuhausen, S.L.
De Ruyck, K.
Razack, A.
Newcomb, L.F.
Lessel, D.
Kaneva, R.
Usmani, N.
Claessens, F.
Townsend, P.A.
Castelao, J.E.
Roobol, M.J.
Menegaux, F.
Khaw, K.-.
Cannon-Albright, L.
Pandha, H.
Thibodeau, S.N.
Hunter, D.J.
Kraft, P.
Blot, W.J.
Riboli, E.
Day, F.R.
Wijndaele, K.
Wareham, N.J.
Matthews, C.E.
Moore, S.C.
Brage, S.
(2024). Observational and genetic associations between cardiorespiratory fitness and cancer: a UK Biobank and international consortia study. British journal of cancer,
Vol.130
(1),
pp. 114-124.
show abstract
Abstract
Background
The association of fitness with cancer risk is not clear.
Methods
We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method.
Results
After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O2⋅min−1⋅kg−1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73–0.89), colorectal (0.94, 0.90–0.99), and breast cancer (0.96, 0.92–0.99). In MR analyses, a 0.5 SD increase in genetically predicted O2⋅min−1⋅kg−1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86–0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated.
Discussion
Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.
.
Darst, B.F.
Saunders, E.
Dadaev, T.
Sheng, X.
Wan, P.
Pooler, L.
Xia, L.Y.
Chanock, S.
Berndt, S.I.
Wang, Y.
Patel, A.V.
Albanes, D.
Weinstein, S.J.
Gnanapragasam, V.
Huff, C.
Couch, F.J.
Wolk, A.
Giles, G.G.
Nguyen-Dumont, T.
Milne, R.L.
Pomerantz, M.M.
Schmidt, J.A.
Travis, R.C.
Key, T.J.
Stopsack, K.H.
Mucci, L.A.
Catalona, W.J.
Marosy, B.
Hetrick, K.N.
Doheny, K.F.
MacInnis, R.J.
Southey, M.C.
Eeles, R.A.
Wiklund, F.
Conti, D.V.
Kote-Jarai, Z.
Haiman, C.A.
(2023). Germline Sequencing Analysis to Inform Clinical Gene Panel Testing for Aggressive Prostate Cancer. Jama oncol,
Vol.9
(11),
pp. 1514-1524.
show abstract
IMPORTANCE: Germline gene panel testing is recommended for men with advanced prostate cancer (PCa) or a family history of cancer. While evidence is limited for some genes currently included in panel testing, gene panels are also likely to be incomplete and missing genes that influence PCa risk and aggressive disease. OBJECTIVE: To identify genes associated with aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: A 2-stage exome sequencing case-only genetic association study was conducted including men of European ancestry from 18 international studies. Data analysis was performed from January 2021 to March 2023. Participants were 9185 men with aggressive PCa (including 6033 who died of PCa and 2397 with confirmed metastasis) and 8361 men with nonaggressive PCa. EXPOSURE: Sequencing data were evaluated exome-wide and in a focused investigation of 29 DNA repair pathway and cancer susceptibility genes, many of which are included on gene panels. MAIN OUTCOMES AND MEASURES: The primary study outcomes were aggressive (category T4 or both T3 and Gleason score ≥8 tumors, metastatic PCa, or PCa death) vs nonaggressive PCa (category T1 or T2 and Gleason score ≤6 tumors without known recurrence), and metastatic vs nonaggressive PCa. RESULTS: A total of 17 546 men of European ancestry were included in the analyses; mean (SD) age at diagnosis was 65.1 (9.2) years in patients with aggressive PCa and 63.7 (8.0) years in those with nonaggressive disease. The strongest evidence of association with aggressive or metastatic PCa was noted for rare deleterious variants in known PCa risk genes BRCA2 and ATM (P ≤ 1.9 × 10-6), followed by NBN (P = 1.7 × 10-4). This study found nominal evidence (P < .05) of association with rare deleterious variants in MSH2, XRCC2, and MRE11A. Five other genes had evidence of greater risk (OR≥2) but carrier frequency differences between aggressive and nonaggressive PCa were not statistically significant: TP53, RAD51D, BARD1, GEN1, and SLX4. Deleterious variants in these 11 candidate genes were carried by 2.3% of patients with nonaggressive, 5.6% with aggressive, and 7.0% with metastatic PCa. CONCLUSIONS AND RELEVANCE: The findings of this study provide further support for DNA repair and cancer susceptibility genes to better inform disease management in men with PCa and for extending testing to men with nonaggressive disease, as men carrying deleterious alleles in these genes are likely to develop more advanced disease..
Gillessen, S.
Bossi, A.
Davis, I.D.
de Bono, J.
Fizazi, K.
James, N.D.
Mottet, N.
Shore, N.
Small, E.
Smith, M.
Sweeney, C.
Tombal, B.
Antonarakis, E.S.
Aparicio, A.M.
Armstrong, A.J.
Attard, G.
Beer, T.M.
Beltran, H.
Bjartell, A.
Blanchard, P.
Briganti, A.
Bristow, R.G.
Bulbul, M.
Caffo, O.
Castellano, D.
Castro, E.
Cheng, H.H.
Chi, K.N.
Chowdhury, S.
Clarke, C.S.
Clarke, N.
Daugaard, G.
De Santis, M.
Duran, I.
Eeles, R.
Efstathiou, E.
Efstathiou, J.
Ngozi Ekeke, O.
Evans, C.P.
Fanti, S.
Feng, F.Y.
Fonteyne, V.
Fossati, N.
Frydenberg, M.
George, D.
Gleave, M.
Gravis, G.
Halabi, S.
Heinrich, D.
Herrmann, K.
Higano, C.
Hofman, M.S.
Horvath, L.G.
Hussain, M.
Jereczek-Fossa, B.A.
Jones, R.
Kanesvaran, R.
Kellokumpu-Lehtinen, P.-.
Khauli, R.B.
Klotz, L.
Kramer, G.
Leibowitz, R.
Logothetis, C.J.
Mahal, B.A.
Maluf, F.
Mateo, J.
Matheson, D.
Mehra, N.
Merseburger, A.
Morgans, A.K.
Morris, M.J.
Mrabti, H.
Mukherji, D.
Murphy, D.G.
Murthy, V.
Nguyen, P.L.
Oh, W.K.
Ost, P.
O'Sullivan, J.M.
Padhani, A.R.
Pezaro, C.
Poon, D.M.
Pritchard, C.C.
Rabah, D.M.
Rathkopf, D.
Reiter, R.E.
Rubin, M.A.
Ryan, C.J.
Saad, F.
Pablo Sade, J.
Sartor, O.A.
Scher, H.I.
Sharifi, N.
Skoneczna, I.
Soule, H.
Spratt, D.E.
Srinivas, S.
Sternberg, C.N.
Steuber, T.
Suzuki, H.
Sydes, M.R.
Taplin, M.-.
Tilki, D.
Türkeri, L.
Turco, F.
Uemura, H.
Uemura, H.
Ürün, Y.
Vale, C.L.
van Oort, I.
Vapiwala, N.
Walz, J.
Yamoah, K.
Ye, D.
Yu, E.Y.
Zapatero, A.
Zilli, T.
Omlin, A.
(2023). Management of Patients with Advanced Prostate Cancer Part I: Intermediate-/High-risk and Locally Advanced Disease, Biochemical Relapse, and Side Effects of Hormonal Treatment: Report of the Advanced Prostate Cancer Consensus Conference 2022. Eur urol,
Vol.83
(3),
pp. 267-293.
show abstract
full text
BACKGROUND: Innovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management. OBJECTIVE: To present consensus voting results for select questions from APCCC 2022. DESIGN, SETTING, AND PARTICIPANTS: Before the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members ("panellists") who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1-3. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. RESULTS AND LIMITATIONS: The voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis. CONCLUSIONS: These voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with health care providers and patients worldwide. At each APCCC, a panel of physician experts vote in response to multiple-choice questions about their clinical opinions and approaches to managing advanced prostate cancer. This report presents voting results for the subset of questions pertaining to intermediate- and high-risk and locally advanced prostate cancer, biochemical relapse after definitive treatment, advanced (next-generation) imaging, and management of side effects caused by hormonal therapies. The results provide a practical guide to help clinicians and patients discuss treatment options as part of shared multidisciplinary decision-making. The findings may be especially useful when there is little or no high-level evidence to guide treatment decisions..
Brook, M.N.
Ní Raghallaigh, H.
Govindasami, K.
Dadaev, T.
Rageevakumar, R.
Keating, D.
Hussain, N.
Osborne, A.
Lophatananon, A.
UKGPCS Collaborators,
Muir, K.R.
Kote-Jarai, Z.
Eeles, R.A.
(2023). Family History of Prostate Cancer and Survival Outcomes in the UK Genetic Prostate Cancer Study. Eur urol,
Vol.83
(3),
pp. 257-266.
show abstract
full text
BACKGROUND: A family history (FH) of prostate cancer (PrCa) is associated with an increased likelihood of PrCa diagnosis. Conflicting evidence exists regarding familial PrCa and clinical outcomes among PrCa patients, including all-cause mortality/overall survival (OS), PrCa-specific survival (PCSS), aggressive histology, and stage at diagnosis. OBJECTIVE: To determine how the number, degree, and age of a PrCa patient's affected relatives are associated with OS and PCSS of those already diagnosed with PrCa. DESIGN, SETTING, AND PARTICIPANTS: The UK Genetic Prostate Cancer Study is a longitudinal, multi-institutional, observational study collecting baseline and follow-up clinical data since 1992. We examined OS and PCSS in 16340 men by degree and number of relatives with prostate and genetically related cancers (breast, ovarian, and colorectal). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was all-cause mortality among PrCa patients. The risk of death with respect to FH was assessed by calculating hazard ratios from Cox proportional hazard regression models, adjusting for relevant factors. RESULTS AND LIMITATIONS: A stronger FH was inversely associated with the risk of all-cause and PrCa-specific mortality. This association was greater in those with an increasing number (p-trend < 0.001) and increasing closeness (p-trend < 0.001) of the diagnosed relatives. Patients with at least one first-degree relative were at a lower risk of all-cause mortality than those with no FH (hazard ratio = 0.82 [95% confidence interval 0.75-0.89]). The population is largely of European ancestry, and this may cause an issue with representation and generalisation. Data are missing on epidemiological risk factors for death such as smoking and on comorbidities. Recall of family members' diagnoses may affect the classification of FH in unconfirmed cases. CONCLUSIONS: Based on the investigation of the type and timing of relatives' cancers, it is likely that reductions in mortality are due almost completely to a greater awareness of the disease. This study provides information for clinicians guiding patients and their relatives based on their familial risk. It shows the importance of screening and awareness programmes, which are likely to improve survival among men with an FH. PATIENT SUMMARY: We were interested in how a family history of prostate cancer affects survival in prostate cancer patients. We studied 16340 patients, categorised them according to the strength of their family history, and found that the stronger their family history, the better they did in terms of overall survival. We looked at the type and timing of patients' diagnoses compared with those of their relatives and found that this effect is likely to be explained by awareness, which indicates the importance of screening and awareness programmes..
Gheybi, K.
Jiang, J.
Mutambirwa, S.B.
Soh, P.X.
Kote-Jarai, Z.
Jaratlerdsiri, W.
Eeles, R.A.
Bornman, M.S.
Hayes, V.M.
(2023). Evaluating Germline Testing Panels in Southern African Males With Advanced Prostate Cancer. J natl compr canc netw,
Vol.21
(3),
pp. 289-296.e3.
show abstract
full text
BACKGROUND: Germline testing for prostate cancer is on the increase, with clinical implications for risk assessment, treatment, and management. Regardless of family history, NCCN recommends germline testing for patients with metastatic, regional, very-high-risk localized, and high-risk localized prostate cancer. Although African ancestry is a significant risk factor for aggressive prostate cancer, due to a lack of available data no testing criteria have been established for ethnic minorities. PATIENTS AND METHODS: Through deep sequencing, we interrogated the 20 most common germline testing panel genes in 113 Black South African males presenting with largely advanced prostate cancer. Bioinformatic tools were then used to identify the pathogenicity of the variants. RESULTS: After we identified 39 predicted deleterious variants (16 genes), further computational annotation classified 17 variants as potentially oncogenic (12 genes; 17.7% of patients). Rare pathogenic variants included CHEK2 Arg95Ter, BRCA2 Trp31Arg, ATM Arg3047Ter (2 patients), and TP53 Arg282Trp. Notable oncogenic variants of unknown pathogenicity included novel BRCA2 Leu3038Ile in a patient with early-onset disease, whereas patients with FANCA Arg504Cys and RAD51C Arg260Gln reported a family history of prostate cancer. Overall, rare pathogenic and early-onset or familial-associated oncogenic variants were identified in 6.9% (5/72) and 9.2% (8/87) of patients presenting with a Gleason score ≥8 or ≥4 + 3 prostate cancer, respectively. CONCLUSIONS: In this first-of-its-kind study of southern African males, we provide support of African inclusion for advanced, early-onset, and familial prostate cancer genetic testing, indicating clinical value for 30% of current gene panels. Recognizing current panel limitations highlights an urgent need to establish testing guidelines for men of African ancestry. We provide a rationale for considering lowering the pathologic diagnostic inclusion criteria and call for further genome-wide interrogation to ensure the best possible African-relevant prostate cancer gene panel..
Dias, A.
Brook, M.N.
Bancroft, E.K.
Page, E.C.
Chamberlain, A.
Saya, S.
Amin, J.
Mikropoulos, C.
Taylor, N.
Myhill, K.
Thomas, S.
Saunders, E.
Dadaev, T.
Leongamornlert, D.
Dyrsø Jensen, T.
Evans, D.G.
Cybulski, C.
Liljegren, A.
Teo, S.H.
Side, L.
IMPACT study collaborators and Steering Committee,
Kote-Jarai, Z.
Eeles, R.A.
(2023). Serum testosterone and prostate cancer in men with germline BRCA1/2 pathogenic variants. Bjui compass,
Vol.4
(3),
pp. 361-373.
show abstract
full text
OBJECTIVES: The relation of serum androgens and the development of prostate cancer (PCa) is subject of debate. Lower total testosterone (TT) levels have been associated with increased PCa detection and worse pathological features after treatment. However, data from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) and Prostate Cancer Prevention (PCPT) trial groups indicate no association. The aim of this study is to investigate the association of serum androgen levels and PCa detection in a prospective screening study of men at higher genetic risk of aggressive PCa due to BRCA1/2 pathogenic variants (PVs), the IMPACT study. METHODS: Men enrolled in the IMPACT study provided serum samples during regular visits. Hormonal levels were calculated using immunoassays. Free testosterone (FT) was calculated from TT and sex hormone binding globulin (SHBG) using the Sodergard mass equation. Age, body mass index (BMI), prostate-specific antigen (PSA) and hormonal concentrations were compared between genetic cohorts. We also explored associations between age and TT, SHBG, FT and PCa, in the whole subset and stratified by BRCA1/2 PVs status. RESULTS: A total of 777 participants in the IMPACT study had TT and SHBG measurements in serum samples at annual visits, giving 3940 prospective androgen levels, from 266 BRCA1 PVs carriers, 313 BRCA2 PVs carriers and 198 non-carriers. The median number of visits per patient was 5. There was no difference in TT, SHBG and FT between carriers and non-carriers. In a univariate analysis, androgen levels were not associated with PCa. In the analysis stratified by carrier status, no significant association was found between hormonal levels and PCa in non-carriers, BRCA1 or BRCA2 PVs carriers. CONCLUSIONS: Male BRCA1/2 PVs carriers have a similar androgen profile to non-carriers. Hormonal levels were not associated with PCa in men with and without BRCA1/2 PVs. Mechanisms related to the particularly aggressive phenotype of PCa in BRCA2 PVs carriers may therefore not be linked with circulating hormonal levels..
Gillessen, S.
Bossi, A.
Davis, I.D.
de Bono, J.
Fizazi, K.
James, N.D.
Mottet, N.
Shore, N.
Small, E.
Smith, M.
Sweeney, C.J.
Tombal, B.
Antonarakis, E.S.
Aparicio, A.M.
Armstrong, A.J.
Attard, G.
Beer, T.M.
Beltran, H.
Bjartell, A.
Blanchard, P.
Briganti, A.
Bristow, R.G.
Bulbul, M.
Caffo, O.
Castellano, D.
Castro, E.
Cheng, H.H.
Chi, K.N.
Chowdhury, S.
Clarke, C.S.
Clarke, N.
Daugaard, G.
De Santis, M.
Duran, I.
Eeles, R.
Efstathiou, E.
Efstathiou, J.
Ekeke, O.N.
Evans, C.P.
Fanti, S.
Feng, F.Y.
Fonteyne, V.
Fossati, N.
Frydenberg, M.
George, D.
Gleave, M.
Gravis, G.
Halabi, S.
Heinrich, D.
Herrmann, K.
Higano, C.
Hofman, M.S.
Horvath, L.G.
Hussain, M.
Jereczek-Fossa, B.A.
Jones, R.
Kanesvaran, R.
Kellokumpu-Lehtinen, P.-.
Khauli, R.B.
Klotz, L.
Kramer, G.
Leibowitz, R.
Logothetis, C.
Mahal, B.
Maluf, F.
Mateo, J.
Matheson, D.
Mehra, N.
Merseburger, A.
Morgans, A.K.
Morris, M.J.
Mrabti, H.
Mukherji, D.
Murphy, D.G.
Murthy, V.
Nguyen, P.L.
Oh, W.K.
Ost, P.
O'Sullivan, J.M.
Padhani, A.R.
Pezaro, C.J.
Poon, D.M.
Pritchard, C.C.
Rabah, D.M.
Rathkopf, D.
Reiter, R.E.
Rubin, M.A.
Ryan, C.J.
Saad, F.
Sade, J.P.
Sartor, O.
Scher, H.I.
Sharifi, N.
Skoneczna, I.
Soule, H.
Spratt, D.E.
Srinivas, S.
Sternberg, C.N.
Steuber, T.
Suzuki, H.
Sydes, M.R.
Taplin, M.-.
Tilki, D.
Türkeri, L.
Turco, F.
Uemura, H.
Uemura, H.
Ürün, Y.
Vale, C.L.
van Oort, I.
Vapiwala, N.
Walz, J.
Yamoah, K.
Ye, D.
Yu, E.Y.
Zapatero, A.
Zilli, T.
Omlin, A.
(2023). Management of patients with advanced prostate cancer-metastatic and/or castration-resistant prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022. Eur j cancer,
Vol.185,
pp. 178-215.
show abstract
full text
BACKGROUND: Innovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence. OBJECTIVE: To present the voting results of the APCCC 2022. DESIGN, SETTING, AND PARTICIPANTS: The experts voted on controversial questions where high-level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration-resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration-resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions. RESULTS AND LIMITATIONS: The voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer. CONCLUSIONS: These voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer. TWITTER SUMMARY: Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer. TAKE-HOME MESSAGE: At APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration-resistant prostate cancer is summarised here..
Gregg, J.R.
Kim, J.
Logothetis, C.
Hanash, S.
Zhang, X.
Manyam, G.
Muir, K.
UKGPCS Collaborative Group,
Giles, G.G.
Stanford, J.L.
Berndt, S.I.
Kogevinas, M.
Brenner, H.
Eeles, R.A.
PRACTICAL Consortium,
Wei, P.
Daniel, C.R.
(2023). Coffee Intake, Caffeine Metabolism Genotype, and Survival Among Men with Prostate Cancer. Eur urol oncol,
Vol.6
(3),
pp. 282-288.
show abstract
BACKGROUND: Coffee intake may lower prostate cancer risk and progression, but postdiagnosis outcomes by caffeine metabolism genotype are not well characterized. OBJECTIVE: To evaluate associations between coffee intake, caffeine metabolism genotype, and survival in a large, multicenter study of men with prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Data from The PRACTICAL Consortium database for 5727 men with prostate cancer from seven US, Australian, and European studies were included. The cases included had data available for the CYP1A2 -163C>A rs762551 single-nucleotide variant associated with caffeine metabolism, coffee intake, and >6 mo of follow-up. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable-adjusted Cox proportional hazards models across pooled patient-level data were used to compare the effect of coffee intake (categorized as low [reference], high, or none/very low) in relation to overall survival (OS) and prostate cancer-specific survival (PCSS), with stratified analyses conducted by clinical disease risk and genotype. RESULTS AND LIMITATIONS: High coffee intake appeared to be associated with longer PCSS (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.68-1.08; p = 0.18) and OS (HR 0.90, 95% CI 0.77-1.07; p = 0.24), although results were not statistically significant. In the group with clinically localized disease, high coffee intake was associated with longer PCSS (HR 0.66, 95% CI 0.44-0.98; p = 0.040), with comparable results for the group with advanced disease (HR 0.92, 95% CI 0.69-1.23; p = 0.6). High coffee intake was associated with longer PCSS among men with the CYP1A2 AA (HR 0.67, 95% CI 0.49-0.93; p = 0.017) but not the AC/CC genotype (p = 0.8); an interaction was detected (p = 0.042). No associations with OS were observed in subgroup analyses (p > 0.05). Limitations include the nominal statistical significance and residual confounding. CONCLUSIONS: Coffee intake was associated with longer PCSS among men with a CYP1A2 -163AA (*1F/*1F) genotype, a finding that will require further replication. PATIENT SUMMARY: It is likely that coffee intake is associated with longer prostate cancer-specific survival in certain groups, but more research is needed to fully understand which men may benefit and why..
Darst, B.F.
Shen, J.
Madduri, R.K.
Rodriguez, A.A.
Xiao, Y.
Sheng, X.
Saunders, E.J.
Dadaev, T.
Brook, M.N.
Hoffmann, T.J.
Muir, K.
Wan, P.
Le Marchand, L.
Wilkens, L.
Wang, Y.
Schleutker, J.
MacInnis, R.J.
Cybulski, C.
Neal, D.E.
Nordestgaard, B.G.
Nielsen, S.F.
Batra, J.
Clements, J.A.
Cancer BioResource, A.P.
Grönberg, H.
Pashayan, N.
Travis, R.C.
Park, J.Y.
Albanes, D.
Weinstein, S.
Mucci, L.A.
Hunter, D.J.
Penney, K.L.
Tangen, C.M.
Hamilton, R.J.
Parent, M.-.
Stanford, J.L.
Koutros, S.
Wolk, A.
Sørensen, K.D.
Blot, W.J.
Yeboah, E.D.
Mensah, J.E.
Lu, Y.-.
Schaid, D.J.
Thibodeau, S.N.
West, C.M.
Maier, C.
Kibel, A.S.
Cancel-Tassin, G.
Menegaux, F.
John, E.M.
Grindedal, E.M.
Khaw, K.-.
Ingles, S.A.
Vega, A.
Rosenstein, B.S.
Teixeira, M.R.
NC-LA PCaP Investigators,
Kogevinas, M.
Cannon-Albright, L.
Huff, C.
Multigner, L.
Kaneva, R.
Leach, R.J.
Brenner, H.
Hsing, A.W.
Kittles, R.A.
Murphy, A.B.
Logothetis, C.J.
Neuhausen, S.L.
Isaacs, W.B.
Nemesure, B.
Hennis, A.J.
Carpten, J.
Pandha, H.
De Ruyck, K.
Xu, J.
Razack, A.
Teo, S.-.
Canary PASS Investigators,
Newcomb, L.F.
Fowke, J.H.
Neslund-Dudas, C.
Rybicki, B.A.
Gamulin, M.
Usmani, N.
Claessens, F.
Gago-Dominguez, M.
Castelao, J.E.
Townsend, P.A.
Crawford, D.C.
Petrovics, G.
Casey, G.
Roobol, M.J.
Hu, J.F.
Berndt, S.I.
Van Den Eeden, S.K.
Easton, D.F.
Chanock, S.J.
Cook, M.B.
Wiklund, F.
Witte, J.S.
Eeles, R.A.
Kote-Jarai, Z.
Watya, S.
Gaziano, J.M.
Justice, A.C.
Conti, D.V.
Haiman, C.A.
(2023). Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry. Am j hum genet,
Vol.110
(7),
pp. 1200-1206.
show abstract
Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping..
Hansen, E.B.
Karlsson, Q.
Merson, S.
Wakerell, S.
Rageevakumar, R.
Jensen, J.B.
Borre, M.
Kote-Jarai, Z.
Eeles, R.A.
Sørensen, K.D.
(2023). Impact of germline DNA repair gene variants on prognosis and treatment of men with advanced prostate cancer. Sci rep,
Vol.13
(1),
p. 19135.
show abstract
full text
The clinical importance of germline variants in DNA repair genes (DRGs) is becoming increasingly recognized, but their impact on advanced prostate cancer prognosis remains unclear. A cohort of 221 newly diagnosed metastatic castration-resistant prostate cancer (mCRPC) patients were screened for pathogenic germline variants in 114 DRGs. The primary endpoint was progression-free survival (PFS) on first-line androgen signaling inhibitor (ARSI) treatment for mCRPC. Secondary endpoints were time to mCRPC progression on initial androgen deprivation therapy (ADT) and overall survival (OS). Twenty-seven patients (12.2%) carried a germline DRG variant. DRG carrier status was independently associated with shorter PFS on first-line ARSI [HR 1.72 (1.06-2.81), P = 0.029]. At initiation of ADT, DRG carrier status was independently associated with shorter progression time to mCRPC [HR 1.56, (1.02-2.39), P = 0.04] and shorter OS [HR 1.99, (1.12-3.52), P = 0.02]. Investigating the contributions of individual germline DRG variants on PFS and OS revealed CHEK2 variants to have little effect. Furthermore, prior taxane treatment was associated with worse PFS on first-line ARSI for DRG carriers excluding CHEK2 (P = 0.0001), but not for noncarriers. In conclusion, germline DRG carrier status holds independent prognostic value for predicting advanced prostate cancer patient outcomes and may potentially inform on optimal treatment sequencing already at the hormone-sensitive stage..
Chen, F.
Madduri, R.K.
Rodriguez, A.A.
Darst, B.F.
Chou, A.
Sheng, X.
Wang, A.
Shen, J.
Saunders, E.J.
Rhie, S.K.
Bensen, J.T.
Ingles, S.A.
Kittles, R.A.
Strom, S.S.
Rybicki, B.A.
Nemesure, B.
Isaacs, W.B.
Stanford, J.L.
Zheng, W.
Sanderson, M.
John, E.M.
Park, J.Y.
Xu, J.
Wang, Y.
Berndt, S.I.
Huff, C.D.
Yeboah, E.D.
Tettey, Y.
Lachance, J.
Tang, W.
Rentsch, C.T.
Cho, K.
Mcmahon, B.H.
Biritwum, R.B.
Adjei, A.A.
Tay, E.
Truelove, A.
Niwa, S.
Sellers, T.A.
Yamoah, K.
Murphy, A.B.
Crawford, D.C.
Patel, A.V.
Bush, W.S.
Aldrich, M.C.
Cussenot, O.
Petrovics, G.
Cullen, J.
Neslund-Dudas, C.M.
Stern, M.C.
Kote-Jarai, Z.
Govindasami, K.
Cook, M.B.
Chokkalingam, A.P.
Hsing, A.W.
Goodman, P.J.
Hoffmann, T.J.
Drake, B.F.
Hu, J.J.
Keaton, J.M.
Hellwege, J.N.
Clark, P.E.
Jalloh, M.
Gueye, S.M.
Niang, L.
Ogunbiyi, O.
Idowu, M.O.
Popoola, O.
Adebiyi, A.O.
Aisuodionoe-Shadrach, O.I.
Ajibola, H.O.
Jamda, M.A.
Oluwole, O.P.
Nwegbu, M.
Adusei, B.
Mante, S.
Darkwa-Abrahams, A.
Mensah, J.E.
Diop, H.
Van Den Eeden, S.K.
Blanchet, P.
Fowke, J.H.
Casey, G.
Hennis, A.J.
Lubwama, A.
Thompson, I.M.
Leach, R.
Easton, D.F.
Preuss, M.H.
Loos, R.J.
Gundell, S.M.
Wan, P.
Mohler, J.L.
Fontham, E.T.
Smith, G.J.
Taylor, J.A.
Srivastava, S.
Eeles, R.A.
Carpten, J.D.
Kibel, A.S.
Multigner, L.
Parent, M.-.
Menegaux, F.
Cancel-Tassin, G.
Klein, E.A.
Andrews, C.
Rebbeck, T.R.
Brureau, L.
Ambs, S.
Edwards, T.L.
Watya, S.
Chanock, S.J.
Witte, J.S.
Blot, W.J.
Michael Gaziano, J.
Justice, A.C.
Conti, D.V.
Haiman, C.A.
(2023). Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry. Eur urol,
Vol.84
(1),
pp. 13-21.
show abstract
full text
BACKGROUND: Genetic factors play an important role in prostate cancer (PCa) susceptibility. OBJECTIVE: To discover common genetic variants contributing to the risk of PCa in men of African ancestry. DESIGN, SETTING, AND PARTICIPANTS: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness. RESULTS AND LIMITATIONS: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4). CONCLUSIONS: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry. PATIENT SUMMARY: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease..
Nyberg, T.
Brook, M.N.
Ficorella, L.
Lee, A.
Dennis, J.
Yang, X.
Wilcox, N.
Dadaev, T.
Govindasami, K.
Lush, M.
Leslie, G.
Lophatananon, A.
Muir, K.
Bancroft, E.
Easton, D.F.
Tischkowitz, M.
Kote-Jarai, Z.
Eeles, R.
Antoniou, A.C.
(2023). CanRisk-Prostate: A Comprehensive, Externally Validated Risk Model for the Prediction of Future Prostate Cancer. J clin oncol,
Vol.41
(5),
pp. 1092-1104.
show abstract
full text
PURPOSE: Prostate cancer (PCa) is highly heritable. No validated PCa risk model currently exists. We therefore sought to develop a genetic risk model that can provide personalized predicted PCa risks on the basis of known moderate- to high-risk pathogenic variants, low-risk common genetic variants, and explicit cancer family history, and to externally validate the model in an independent prospective cohort. MATERIALS AND METHODS: We developed a risk model using a kin-cohort comprising individuals from 16,633 PCa families ascertained in the United Kingdom from 1993 to 2017 from the UK Genetic Prostate Cancer Study, and complex segregation analysis adjusting for ascertainment. The model was externally validated in 170,850 unaffected men (7,624 incident PCas) recruited from 2006 to 2010 to the independent UK Biobank prospective cohort study. RESULTS: The most parsimonious model included the effects of pathogenic variants in BRCA2, HOXB13, and BRCA1, and a polygenic score on the basis of 268 common low-risk variants. Residual familial risk was modeled by a hypothetical recessively inherited variant and a polygenic component whose standard deviation decreased log-linearly with age. The model predicted familial risks that were consistent with those reported in previous observational studies. In the validation cohort, the model discriminated well between unaffected men and men with incident PCas within 5 years (C-index, 0.790; 95% CI, 0.783 to 0.797) and 10 years (C-index, 0.772; 95% CI, 0.768 to 0.777). The 50% of men with highest predicted risks captured 86.3% of PCa cases within 10 years. CONCLUSION: To our knowledge, this is the first validated risk model offering personalized PCa risks. The model will assist in counseling men concerned about their risk and can facilitate future risk-stratified population screening approaches..
Wang, A.
Xu, Y.
Yu, Y.
Nead, K.T.
Kim, T.
Xu, K.
Dadaev, T.
Saunders, E.
Sheng, X.
Wan, P.
Pooler, L.
Xia, L.Y.
Chanock, S.
Berndt, S.I.
Gapstur, S.M.
Stevens, V.
Albanes, D.
Weinstein, S.J.
Gnanapragasam, V.
Giles, G.G.
Nguyen-Dumont, T.
Milne, R.L.
Pomerantz, M.M.
Schmidt, J.A.
Stopsack, K.H.
Mucci, L.A.
Catalona, W.J.
Hetrick, K.N.
Doheny, K.F.
MacInnis, R.J.
Southey, M.C.
Eeles, R.A.
Wiklund, F.
Kote-Jarai, Z.
de Smith, A.J.
Conti, D.V.
Huff, C.
Haiman, C.A.
Darst, B.F.
(2023). Clonal hematopoiesis and risk of prostate cancer in large samples of European ancestry men. Hum mol genet,
Vol.32
(3),
pp. 489-495.
show abstract
full text
Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.93, 95% CI = 0.76-1.13, P = 0.46) or aggressive (aggregate OR = 1.14, 95% CI = 0.92-1.41, P = 0.22) prostate cancer risk. CHIP was weakly associated with genetic risk of overall prostate cancer, measured using a polygenic risk score (OR = 1.05 per unit increase, 95% CI = 1.01-1.10, P = 0.01). CHIP was not significantly associated with carrying pathogenic/likely pathogenic/deleterious variants in DNA repair genes, which have previously been found to be associated with aggressive prostate cancer. While findings from this study suggest that CHIP is likely not a risk factor for prostate cancer, it will be important to investigate other types of CH in association with prostate cancer risk..
Ito, S.
Liu, X.
Ishikawa, Y.
Conti, D.D.
Otomo, N.
Kote-Jarai, Z.
Suetsugu, H.
Eeles, R.A.
Koike, Y.
Hikino, K.
Yoshino, S.
Tomizuka, K.
Horikoshi, M.
Ito, K.
Uchio, Y.
Momozawa, Y.
Kubo, M.
BioBank Japan Project,
Kamatani, Y.
Matsuda, K.
Haiman, C.A.
Ikegawa, S.
Nakagawa, H.
Terao, C.
(2023). Androgen receptor binding sites enabling genetic prediction of mortality due to prostate cancer in cancer-free subjects. Nat commun,
Vol.14
(1),
p. 4863.
show abstract
full text
Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its development, is challenging. Here, we address this issue by maximizing the statistical power of genetic data with multi-ancestry meta-analysis and focusing on binding sites of the androgen receptor (AR), which has a critical role in PrCa. Taking advantage of large Japanese samples ever, a multi-ancestry meta-analysis comprising more than 300,000 subjects in total identifies 9 unreported loci including ZFHX3, a tumor suppressor gene, and successfully narrows down the statistically finemapped variants compared to European-only studies, and these variants strongly enrich in AR binding sites. A polygenic risk scores (PRS) analysis restricting to statistically finemapped variants in AR binding sites shows among cancer-free subjects, individuals with a PRS in the top 10% have a strongly higher risk of the future death of PrCa (HR: 5.57, P = 4.2 × 10-10). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa..
Karunamuni, R.A.
Huynh-Le, M.-.
Fan, C.C.
Thompson, W.
Lui, A.
Martinez, M.E.
Rose, B.S.
Mahal, B.
Eeles, R.A.
Kote-Jarai, Z.
Muir, K.
Lophatananon, A.
UKGPCS Collaborators,
Tangen, C.M.
Goodman, P.J.
Thompson, I.M.
Blot, W.J.
Zheng, W.
Kibel, A.S.
Drake, B.F.
Cussenot, O.
Cancel-Tassin, G.
Menegaux, F.
Truong, T.
Park, J.Y.
Lin, H.-.
Taylor, J.A.
Bensen, J.T.
Mohler, J.L.
Fontham, E.T.
Multigner, L.
Blanchet, P.
Brureau, L.
Romana, M.
Leach, R.J.
John, E.M.
Fowke, J.H.
Bush, W.S.
Aldrich, M.C.
Crawford, D.C.
Cullen, J.
Petrovics, G.
Parent, M.-.
Hu, J.J.
Sanderson, M.
PRACTICAL Consortium,
Mills, I.G.
Andreassen, O.A.
Dale, A.M.
Seibert, T.M.
(2022). Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24. Prostate cancer prostatic dis,
Vol.25
(2),
pp. 229-237.
show abstract
full text
BACKGROUND: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. MATERIALS AND METHODS: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. RESULTS: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. CONCLUSION: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry..
Benafif, S.
Ni Raghallaigh, H.
McGrowder, E.
Saunders, E.J.
Brook, M.N.
Saya, S.
Rageevakumar, R.
Wakerell, S.
James, D.
Chamberlain, A.
Taylor, N.
Hogben, M.
Benton, B.
D'Mello, L.
Myhill, K.
Mikropoulos, C.
Bowen-Perkins, H.
Rafi, I.
Ferris, M.
Beattie, A.
Kuganolipava, S.
Sevenoaks, T.
Bower, J.
Kumar, P.
Hazell, S.
deSouza, N.M.
Antoniou, A.
Bancroft, E.
Kote-Jarai, Z.
Eeles, R.
(2022). The BARCODE1 Pilot: a feasibility study of using germline single nucleotide polymorphisms to target prostate cancer screening. Bju int,
Vol.129
(3),
pp. 325-336.
show abstract
full text
OBJECTIVES: To assess the feasibility and uptake of a community-based prostate cancer (PCa) screening programme selecting men according to their genetic risk of PCa. To assess the uptake of PCa screening investigations by men invited for screening. The uptake of the pilot study would guide the opening of the larger BARCODE1 study recruiting 5000 men. SUBJECTS AND METHODS: Healthy males aged 55-69 years were invited to participate via their general practitioners (GPs). Saliva samples were collected via mailed collection kits. After DNA extraction, genotyping was conducted using a study specific assay. Genetic risk was based on genotyping 130 germline PCa risk single nucleotide polymorphisms (SNPs). A polygenic risk score (PRS) was calculated for each participant using the sum of weighted alleles for 130 SNPs. Study participants with a PRS lying above the 90th centile value were invited for PCa screening by prostate magnetic resonance imaging (MRI) and biopsy. RESULTS: Invitation letters were sent to 1434 men. The overall study uptake was 26% (375/1436) and 87% of responders were eligible for study entry. DNA genotyping data were available for 297 men and 25 were invited for screening. After exclusions due to medical comorbidity/invitations declined, 18 of 25 men (72%) underwent MRI and biopsy of the prostate. There were seven diagnoses of PCa (38.9%). All cancers were low-risk and were managed with active surveillance. CONCLUSION: The BARCODE1 Pilot has shown this community study in the UK to be feasible, with an overall uptake of 26%. The main BARCODE1 study is now open and will recruit 5000 men. The results of BARCODE1 will be important in defining the role of genetic profiling in targeted PCa population screening. Patient Summary What is the paper about? Very few prostate cancer screening programmes currently exist anywhere in the world. Our pilot study investigated if men in the UK would find it acceptable to have a genetic test based on a saliva sample to examine their risk of prostate cancer development. This test would guide whether men are offered prostate cancer screening tests. What does it mean for patients? We found that the study design was acceptable: 26% of men invited to take part agreed to have the test. The majority of men who were found to have an increased genetic risk of prostate cancer underwent further tests offered (prostate MRI scan and biopsy). We have now expanded the study to enrol 5000 men. The BARCODE1 study will be important in examining whether this approach could be used for large-scale population prostate cancer screening..
Lesueur, F.
Easton, D.F.
Renault, A.-.
Tavtigian, S.V.
Bernstein, J.L.
Kote-Jarai, Z.
Eeles, R.A.
Plaseska-Karanfia, D.
Feliubadaló, L.
Spanish ATM working group,
Arun, B.
Herold, N.
Versmold, B.
Schmutzler, R.K.
GC-HBOC,
Nguyen-Dumont, T.
Southey, M.C.
Dorling, L.
Dunning, A.M.
Ghiorzo, P.
Dalmasso, B.S.
Cavaciuti, E.
Le Gal, D.
Roberts, N.J.
Dominguez-Valentin, M.
Rookus, M.
Taylor, A.M.
Goldstein, A.M.
Goldgar, D.E.
CARRIERS and Ambry Groups,
Stoppa-Lyonnet, D.
Andrieu, N.
(2022). First international workshop of the ATM and cancer risk group (4-5 December 2019). Fam cancer,
Vol.21
(2),
pp. 211-227.
show abstract
full text
The first International Workshop of the ATM and Cancer Risk group focusing on the role of Ataxia-Telangiectasia Mutated (ATM) gene in cancer was held on December 4 and 5, 2019 at Institut Curie in Paris, France. It was motivated by the fact that germline ATM pathogenic variants have been found to be associated with different cancer types. However, due to the lack of precise age-, sex-, and site-specific risk estimates, no consensus on management guidelines for variant carriers exists, and the clinical utility of ATM variant testing is uncertain. The meeting brought together epidemiologists, geneticists, biologists and clinicians to review current knowledge and on-going challenges related to ATM and cancer risk. This report summarizes the meeting sessions content that covered the latest results in family-based and population-based studies, the importance of accurate variant classification, the effect of radiation exposures for ATM variant carriers, and the characteristics of ATM-deficient tumors. The report concludes that ATM variant carriers outside of the context of Ataxia-Telangiectasia may benefit from effective cancer risk management and therapeutic strategies and that efforts to set up large-scale studies in the international framework to achieve this goal are necessary..
Huynh-Le, M.-.
Karunamuni, R.
Fan, C.C.
Asona, L.
Thompson, W.K.
Martinez, M.E.
Eeles, R.A.
Kote-Jarai, Z.
Muir, K.R.
Lophatananon, A.
Schleutker, J.
Pashayan, N.
Batra, J.
Grönberg, H.
Neal, D.E.
Nordestgaard, B.G.
Tangen, C.M.
MacInnis, R.J.
Wolk, A.
Albanes, D.
Haiman, C.A.
Travis, R.C.
Blot, W.J.
Stanford, J.L.
Mucci, L.A.
West, C.M.
Nielsen, S.F.
Kibel, A.S.
Cussenot, O.
Berndt, S.I.
Koutros, S.
Sørensen, K.D.
Cybulski, C.
Grindedal, E.M.
Menegaux, F.
Park, J.Y.
Ingles, S.A.
Maier, C.
Hamilton, R.J.
Rosenstein, B.S.
Lu, Y.-.
Watya, S.
Vega, A.
Kogevinas, M.
Wiklund, F.
Penney, K.L.
Huff, C.D.
Teixeira, M.R.
Multigner, L.
Leach, R.J.
Brenner, H.
John, E.M.
Kaneva, R.
Logothetis, C.J.
Neuhausen, S.L.
De Ruyck, K.
Ost, P.
Razack, A.
Newcomb, L.F.
Fowke, J.H.
Gamulin, M.
Abraham, A.
Claessens, F.
Castelao, J.E.
Townsend, P.A.
Crawford, D.C.
Petrovics, G.
van Schaik, R.H.
Parent, M.-.
Hu, J.J.
Zheng, W.
UKGPCS collaborators,
APCB (Australian Prostate Cancer BioResource),
NC-LA PCaP Investigators,
IMPACT Study Steering Committee and Collaborators,
Canary PASS Investigators,
Profile Study Steering Committee,
PRACTICAL Consortium,
Mills, I.G.
Andreassen, O.A.
Dale, A.M.
Seibert, T.M.
(2022). Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score. Prostate cancer prostatic dis,
Vol.25
(4),
pp. 755-761.
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full text
BACKGROUND: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. METHODS: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. RESULTS: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively. CONCLUSIONS: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations..
Darst, B.F.
Hughley, R.
Pfennig, A.
Hazra, U.
Fan, C.
Wan, P.
Sheng, X.
Xia, L.
Andrews, C.
Chen, F.
Berndt, S.I.
Kote-Jarai, Z.
Govindasami, K.
Bensen, J.T.
Ingles, S.A.
Rybicki, B.A.
Nemesure, B.
John, E.M.
Fowke, J.H.
Huff, C.D.
Strom, S.S.
Isaacs, W.B.
Park, J.Y.
Zheng, W.
Ostrander, E.A.
Walsh, P.C.
Carpten, J.
Sellers, T.A.
Yamoah, K.
Murphy, A.B.
Sanderson, M.
Crawford, D.C.
Gapstur, S.M.
Bush, W.S.
Aldrich, M.C.
Cussenot, O.
Petrovics, G.
Cullen, J.
Neslund-Dudas, C.
Kittles, R.A.
Xu, J.
Stern, M.C.
Chokkalingam, A.P.
Multigner, L.
Parent, M.-.
Menegaux, F.
Cancel-Tassin, G.
Kibel, A.S.
Klein, E.A.
Goodman, P.J.
Stanford, J.L.
Drake, B.F.
Hu, J.J.
Clark, P.E.
Blanchet, P.
Casey, G.
Hennis, A.J.
Lubwama, A.
Thompson, I.M.
Leach, R.J.
Gundell, S.M.
Pooler, L.
Mohler, J.L.
Fontham, E.T.
Smith, G.J.
Taylor, J.A.
Brureau, L.
Blot, W.J.
Biritwum, R.
Tay, E.
Truelove, A.
Niwa, S.
Tettey, Y.
Varma, R.
McKean-Cowdin, R.
Torres, M.
Jalloh, M.
Magueye Gueye, S.
Niang, L.
Ogunbiyi, O.
Oladimeji Idowu, M.
Popoola, O.
Adebiyi, A.O.
Aisuodionoe-Shadrach, O.I.
Nwegbu, M.
Adusei, B.
Mante, S.
Darkwa-Abrahams, A.
Yeboah, E.D.
Mensah, J.E.
Anthony Adjei, A.
Diop, H.
Cook, M.B.
Chanock, S.J.
Watya, S.
Eeles, R.A.
Chiang, C.W.
Lachance, J.
Rebbeck, T.R.
Conti, D.V.
Haiman, C.A.
(2022). A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry. Eur urol,
Vol.81
(5),
pp. 458-462.
show abstract
full text
A rare African ancestry-specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0-0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 × 10-4), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR] = 4.7, 95% CI = 2.3-9.5, p = 2 × 10-5; stage T3/T4: OR = 4.5, 95% CI = 2.0-10.0, p = 2 × 10-4; metastatic disease: OR = 5.1, 95% CI = 1.9-13.7, p = 0.001). We estimated that the allele arose in West Africa 1500-4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. PATIENT SUMMARY: A rare African ancestry-specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry..
McHugh, J.
Saunders, E.J.
Dadaev, T.
McGrowder, E.
Bancroft, E.
Kote-Jarai, Z.
Eeles, R.
(2022). Prostate cancer risk in men of differing genetic ancestry and approaches to disease screening and management in these groups. Br j cancer,
Vol.126
(10),
pp. 1366-1373.
show abstract
full text
Prostate cancer is the second most common solid tumour in men worldwide and it is also the most common cancer affecting men of African descent. Prostate cancer incidence and mortality vary across regions and populations. Some of this is explained by a large heritable component of this disease. It has been established that men of African and African Caribbean ethnicity are predisposed to prostate cancer (PrCa) that can have an earlier onset and a more aggressive course, thereby leading to poorer outcomes for patients in this group. Literature searches were carried out using the PubMed, EMBASE and Cochrane Library databases to identify studies associated with PrCa risk and its association with ancestry, screening and management of PrCa. In order to be included, studies were required to be published in English in full-text form. An attractive approach is to identify high-risk groups and develop a targeted screening programme for them as the benefits of population-wide screening in PrCa using prostate-specific antigen (PSA) testing in general population screening have shown evidence of benefit; however, the harms are considered to weigh heavier because screening using PSA testing can lead to over-diagnosis and over-treatment. The aim of targeted screening of higher-risk groups identified by genetic risk stratification is to reduce over-diagnosis and treat those who are most likely to benefit..
Turco, F.
Armstrong, A.
Attard, G.
Beer, T.M.
Beltran, H.
Bjartell, A.
Bossi, A.
Briganti, A.
Bristow, R.G.
Bulbul, M.
Caffo, O.
Chi, K.N.
Clarke, C.
Clarke, N.
Davis, I.D.
de Bono, J.
Duran, I.
Eeles, R.
Efstathiou, E.
Efstathiou, J.
Evans, C.P.
Fanti, S.
Feng, F.Y.
Fizazi, K.
Frydenberg, M.
George, D.
Gleave, M.
Halabi, S.
Heinrich, D.
Higano, C.
Hofman, M.S.
Hussain, M.
James, N.
Jones, R.
Kanesvaran, R.
Khauli, R.B.
Klotz, L.
Leibowitz, R.
Logothetis, C.
Maluf, F.
Millman, R.
Morgans, A.K.
Morris, M.J.
Mottet, N.
Mrabti, H.
Murphy, D.G.
Murthy, V.
Oh, W.K.
Ekeke Onyeanunam, N.
Ost, P.
O'Sullivan, J.M.
Padhani, A.R.
Parker, C.
Poon, D.M.
Pritchard, C.C.
Rabah, D.M.
Rathkopf, D.
Reiter, R.E.
Rubin, M.
Ryan, C.J.
Saad, F.
Pablo Sade, J.
Sartor, O.
Scher, H.I.
Shore, N.
Skoneczna, I.
Small, E.
Smith, M.
Soule, H.
Spratt, D.
Sternberg, C.N.
Suzuki, H.
Sweeney, C.
Sydes, M.
Taplin, M.-.
Tilki, D.
Tombal, B.
Türkeri, L.
Uemura, H.
Uemura, H.
van Oort, I.
Yamoah, K.
Ye, D.
Zapatero, A.
Gillessen, S.
Omlin, A.
(2022). What Experts Think About Prostate Cancer Management During the COVID-19 Pandemic: Report from the Advanced Prostate Cancer Consensus Conference 2021. Eur urol,
Vol.82
(1),
pp. 6-11.
show abstract
full text
Patients with advanced prostate cancer (APC) may be at greater risk for severe illness, hospitalisation, or death from coronavirus disease 2019 (COVID-19) due to male gender, older age, potential immunosuppressive treatments, or comorbidities. Thus, the optimal management of APC patients during the COVID-19 pandemic is complex. In October 2021, during the Advanced Prostate Cancer Consensus Conference (APCCC) 2021, the 73 voting members of the panel members discussed and voted on 13 questions on this topic that could help clinicians make treatment choices during the pandemic. There was a consensus for full COVID-19 vaccination and booster injection in APC patients. Furthermore, the voting results indicate that the expert's treatment recommendations are influenced by the vaccination status: the COVID-19 pandemic altered management of APC patients for 70% of the panellists before the vaccination was available but only for 25% of panellists for fully vaccinated patients. Most experts (71%) were less likely to use docetaxel and abiraterone in unvaccinated patients with metastatic hormone-sensitive prostate cancer. For fully vaccinated patients with high-risk localised prostate cancer, there was a consensus (77%) to follow the usual treatment schedule, whereas in unvaccinated patients, 55% of the panel members voted for deferring radiation therapy. Finally, there was a strong consensus for the use of telemedicine for monitoring APC patients. PATIENT SUMMARY: In the Advanced Prostate Cancer Consensus Conference 2021, the panellists reached a consensus regarding the recommendation of the COVID-19 vaccine in prostate cancer patients and use of telemedicine for monitoring these patients..
Gillessen, S.
Armstrong, A.
Attard, G.
Beer, T.M.
Beltran, H.
Bjartell, A.
Bossi, A.
Briganti, A.
Bristow, R.G.
Bulbul, M.
Caffo, O.
Chi, K.N.
Clarke, C.S.
Clarke, N.
Davis, I.D.
de Bono, J.S.
Duran, I.
Eeles, R.
Efstathiou, E.
Efstathiou, J.
Ekeke, O.N.
Evans, C.P.
Fanti, S.
Feng, F.Y.
Fizazi, K.
Frydenberg, M.
George, D.
Gleave, M.
Halabi, S.
Heinrich, D.
Higano, C.
Hofman, M.S.
Hussain, M.
James, N.
Jones, R.
Kanesvaran, R.
Khauli, R.B.
Klotz, L.
Leibowitz, R.
Logothetis, C.
Maluf, F.
Millman, R.
Morgans, A.K.
Morris, M.J.
Mottet, N.
Mrabti, H.
Murphy, D.G.
Murthy, V.
Oh, W.K.
Ost, P.
O'Sullivan, J.M.
Padhani, A.R.
Parker, C.
Poon, D.M.
Pritchard, C.C.
Rabah, D.M.
Rathkopf, D.
Reiter, R.E.
Rubin, M.
Ryan, C.J.
Saad, F.
Sade, J.P.
Sartor, O.
Scher, H.I.
Shore, N.
Skoneczna, I.
Small, E.
Smith, M.
Soule, H.
Spratt, D.E.
Sternberg, C.N.
Suzuki, H.
Sweeney, C.
Sydes, M.R.
Taplin, M.-.
Tilki, D.
Tombal, B.
Türkeri, L.
Uemura, H.
Uemura, H.
van Oort, I.
Yamoah, K.
Ye, D.
Zapatero, A.
Omlin, A.
(2022). Management of Patients with Advanced Prostate Cancer: Report from the Advanced Prostate Cancer Consensus Conference 2021. Eur urol,
Vol.82
(1),
pp. 115-141.
show abstract
full text
BACKGROUND: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but various areas of management still lack high-level evidence to inform clinical practice. The 2021 Advanced Prostate Cancer Consensus Conference (APCCC) addressed some of these questions to supplement guidelines that are based on level 1 evidence. OBJECTIVE: To present the voting results from APCCC 2021. DESIGN, SETTING, AND PARTICIPANTS: The experts identified three major areas of controversy related to management of advanced prostate cancer: newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), the use of prostate-specific membrane antigen ligands in diagnostics and therapy, and molecular characterisation of tissue and blood. A panel of 86 international prostate cancer experts developed the programme and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 107 pre-defined questions, which were developed by both voting and non-voting panel members prior to the conference following a modified Delphi process. RESULTS AND LIMITATIONS: The voting reflected the opinions of panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results reported in the Supplementary material. CONCLUSIONS: These voting results from a panel of experts in advanced prostate cancer can help clinicians and patients to navigate controversial areas of management for which high-level evidence is scant. However, diagnostic and treatment decisions should always be individualised according to patient characteristics, such as the extent and location of disease, prior treatment(s), comorbidities, patient preferences, and treatment recommendations, and should also incorporate current and emerging clinical evidence and logistic and economic constraints. Enrolment in clinical trials should be strongly encouraged. Importantly, APCCC 2021 once again identified salient questions that merit evaluation in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference is a forum for discussing current diagnosis and treatment options for patients with advanced prostate cancer. An expert panel votes on predefined questions focused on the most clinically relevant areas for treatment of advanced prostate cancer for which there are gaps in knowledge. The voting results provide a practical guide to help clinicians in discussing treatment options with patients as part of shared decision-making..
Burns, D.
Anokian, E.
Saunders, E.J.
Bristow, R.G.
Fraser, M.
Reimand, J.
Schlomm, T.
Sauter, G.
Brors, B.
Korbel, J.
Weischenfeldt, J.
Waszak, S.M.
Corcoran, N.M.
Jung, C.-.
Pope, B.J.
Hovens, C.M.
Cancel-Tassin, G.
Cussenot, O.
Loda, M.
Sander, C.
Hayes, V.M.
Dalsgaard Sorensen, K.
Lu, Y.-.
Hamdy, F.C.
Foster, C.S.
Gnanapragasam, V.
Butler, A.
Lynch, A.G.
Massie, C.E.
CR-UK/Prostate Cancer UK, ICGC, The PPCG,
Woodcock, D.J.
Cooper, C.S.
Wedge, D.C.
Brewer, D.S.
Kote-Jarai, Z.
Eeles, R.A.
(2022). Rare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment: A Pan Prostate Cancer Group Study. Eur urol,
Vol.82
(2),
pp. 201-211.
show abstract
full text
BACKGROUND: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression. OBJECTIVE: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa and understand the genetic factors associated with such progression. DESIGN, SETTING, AND PARTICIPANTS: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG) consortium from the UK, Canada, Germany, Australia, and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA) dataset. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A total of 15,822 rare (MAF <1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene sets. Models were tested for robustness using bootstrap resampling. RESULTS AND LIMITATIONS: Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in "Hallmark" gene sets were consistently associated with altered time to BCR. Three gene sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response, and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher-grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB, and Hypoxia, the latter of which was validated in the independent TCGA dataset. CONCLUSIONS: We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort-independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management. PATIENT SUMMARY: Prostate cancer patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportunities to identify patients who might need additional treatments earlier..
Boonen, R.A.
Wiegant, W.W.
Celosse, N.
Vroling, B.
Heijl, S.
Kote-Jarai, Z.
Mijuskovic, M.
Cristea, S.
Solleveld-Westerink, N.
van Wezel, T.
Beerenwinkel, N.
Eeles, R.
Devilee, P.
Vreeswijk, M.P.
Marra, G.
van Attikum, H.
(2022). Functional Analysis Identifies Damaging CHEK2 Missense Variants Associated with Increased Cancer Risk. Cancer res,
Vol.82
(4),
pp. 615-631.
show abstract
full text
UNLABELLED: Heterozygous carriers of germline loss-of-function variants in the tumor suppressor gene checkpoint kinase 2 (CHEK2) are at an increased risk for developing breast and other cancers. While truncating variants in CHEK2 are known to be pathogenic, the interpretation of missense variants of uncertain significance (VUS) is challenging. Consequently, many VUS remain unclassified both functionally and clinically. Here we describe a mouse embryonic stem (mES) cell-based system to quantitatively determine the functional impact of 50 missense VUS in human CHEK2. By assessing the activity of human CHK2 to phosphorylate one of its main targets, Kap1, in Chek2 knockout mES cells, 31 missense VUS in CHEK2 were found to impair protein function to a similar extent as truncating variants, while 9 CHEK2 missense VUS resulted in intermediate functional defects. Mechanistically, most VUS impaired CHK2 kinase function by causing protein instability or by impairing activation through (auto)phosphorylation. Quantitative results showed that the degree of CHK2 kinase dysfunction correlates with an increased risk for breast cancer. Both damaging CHEK2 variants as a group [OR 2.23; 95% confidence interval (CI), 1.62-3.07; P < 0.0001] and intermediate variants (OR 1.63; 95% CI, 1.21-2.20; P = 0.0014) were associated with an increased breast cancer risk, while functional variants did not show this association (OR 1.13; 95% CI, 0.87-1.46; P = 0.378). Finally, a damaging VUS in CHEK2, c.486A>G/p.D162G, was also identified, which cosegregated with familial prostate cancer. Altogether, these functional assays efficiently and reliably identified VUS in CHEK2 that associate with cancer. SIGNIFICANCE: Quantitative assessment of the functional consequences of CHEK2 variants of uncertain significance identifies damaging variants associated with increased cancer risk, which may aid in the clinical management of patients and carriers..
Hainsworth, E.
McGrowder, E.
McHugh, J.
Bancroft, E.
Mahabir, S.
Webber, W.
Eeles, R.
Cruickshank, S.
(2022). How can we recruit more men of African or African-Caribbean ancestry into our research? Co-creating a video to raise awareness of prostate cancer risk and the PROFILE study. Res involv engagem,
Vol.8
(1),
p. 14.
show abstract
full text
BACKGROUND: Men of African ancestry are at increased risk of developing prostate cancer (PrCa) compared to men from other backgrounds. The PROFILE study aims to understand whether genetic information can better target who needs PrCa screening. PROFILE has so far had difficulty reaching men of African or African -Caribbean ancestry to take part. In this involvement project we worked in partnership with a group of such men to co-create a video to raise awareness of PrCa risk amongst this community and promote participation in the study. METHODS: We recruited seven men of African or African-Caribbean ancestry who completed an initial survey on the Cancer Patients' Voice platform. We then held an online discussion panel and maintained contact to encourage dialogue and planning of the video. Utilising a participatory approach, the ideas for the video were decided in collaboration with the panel who held expert knowledge of various communities and understood the messages that would best resonate and engage with other men of the same origins. Once the video had been edited and finalised, two members of the group expressed interest in writing up the project and are listed as co-authors. RESULTS: The video in its entirety was driven by the panel's ideas. The choice of a barber shop setting; leading with a positive case study and highlighting the importance of men's family members rather than a focus on scientific language, statistics or researchers were all features that were discussed and agreed upon by the panel. The men shared the video within their networks. It was placed on websites and promoted as part of a social media campaign during Black History Month. CONCLUSIONS: Groups with the greater healthcare needs and the most to gain from advances in care and treatment can often be the most excluded from research participation. This is pertinent in PrCa research where men of African or African-Caribbean ancestry are at greater risk. The project gave equal power and decision making to the men and provides an example of successful inclusive involvement. The result was a unique approach to making a study video..
Andoni, T.
Wiggins, J.
Robinson, R.
Charlton, R.
Sandberg, M.
Eeles, R.
(2022). Half of germline pathogenic and likely pathogenic variants found on panel tests do not fulfil NHS testing criteria. Sci rep,
Vol.12
(1),
p. 2507.
show abstract
full text
Genetic testing for cancer predisposition has been curtailed by the cost of sequencing, and testing has been restricted by eligibility criteria. As the cost of sequencing decreases, the question of expanding multi-gene cancer panels to a broader population arises. We evaluated how many additional actionable genetic variants are returned by unrestricted panel testing in the private sector compared to those which would be returned by adhering to current NHS eligibility criteria. We reviewed 152 patients referred for multi-gene cancer panels in the private sector between 2014 and 2016. Genetic counselling and disclosure of all results was standard of care provided by the Consultant. Every panel conducted was compared to current eligibility criteria. A germline pathogenic / likely pathogenic variant (P/LP), in a gene relevant to the personal or family history of cancer, was detected in 15 patients (detection rate of 10%). 46.7% of those found to have the P/LP variants (7 of 15), or 4.6% of the entire set (7 of 152), did not fulfil NHS eligibility criteria. 46.7% of P/LP variants in this study would have been missed by national testing guidelines, all of which were actionable. However, patients who do not fulfil eligibility criteria have a higher Variant of Uncertain Significance (VUS) burden. We demonstrated that the current England NHS threshold for genetic testing is missing pathogenic variants which would alter management in 4.6%, nearly 1 in 20 individuals. However, the clinical service burden that would ensue is a detection of VUS of 34%..
Buhigas, C.
Warren, A.Y.
Leung, W.-.
Whitaker, H.C.
Luxton, H.J.
Hawkins, S.
Kay, J.
Butler, A.
Xu, Y.
Woodcock, D.J.
Merson, S.
Frame, F.M.
Sahli, A.
Abascal, F.
CRUK-ICGC Prostate Cancer Group,
Martincorena, I.
Bova, G.S.
Foster, C.S.
Campbell, P.
Maitland, N.J.
Neal, D.E.
Massie, C.E.
Lynch, A.G.
Eeles, R.A.
Cooper, C.S.
Wedge, D.C.
Brewer, D.S.
(2022). The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates. Mol cancer,
Vol.21
(1),
p. 183.
show abstract
BACKGROUND: Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue (n = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate. RESULTS: Single nucleotide variants (P = 7.0 × 10-03, Wilcoxon rank sum test) and small insertions and deletions (indels, P = 8.7 × 10-06) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer (P = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial (P = 5.94 × 10-05, paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants (P = 3.72 × 10-09, paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations. CONCLUSIONS: Cells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches..
Patel, P.H.
Tunariu, N.
Levine, D.S.
de Bono, J.S.
Eeles, R.A.
Khoo, V.
Murray, J.
Parker, C.C.
Pathmanathan, A.
Reid, A.
van As, N.
Tree, A.C.
(2022). Oligoprogression in Metastatic, Castrate-Resistant Prostate Cancer-Prevalence and Current Clinical Practice. Front oncol,
Vol.12,
p. 862995.
show abstract
full text
AIMS: Oligoprogression is poorly defined in current literature. Little is known about the natural history and significance of oligoprogression in patients with hormone-resistant prostate cancer on abiraterone or enzalutamide treatment [termed androgen receptor-targeted therapy (ARTT)]. The aim of this study was to determine the prevalence of oligoprogression, describe the characteristics of oligoprogression in a cohort of patients from a single center, and identify the number of patients potentially treatable with stereotactic body radiotherapy (SBRT). METHODS: Castration-resistant prostate cancer (CRPC) patients who radiologically progressed while on ARTT were included. Patients with oligoprogressive disease (OPD) (≤3 lesions) on any imaging were identified in a retrospective analysis of electronic patient records. Kaplan-Meier method and log-rank test were used to calculate progression-free and overall survival. RESULTS: A total of 102 patients with metastatic CRPC on ARTT were included. Thirty (29%) patients presented with oligoprogression (46 lesions in total); 21 (21% of total) patients had lesions suitable for SBRT. The majority of lesions were in the bone (21, 46%) or lymph nodes (15, 33%). Patients with oligoprogression while on ARTT had a significantly better prostate-specific antigen (PSA) response on commencing ARTT as compared to patients who later developed polyprogression. However, PSA doubling time immediately prior to progression did not predict OPD. Median progression-free survival to oligoprogression versus polyprogression was 16.8 vs. 11.7 months. Time to further progression after oligoprogression was 13.6 months in those treated with radiotherapy (RT) for oligoprogression vs. 5.7 months in those treated with the continuation of ARTT alone. CONCLUSIONS: In this study, nearly a third of patients on ARTT for CRPC were found to have OPD. OPD patients had a better PSA response on ART and a longer duration on ARTT before developing OPD as compared to those developing polyprogressive disease (Poly-PD). The majority of patients (70%) with OPD had lesions suitable for SBRT treatment. Prospective randomized control trials are needed to establish if there is a survival benefit of SBRT in oligoprogressive prostate cancer and to determine predictive indicators..
Karunamuni, R.A.
Huynh-Le, M.-.
Fan, C.C.
Thompson, W.
Eeles, R.A.
Kote-Jarai, Z.
Muir, K.
UKGPCS Collaborators,
Lophatananon, A.
Tangen, C.M.
Goodman, P.J.
Thompson, I.M.
Blot, W.J.
Zheng, W.
Kibel, A.S.
Drake, B.F.
Cussenot, O.
Cancel-Tassin, G.
Menegaux, F.
Truong, T.
Park, J.Y.
Lin, H.-.
Bensen, J.T.
Fontham, E.T.
Mohler, J.L.
Taylor, J.A.
Multigner, L.
Blanchet, P.
Brureau, L.
Romana, M.
Leach, R.J.
John, E.M.
Fowke, J.
Bush, W.S.
Aldrich, M.
Crawford, D.C.
Srivastava, S.
Cullen, J.C.
Petrovics, G.
Parent, M.-.
Hu, J.J.
Sanderson, M.
Mills, I.G.
Andreassen, O.A.
Dale, A.M.
Seibert, T.M.
PRACTICAL Consortium,
(2021). African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer. Int j cancer,
Vol.148
(1),
pp. 99-105.
show abstract
Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans..
Haldrup, J.
Strand, S.H.
Cieza-Borrella, C.
Jakobsson, M.E.
Riedel, M.
Norgaard, M.
Hedensted, S.
Dagnaes-Hansen, F.
Ulhoi, B.P.
Eeles, R.
Borre, M.
Olsen, J.V.
Thomsen, M.
Kote-Jarai, Z.
Sorensen, K.D.
(2021). FRMD6 has tumor suppressor functions in prostate cancer. Oncogene,
Vol.40
(4),
pp. 763-776.
show abstract
full text
Available tools for prostate cancer (PC) prognosis are suboptimal but may be improved by better knowledge about genes driving tumor aggressiveness. Here, we identified FRMD6 (FERM domain-containing protein 6) as an aberrantly hypermethylated and significantly downregulated gene in PC. Low FRMD6 expression was associated with postoperative biochemical recurrence in two large PC patient cohorts. In overexpression and CRISPR/Cas9 knockout experiments in PC cell lines, FRMD6 inhibited viability, proliferation, cell cycle progression, colony formation, 3D spheroid growth, and tumor xenograft growth in mice. Transcriptomic, proteomic, and phospho-proteomic profiling revealed enrichment of Hippo/YAP and c-MYC signaling upon FRMD6 knockout. Connectivity Map analysis and drug repurposing experiments identified pyroxamide as a new potential therapy for FRMD6 deficient PC cells. Finally, we established orthotropic Frmd6 and Pten, or Pten only (control) knockout in the ROSA26 mouse prostate. After 12 weeks, Frmd6/Pten double knockouts presented high-grade prostatic intraepithelial neoplasia (HG-PIN) and hyperproliferation, while Pten single-knockouts developed only regular PIN lesions and displayed lower proliferation. In conclusion, FRMD6 was identified as a novel tumor suppressor gene and prognostic biomarker candidate in PC..
Conti, D.V.
Darst, B.F.
Moss, L.C.
Saunders, E.J.
Sheng, X.
Chou, A.
Schumacher, F.R.
Olama, A.A.
Benlloch, S.
Dadaev, T.
Brook, M.N.
Sahimi, A.
Hoffmann, T.J.
Takahashi, A.
Matsuda, K.
Momozawa, Y.
Fujita, M.
Muir, K.
Lophatananon, A.
Wan, P.
Le Marchand, L.
Wilkens, L.R.
Stevens, V.L.
Gapstur, S.M.
Carter, B.D.
Schleutker, J.
Tammela, T.L.
Sipeky, C.
Auvinen, A.
Giles, G.G.
Southey, M.C.
MacInnis, R.J.
Cybulski, C.
Wokołorczyk, D.
Lubiński, J.
Neal, D.E.
Donovan, J.L.
Hamdy, F.C.
Martin, R.M.
Nordestgaard, B.G.
Nielsen, S.F.
Weischer, M.
Bojesen, S.E.
Røder, M.A.
Iversen, P.
Batra, J.
Chambers, S.
Moya, L.
Horvath, L.
Clements, J.A.
Tilley, W.
Risbridger, G.P.
Gronberg, H.
Aly, M.
Szulkin, R.
Eklund, M.
Nordström, T.
Pashayan, N.
Dunning, A.M.
Ghoussaini, M.
Travis, R.C.
Key, T.J.
Riboli, E.
Park, J.Y.
Sellers, T.A.
Lin, H.-.
Albanes, D.
Weinstein, S.J.
Mucci, L.A.
Giovannucci, E.
Lindstrom, S.
Kraft, P.
Hunter, D.J.
Penney, K.L.
Turman, C.
Tangen, C.M.
Goodman, P.J.
Thompson, I.M.
Hamilton, R.J.
Fleshner, N.E.
Finelli, A.
Parent, M.-.
Stanford, J.L.
Ostrander, E.A.
Geybels, M.S.
Koutros, S.
Freeman, L.E.
Stampfer, M.
Wolk, A.
Håkansson, N.
Andriole, G.L.
Hoover, R.N.
Machiela, M.J.
Sørensen, K.D.
Borre, M.
Blot, W.J.
Zheng, W.
Yeboah, E.D.
Mensah, J.E.
Lu, Y.-.
Zhang, H.-.
Feng, N.
Mao, X.
Wu, Y.
Zhao, S.-.
Sun, Z.
Thibodeau, S.N.
McDonnell, S.K.
Schaid, D.J.
West, C.M.
Burnet, N.
Barnett, G.
Maier, C.
Schnoeller, T.
Luedeke, M.
Kibel, A.S.
Drake, B.F.
Cussenot, O.
Cancel-Tassin, G.
Menegaux, F.
Truong, T.
Koudou, Y.A.
John, E.M.
Grindedal, E.M.
Maehle, L.
Khaw, K.-.
Ingles, S.A.
Stern, M.C.
Vega, A.
Gómez-Caamaño, A.
Fachal, L.
Rosenstein, B.S.
Kerns, S.L.
Ostrer, H.
Teixeira, M.R.
Paulo, P.
Brandão, A.
Watya, S.
Lubwama, A.
Bensen, J.T.
Fontham, E.T.
Mohler, J.
Taylor, J.A.
Kogevinas, M.
Llorca, J.
Castaño-Vinyals, G.
Cannon-Albright, L.
Teerlink, C.C.
Huff, C.D.
Strom, S.S.
Multigner, L.
Blanchet, P.
Brureau, L.
Kaneva, R.
Slavov, C.
Mitev, V.
Leach, R.J.
Weaver, B.
Brenner, H.
Cuk, K.
Holleczek, B.
Saum, K.-.
Klein, E.A.
Hsing, A.W.
Kittles, R.A.
Murphy, A.B.
Logothetis, C.J.
Kim, J.
Neuhausen, S.L.
Steele, L.
Ding, Y.C.
Isaacs, W.B.
Nemesure, B.
Hennis, A.J.
Carpten, J.
Pandha, H.
Michael, A.
De Ruyck, K.
De Meerleer, G.
Ost, P.
Xu, J.
Razack, A.
Lim, J.
Teo, S.-.
Newcomb, L.F.
Lin, D.W.
Fowke, J.H.
Neslund-Dudas, C.
Rybicki, B.A.
Gamulin, M.
Lessel, D.
Kulis, T.
Usmani, N.
Singhal, S.
Parliament, M.
Claessens, F.
Joniau, S.
Van den Broeck, T.
Gago-Dominguez, M.
Castelao, J.E.
Martinez, M.E.
Larkin, S.
Townsend, P.A.
Aukim-Hastie, C.
Bush, W.S.
Aldrich, M.C.
Crawford, D.C.
Srivastava, S.
Cullen, J.C.
Petrovics, G.
Casey, G.
Roobol, M.J.
Jenster, G.
van Schaik, R.H.
Hu, J.J.
Sanderson, M.
Varma, R.
McKean-Cowdin, R.
Torres, M.
Mancuso, N.
Berndt, S.I.
Van Den Eeden, S.K.
Easton, D.F.
Chanock, S.J.
Cook, M.B.
Wiklund, F.
Nakagawa, H.
Witte, J.S.
Eeles, R.A.
Kote-Jarai, Z.
Haiman, C.A.
(2021). Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction. Nat genet,
Vol.53
(1),
pp. 65-75.
show abstract
full text
Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction..
Lin, H.-.
Wang, X.
Tseng, T.-.
Kao, Y.-.
Fang, Z.
Molina, P.E.
Cheng, C.-.
Berglund, A.E.
Eeles, R.A.
Muir, K.R.
Pashayan, N.
Haiman, C.A.
Brenner, H.
Consortium, T.P.
Park, J.Y.
(2021). Alcohol Intake and Alcohol-SNP Interactions Associated with Prostate Cancer Aggressiveness. J clin med,
Vol.10
(3).
show abstract
full text
Excessive alcohol intake is a well-known modifiable risk factor for many cancers. It is still unclear whether genetic variants or single nucleotide polymorphisms (SNPs) can modify alcohol intake's impact on prostate cancer (PCa) aggressiveness. The objective is to test the alcohol-SNP interactions of the 7501 SNPs in the four pathways (angiogenesis, mitochondria, miRNA, and androgen metabolism-related pathways) associated with PCa aggressiveness. We evaluated the impacts of three excessive alcohol intake behaviors in 3306 PCa patients with European ancestry from the PCa Consortium. We tested the alcohol-SNP interactions using logistic models with the discovery-validation study design. All three excessive alcohol intake behaviors were not significantly associated with PCa aggressiveness. However, the interactions of excessive alcohol intake and three SNPs (rs13107662 [CAMK2D, p = 6.2 × 10-6], rs9907521 [PRKCA, p = 7.1 × 10-5], and rs11925452 [ROBO1, p = 8.2 × 10-4]) were significantly associated with PCa aggressiveness. These alcohol-SNP interactions revealed contrasting effects of excessive alcohol intake on PCa aggressiveness according to the genotypes in the identified SNPs. We identified PCa patients with the rs13107662 (CAMK2D) AA genotype, the rs11925452 (ROBO1) AA genotype, and the rs9907521 (PRKCA) AG genotype were more vulnerable to excessive alcohol intake for developing aggressive PCa. Our findings support that the impact of excessive alcohol intake on PCa aggressiveness was varied by the selected genetic profiles..
Schaid, D.J.
McDonnell, S.K.
FitzGerald, L.M.
DeRycke, L.
Fogarty, Z.
Giles, G.G.
MacInnis, R.J.
Southey, M.C.
Nguyen-Dumont, T.
Cancel-Tassin, G.
Cussenot, O.
Whittemore, A.S.
Sieh, W.
Ioannidis, N.M.
Hsieh, C.-.
Stanford, J.L.
Schleutker, J.
Cropp, C.D.
Carpten, J.
Hoegel, J.
Eeles, R.
Kote-Jarai, Z.
Ackerman, M.J.
Klein, C.J.
Mandal, D.
Cooney, K.A.
Bailey-Wilson, J.E.
Helfand, B.
Catalona, W.J.
Wiklund, F.
Riska, S.
Bahetti, S.
Larson, M.C.
Cannon Albright, L.
Teerlink, C.
Xu, J.
Isaacs, W.
Ostrander, E.A.
Thibodeau, S.N.
(2021). Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer. Eur urol,
Vol.79
(3),
pp. 353-361.
show abstract
full text
BACKGROUND: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease. OBJECTIVE: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls. RESULTS AND LIMITATIONS: Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa. CONCLUSIONS: Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease. PATIENT SUMMARY: Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa..
Darst, B.F.
Dadaev, T.
Saunders, E.
Sheng, X.
Wan, P.
Pooler, L.
Xia, L.Y.
Chanock, S.
Berndt, S.I.
Gapstur, S.M.
Stevens, V.
Albanes, D.
Weinstein, S.J.
Gnanapragasam, V.
Giles, G.G.
Nguyen-Dumont, T.
Milne, R.L.
Pomerantz, M.
Schmidt, J.A.
Mucci, L.
Catalona, W.J.
Hetrick, K.N.
Doheny, K.F.
MacInnis, R.J.
Southey, M.C.
Eeles, R.A.
Wiklund, F.
Kote-Jarai, Z.
Conti, D.V.
Haiman, C.A.
(2021). Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer. J natl cancer inst,
Vol.113
(5),
pp. 616-625.
show abstract
full text
BACKGROUND: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease. METHODS: Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided. RESULTS: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4). CONCLUSIONS: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations..
Karunamuni, R.A.
Huynh-Le, M.-.
Fan, C.C.
Thompson, W.
Eeles, R.A.
Kote-Jarai, Z.
Muir, K.
Lophatananon, A.
UKGPCS collaborators,
Schleutker, J.
Pashayan, N.
Batra, J.
APCB BioResource (Australian Prostate Cancer BioResource),
Grönberg, H.
Walsh, E.I.
Turner, E.L.
Lane, A.
Martin, R.M.
Neal, D.E.
Donovan, J.L.
Hamdy, F.C.
Nordestgaard, B.G.
Tangen, C.M.
MacInnis, R.J.
Wolk, A.
Albanes, D.
Haiman, C.A.
Travis, R.C.
Stanford, J.L.
Mucci, L.A.
West, C.M.
Nielsen, S.F.
Kibel, A.S.
Wiklund, F.
Cussenot, O.
Berndt, S.I.
Koutros, S.
Sørensen, K.D.
Cybulski, C.
Grindedal, E.M.
Park, J.Y.
Ingles, S.A.
Maier, C.
Hamilton, R.J.
Rosenstein, B.S.
Vega, A.
IMPACT Study Steering Committee and Collaborators,
Kogevinas, M.
Penney, K.L.
Teixeira, M.R.
Brenner, H.
John, E.M.
Kaneva, R.
Logothetis, C.J.
Neuhausen, S.L.
Razack, A.
Newcomb, L.F.
Canary PASS Investigators,
Gamulin, M.
Usmani, N.
Claessens, F.
Gago-Dominguez, M.
Townsend, P.A.
Roobol, M.J.
Zheng, W.
Profile Study Steering Committee,
Mills, I.G.
Andreassen, O.A.
Dale, A.M.
Seibert, T.M.
PRACTICAL Consortium,
(2021). Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer. Prostate cancer prostatic dis,
Vol.24
(2),
pp. 532-541.
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BACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same..
Petralia, G.
Koh, D.-.
Attariwala, R.
Busch, J.J.
Eeles, R.
Karow, D.
Lo, G.G.
Messiou, C.
Sala, E.
Vargas, H.A.
Zugni, F.
Padhani, A.R.
(2021). Oncologically Relevant Findings Reporting and Data System (ONCO-RADS): Guidelines for the Acquisition, Interpretation, and Reporting of Whole-Body MRI for Cancer Screening. Radiology,
Vol.299
(3),
pp. 494-507.
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Acknowledging the increasing number of studies describing the use of whole-body MRI for cancer screening, and the increasing number of examinations being performed in patients with known cancers, an international multidisciplinary expert panel of radiologists and a geneticist with subject-specific expertise formulated technical acquisition standards, interpretation criteria, and limitations of whole-body MRI for cancer screening in individuals at higher risk, including those with cancer predisposition syndromes. The Oncologically Relevant Findings Reporting and Data System (ONCO-RADS) proposes a standard protocol for individuals at higher risk, including those with cancer predisposition syndromes. ONCO-RADS emphasizes structured reporting and five assessment categories for the classification of whole-body MRI findings. The ONCO-RADS guidelines are designed to promote standardization and limit variations in the acquisition, interpretation, and reporting of whole-body MRI scans for cancer screening. Published under a CC BY 4.0 license Online supplemental material is available for this article..
Gonzalez, D.
Mateo, J.
Stenzinger, A.
Rojo, F.
Shiller, M.
Wyatt, A.W.
Penault-Llorca, F.
Gomella, L.G.
Eeles, R.
Bjartell, A.
(2021). Practical considerations for optimising homologous recombination repair mutation testing in patients with metastatic prostate cancer. J pathol clin res,
Vol.7
(4),
pp. 311-325.
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Analysis of the genomic landscape of prostate cancer has identified different molecular subgroups with relevance for novel or existing targeted therapies. The recent approvals of the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib in the metastatic castration-resistant prostate cancer (mCRPC) setting signal the need to embed molecular diagnostics in the clinical pathway of patients with mCRPC to identify those who can benefit from targeted therapies. Best practice guidelines in overall biospecimen collection and processing for molecular analysis are widely available for several tumour types. However, there is no standard protocol for molecular diagnostic testing in prostate cancer. Here, we provide a series of recommendations on specimen handling, sample pre-analytics, laboratory workflow, and testing pathways to maximise the success rates for clinical genomic analysis in prostate cancer. Early involvement of a multidisciplinary team of pathologists, urologists, oncologists, radiologists, nurses, molecular scientists, and laboratory staff is key to enable optimal workflow for specimen selection and preservation at the time of diagnosis so that samples are available for molecular analysis when required. Given the improved outcome of patients with mCRPC and homologous recombination repair gene alterations who have been treated with PARP inhibitors, there is an urgent need to incorporate high-quality genomic testing in the routine clinical pathway of these patients..
Wang, V.
Geybels, M.S.
Jordahl, K.M.
Gerke, T.
Hamid, A.
Penney, K.L.
Markt, S.C.
Freedman, M.
Pomerantz, M.
Lee, G.-.
Rana, H.
Börnigen, D.
Rebbeck, T.R.
Huttenhower, C.
Eeles, R.A.
Stanford, J.L.
Consortium, P.
Berndt, S.I.
Claessens, F.
Sørensen, K.D.
Park, J.Y.
Vega, A.
Usmani, N.
Mucci, L.
Sweeney, C.J.
(2021). A polymorphism in the promoter of FRAS1 is a candidate SNP associated with metastatic prostate cancer. Prostate,
Vol.81
(10),
pp. 683-693.
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BACKGROUND: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer). METHODS: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian. RESULTS: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years. CONCLUSIONS: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men..
Karlsson, Q.
Brook, M.N.
Dadaev, T.
Wakerell, S.
Saunders, E.J.
Muir, K.
Neal, D.E.
Giles, G.G.
MacInnis, R.J.
Thibodeau, S.N.
McDonnell, S.K.
Cannon-Albright, L.
Teixeira, M.R.
Paulo, P.
Cardoso, M.
Huff, C.
Li, D.
Yao, Y.
Scheet, P.
Permuth, J.B.
Stanford, J.L.
Dai, J.Y.
Ostrander, E.A.
Cussenot, O.
Cancel-Tassin, G.
Hoegel, J.
Herkommer, K.
Schleutker, J.
Tammela, T.L.
Rathinakannan, V.
Sipeky, C.
Wiklund, F.
Grönberg, H.
Aly, M.
Isaacs, W.B.
Dickinson, J.L.
FitzGerald, L.M.
Chua, M.L.
Nguyen-Dumont, T.
PRACTICAL Consortium,
Schaid, D.J.
Southey, M.C.
Eeles, R.A.
Kote-Jarai, Z.
(2021). Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study. Eur urol oncol,
Vol.4
(4),
pp. 570-579.
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BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7). CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier..
Chen, H.
Majumdar, A.
Wang, L.
Kar, S.
Brown, K.M.
Feng, H.
Turman, C.
Dennis, J.
Easton, D.
Michailidou, K.
Simard, J.
Breast Cancer Association Consortium (BCAC),
Bishop, T.
Cheng, I.C.
Huyghe, J.R.
Schmit, S.L.
Colorectal Transdisciplinary Study (CORECT),
Colon Cancer Family Registry Study (CCFR),
Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO),
O'Mara, T.A.
Spurdle, A.B.
Endometrial Cancer Association Consortium (ECAC),
Gharahkhani, P.
Schumacher, J.
Jankowski, J.
Gockel, I.
Esophageal Cancer GWAS Consortium,
Bondy, M.L.
Houlston, R.S.
Jenkins, R.B.
Melin, B.
Glioma International Case Control Consortium (GICC),
Lesseur, C.
Ness, A.R.
Diergaarde, B.
Olshan, A.F.
Head-Neck Cancer GWAS Consortium,
Amos, C.I.
Christiani, D.C.
Landi, M.T.
McKay, J.D.
International Lung Cancer Consortium (ILCCO),
Brossard, M.
Iles, M.M.
Law, M.H.
MacGregor, S.
Melanoma GWAS Consortium,
Beesley, J.
Jones, M.R.
Tyrer, J.
Winham, S.J.
Ovarian Cancer Association Consortium (OCAC),
Klein, A.P.
Petersen, G.
Li, D.
Wolpin, B.M.
Pancreatic Cancer Case-Control Consortium (PANC4),
Pancreatic Cancer Cohort Consortium (PanScan),
Eeles, R.A.
Haiman, C.A.
Kote-Jarai, Z.
Schumacher, F.R.
PRACTICAL consortium,
CRUK,
BPC3,
CAPS,
PEGASUS,
Brennan, P.
Chanock, S.J.
Gaborieau, V.
Purdue, M.P.
Renal Cancer GWAS Consortium,
Pharoah, P.
Hung, R.J.
Amundadottir, L.T.
Kraft, P.
Pasaniuc, B.
Lindström, S.
(2021). Large-scale cross-cancer fine-mapping of the 5p15 33 region reveals multiple independent signals. Hgg adv,
Vol.2
(3),
p. 100041.
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Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis..
Salmon, C.
Song, L.
Muir, K.
UKGPCS Collaborators,
Pashayan, N.
Dunning, A.M.
Batra, J.
APCB BioResource (Australian Prostate Cancer BioResource),
Chambers, S.
Stanford, J.L.
Ostrander, E.A.
Park, J.Y.
Lin, H.-.
Cussenot, O.
Cancel-Tassin, G.
Menegaux, F.
Cordina-Duverger, E.
Kogevinas, M.
Llorca, J.
Kaneva, R.
Slavov, C.
Razack, A.
Lim, J.
Gago-Dominguez, M.
Castelao, J.E.
Kote-Jarai, Z.
Eeles, R.A.
on behalf of the PRACTICAL Consortium,
Parent, M.-.
(2021). Marital status and prostate cancer incidence: a pooled analysis of 12 case-control studies from the PRACTICAL consortium. Eur j epidemiol,
Vol.36
(9),
pp. 913-925.
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full text
While being in a committed relationship is associated with a better prostate cancer prognosis, little is known about how marital status relates to its incidence. Social support provided by marriage/relationship could promote a healthy lifestyle and an increased healthcare seeking behavior. We investigated the association between marital status and prostate cancer risk using data from the PRACTICAL Consortium. Pooled analyses were conducted combining 12 case-control studies based on histologically-confirmed incident prostate cancers and controls with information on marital status prior to diagnosis/interview. Marital status was categorized as married/partner, separated/divorced, single, or widowed. Tumours with Gleason scores ≥ 8 defined high-grade cancers, and low-grade otherwise. NCI-SEER's summary stages (local, regional, distant) indicated the extent of the cancer. Logistic regression was used to derive odds ratios (ORs) and 95% confidence intervals (CI) for the association between marital status and prostate cancer risk, adjusting for potential confounders. Overall, 14,760 cases and 12,019 controls contributed to analyses. Compared to men who were married/with a partner, widowed men had an OR of 1.19 (95% CI 1.03-1.35) of prostate cancer, with little difference between low- and high-grade tumours. Risk estimates among widowers were 1.14 (95% CI 0.97-1.34) for local, 1.53 (95% CI 1.22-1.92) for regional, and 1.56 (95% CI 1.05-2.32) for distant stage tumours. Single men had elevated risks of high-grade cancers. Our findings highlight elevated risks of incident prostate cancer among widowers, more often characterized by tumours that had spread beyond the prostate at the time of diagnosis. Social support interventions and closer medical follow-up in this sub-population are warranted..
Lakeman, I.M.
van den Broek, A.J.
Vos, J.A.
Barnes, D.R.
Adlard, J.
Andrulis, I.L.
Arason, A.
Arnold, N.
Arun, B.K.
Balmaña, J.
Barrowdale, D.
Benitez, J.
Borg, A.
Caldés, T.
Caligo, M.A.
Chung, W.K.
Claes, K.B.
GEMO Study Collaborators,
EMBRACE Collaborators,
Collée, J.M.
Couch, F.J.
Daly, M.B.
Dennis, J.
Dhawan, M.
Domchek, S.M.
Eeles, R.
Engel, C.
Evans, D.G.
Feliubadaló, L.
Foretova, L.
Friedman, E.
Frost, D.
Ganz, P.A.
Garber, J.
Gayther, S.A.
Gerdes, A.-.
Godwin, A.K.
Goldgar, D.E.
Hahnen, E.
Hake, C.R.
Hamann, U.
Hogervorst, F.B.
Hooning, M.J.
Hopper, J.L.
Hulick, P.J.
Imyanitov, E.N.
OCGN Investigators,
HEBON Investigators,
KconFab Investigators,
Isaacs, C.
Izatt, L.
Jakubowska, A.
James, P.A.
Janavicius, R.
Jensen, U.B.
Jiao, Y.
John, E.M.
Joseph, V.
Karlan, B.Y.
Kets, C.M.
Konstantopoulou, I.
Kwong, A.
Legrand, C.
Leslie, G.
Lesueur, F.
Loud, J.T.
Lubiński, J.
Manoukian, S.
McGuffog, L.
Miller, A.
Gomes, D.M.
Montagna, M.
Mouret-Fourme, E.
Nathanson, K.L.
Neuhausen, S.L.
Nevanlinna, H.
Yie, J.N.
Olah, E.
Olopade, O.I.
Park, S.K.
Parsons, M.T.
Peterlongo, P.
Piedmonte, M.
Radice, P.
Rantala, J.
Rennert, G.
Risch, H.A.
Schmutzler, R.K.
Sharma, P.
Simard, J.
Singer, C.F.
Stadler, Z.
Stoppa-Lyonnet, D.
Sutter, C.
Tan, Y.Y.
Teixeira, M.R.
Teo, S.H.
Teulé, A.
Thomassen, M.
Thull, D.L.
Tischkowitz, M.
Toland, A.E.
Tung, N.
van Rensburg, E.J.
Vega, A.
Wappenschmidt, B.
Devilee, P.
van Asperen, C.J.
Bernstein, J.L.
Offit, K.
Easton, D.F.
Rookus, M.A.
Chenevix-Trench, G.
Antoniou, A.C.
Robson, M.
Schmidt, M.K.
(2021). The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant. Genet med,
Vol.23
(9),
pp. 1726-1737.
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full text
PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making..
Bancroft, E.K.
Page, E.C.
Brook, M.N.
Thomas, S.
Taylor, N.
Pope, J.
McHugh, J.
Jones, A.-.
Karlsson, Q.
Merson, S.
Ong, K.R.
Hoffman, J.
Huber, C.
Maehle, L.
Grindedal, E.M.
Stormorken, A.
Evans, D.G.
Rothwell, J.
Lalloo, F.
Brady, A.F.
Bartlett, M.
Snape, K.
Hanson, H.
James, P.
McKinley, J.
Mascarenhas, L.
Syngal, S.
Ukaegbu, C.
Side, L.
Thomas, T.
Barwell, J.
Teixeira, M.R.
Izatt, L.
Suri, M.
Macrae, F.A.
Poplawski, N.
Chen-Shtoyerman, R.
Ahmed, M.
Musgrave, H.
Nicolai, N.
Greenhalgh, L.
Brewer, C.
Pachter, N.
Spigelman, A.D.
Azzabi, A.
Helfand, B.T.
Halliday, D.
Buys, S.
Ramon Y Cajal, T.
Donaldson, A.
Cooney, K.A.
Harris, M.
McGrath, J.
Davidson, R.
Taylor, A.
Cooke, P.
Myhill, K.
Hogben, M.
Aaronson, N.K.
Ardern-Jones, A.
Bangma, C.H.
Castro, E.
Dearnaley, D.
Dias, A.
Dudderidge, T.
Eccles, D.M.
Green, K.
Eyfjord, J.
Falconer, A.
Foster, C.S.
Gronberg, H.
Hamdy, F.C.
Johannsson, O.
Khoo, V.
Lilja, H.
Lindeman, G.J.
Lubinski, J.
Axcrona, K.
Mikropoulos, C.
Mitra, A.V.
Moynihan, C.
Ni Raghallaigh, H.
Rennert, G.
Collier, R.
IMPACT Study Collaborators,
Offman, J.
Kote-Jarai, Z.
Eeles, R.A.
(2021). A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study. Lancet oncol,
Vol.22
(11),
pp. 1618-1631.
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BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer..
Saunders, E.J.
Kote-Jarai, Z.
Eeles, R.A.
(2021). Identification of Germline Genetic Variants that Increase Prostate Cancer Risk and Influence Development of Aggressive Disease. Cancers (basel),
Vol.13
(4).
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Prostate cancer (PrCa) is a heterogeneous disease, which presents in individual patients across a diverse phenotypic spectrum ranging from indolent to fatal forms. No robust biomarkers are currently available to enable routine screening for PrCa or to distinguish clinically significant forms, therefore late stage identification of advanced disease and overdiagnosis plus overtreatment of insignificant disease both remain areas of concern in healthcare provision. PrCa has a substantial heritable component, and technological advances since the completion of the Human Genome Project have facilitated improved identification of inherited genetic factors influencing susceptibility to development of the disease within families and populations. These genetic markers hold promise to enable improved understanding of the biological mechanisms underpinning PrCa development, facilitate genetically informed PrCa screening programmes and guide appropriate treatment provision. However, insight remains largely lacking regarding many aspects of their manifestation; especially in relation to genes associated with aggressive phenotypes, risk factors in non-European populations and appropriate approaches to enable accurate stratification of higher and lower risk individuals. This review discusses the methodology used in the elucidation of genetic loci, genes and individual causal variants responsible for modulating PrCa susceptibility; the current state of understanding of the allelic spectrum contributing to PrCa risk; and prospective future translational applications of these discoveries in the developing eras of genomics and personalised medicine..
Huynh-Le, M.-.
Fan, C.C.
Karunamuni, R.
Thompson, W.K.
Martinez, M.E.
Eeles, R.A.
Kote-Jarai, Z.
Muir, K.
Schleutker, J.
Pashayan, N.
Batra, J.
Grönberg, H.
Neal, D.E.
Donovan, J.L.
Hamdy, F.C.
Martin, R.M.
Nielsen, S.F.
Nordestgaard, B.G.
Wiklund, F.
Tangen, C.M.
Giles, G.G.
Wolk, A.
Albanes, D.
Travis, R.C.
Blot, W.J.
Zheng, W.
Sanderson, M.
Stanford, J.L.
Mucci, L.A.
West, C.M.
Kibel, A.S.
Cussenot, O.
Berndt, S.I.
Koutros, S.
Sørensen, K.D.
Cybulski, C.
Grindedal, E.M.
Menegaux, F.
Khaw, K.-.
Park, J.Y.
Ingles, S.A.
Maier, C.
Hamilton, R.J.
Thibodeau, S.N.
Rosenstein, B.S.
Lu, Y.-.
Watya, S.
Vega, A.
Kogevinas, M.
Penney, K.L.
Huff, C.
Teixeira, M.R.
Multigner, L.
Leach, R.J.
Cannon-Albright, L.
Brenner, H.
John, E.M.
Kaneva, R.
Logothetis, C.J.
Neuhausen, S.L.
De Ruyck, K.
Pandha, H.
Razack, A.
Newcomb, L.F.
Fowke, J.H.
Gamulin, M.
Usmani, N.
Claessens, F.
Gago-Dominguez, M.
Townsend, P.A.
Bush, W.S.
Roobol, M.J.
Parent, M.-.
Hu, J.J.
Mills, I.G.
Andreassen, O.A.
Dale, A.M.
Seibert, T.M.
UKGPCS collaborators,
APCB (Australian Prostate Cancer BioResource),
NC-LA PCaP Investigators,
IMPACT Study Steering Committee and Collaborators,
Canary PASS Investigators,
Profile Study Steering Committee,
PRACTICAL Consortium,
(2021). Polygenic hazard score is associated with prostate cancer in multi-ethnic populations. Nat commun,
Vol.12
(1),
p. 1236.
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Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset..
Lin, H.-.
Huang, P.-.
Cheng, C.-.
Tung, H.-.
Fang, Z.
Berglund, A.E.
Chen, A.
French-Kwawu, J.
Harris, D.
Pow-Sang, J.
Yamoah, K.
Cleveland, J.L.
Awasthi, S.
Rounbehler, R.J.
Gerke, T.
Dhillon, J.
Eeles, R.
Kote-Jarai, Z.
Muir, K.
UKGPCS collaborators,
Schleutker, J.
Pashayan, N.
APCB (Australian Prostate Cancer BioResource),
Neal, D.E.
Nielsen, S.F.
Nordestgaard, B.G.
Gronberg, H.
Wiklund, F.
Giles, G.G.
Haiman, C.A.
Travis, R.C.
Stanford, J.L.
Kibel, A.S.
Cybulski, C.
Khaw, K.-.
Maier, C.
Thibodeau, S.N.
Teixeira, M.R.
Cannon-Albright, L.
Brenner, H.
Kaneva, R.
Pandha, H.
PRACTICAL consortium,
Srinivasan, S.
Clements, J.
Batra, J.
Park, J.Y.
(2021). KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness. Sci rep,
Vol.11
(1),
p. 9264.
show abstract
Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10-9) and 3145 (P < 1 × 10-5) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness..
Bancroft, E.K.
Raghallaigh, H.N.
Page, E.C.
Eeles, R.A.
(2021). Updates in Prostate Cancer Research and Screening in Men at Genetically Higher Risk. Curr genet med rep,
Vol.9
(4),
pp. 47-58.
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PURPOSE OF REVIEW: Prostate cancer (PrCa) is the most common cancer in men in the western world and is a major source of morbidity and mortality. Currently, general population PrCa screening is not recommended due to the limitations of the prostate-specific antigen (PSA) test. As such, there is increasing interest in identifying and screening higher-risk groups. The only established risk factors for PrCa are age, ethnicity, and having a family history of PrCa. A significant proportion of PrCa cases are caused by genetic factors. RECENT FINDINGS: Several rare germline variants have been identified that moderately increase risk of PrCa, and targeting screening to these men is proving useful at detecting clinically significant disease. The use of a "polygenic risk score" (PRS) that can calculate a man's personalized risk based on a number of lower-risk, but common genetic variants is the subject of ongoing research. Research efforts are currently focusing on the utility of screening in specific at-risk populations based on ethnicity, such as men of Black Afro-Caribbean descent. Whilst most screening studies have focused on use of PSA testing, the incorporation of additional molecular and genomic biomarkers alongside increasingly sophisticated imaging modalities is being designed to further refine and individualise both the screening and diagnostic pathway. Approximately 10% of men with advanced PrCa have a germline genetic predisposition leading to the opportunity for novel, targeted precision treatments. SUMMARY: The mainstreaming of genomics into the PrCa screening, diagnostic and treatment pathway will soon become standard practice and this review summarises current knowledge on genetic predisposition to PrCa and screening studies that are using genomics within their algorithms to target screening to higher-risk groups of men. Finally, we evaluate the importance of germline genetics beyond screening and diagnostics, and its role in the identification of lethal PrCa and in the selection of targeted treatments for advanced disease..
Kerns, S.L.
Fachal, L.
Dorling, L.
Barnett, G.C.
Baran, A.
Peterson, D.R.
Hollenberg, M.
Hao, K.
Narzo, A.D.
Ahsen, M.E.
Pandey, G.
Bentzen, S.M.
Janelsins, M.
Elliott, R.M.
Pharoah, P.D.
Burnet, N.G.
Dearnaley, D.P.
Gulliford, S.L.
Hall, E.
Sydes, M.R.
Aguado-Barrera, M.E.
Gómez-Caamaño, A.
Carballo, A.M.
Peleteiro, P.
Lobato-Busto, R.
Stock, R.
Stone, N.N.
Ostrer, H.
Usmani, N.
Singhal, S.
Tsuji, H.
Imai, T.
Saito, S.
Eeles, R.
DeRuyck, K.
Parliament, M.
Dunning, A.M.
Vega, A.
Rosenstein, B.S.
West, C.M.
(2020). Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy. J natl cancer inst,
Vol.112
(2),
pp. 179-190.
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BACKGROUND: A total of 10%-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. METHODS: We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided. RESULTS: Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10-10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10-10), and rs11122573 with hematuria (Pmeta = 1.8 × 10-8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. CONCLUSIONS: This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile..
Nyberg, T.
Frost, D.
Barrowdale, D.
Evans, D.G.
Bancroft, E.
Adlard, J.
Ahmed, M.
Barwell, J.
Brady, A.F.
Brewer, C.
Cook, J.
Davidson, R.
Donaldson, A.
Eason, J.
Gregory, H.
Henderson, A.
Izatt, L.
Kennedy, M.J.
Miller, C.
Morrison, P.J.
Murray, A.
Ong, K.-.
Porteous, M.
Pottinger, C.
Rogers, M.T.
Side, L.
Snape, K.
Walker, L.
Tischkowitz, M.
Eeles, R.
Easton, D.F.
Antoniou, A.C.
(2020). Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study. Eur urol,
Vol.77
(1),
pp. 24-35.
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BACKGROUND: BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies. OBJECTIVE: To estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3 yr, respectively). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Standardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods. RESULTS AND LIMITATIONS: Sixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval [CI] 2.99-6.61) and absolute PCa risk of 27% (95% CI 17-41%) and 60% (95% CI 43-78%) by ages 75 and 85 yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43-3.88); the corresponding SIR at age <65 yr was 3.57 (95% CI 1.68-7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99-2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07-5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14-0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ≥7 (SIR 5.07, 95% CI 3.20-8.02) than Gleason score ≤6 PCa (SIR 3.03, 95% CI 1.24-7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44-10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses. CONCLUSIONS: The results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers. PATIENT SUMMARY: In this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene..
Patel, V.L.
Busch, E.L.
Friebel, T.M.
Cronin, A.
Leslie, G.
McGuffog, L.
Adlard, J.
Agata, S.
Agnarsson, B.A.
Ahmed, M.
Aittomäki, K.
Alducci, E.
Andrulis, I.L.
Arason, A.
Arnold, N.
Artioli, G.
Arver, B.
Auber, B.
Azzollini, J.
Balmaña, J.
Barkardottir, R.B.
Barnes, D.R.
Barroso, A.
Barrowdale, D.
Belotti, M.
Benitez, J.
Bertelsen, B.
Blok, M.J.
Bodrogi, I.
Bonadona, V.
Bonanni, B.
Bondavalli, D.
Boonen, S.E.
Borde, J.
Borg, A.
Bradbury, A.R.
Brady, A.
Brewer, C.
Brunet, J.
Buecher, B.
Buys, S.S.
Cabezas-Camarero, S.
Caldés, T.
Caliebe, A.
Caligo, M.A.
Calvello, M.
Campbell, I.G.
Carnevali, I.
Carrasco, E.
Chan, T.L.
Chu, A.T.
Chung, W.K.
Claes, K.B.
Collaborators, G.S.
Collaborators, E.
Cook, J.
Cortesi, L.
Couch, F.J.
Daly, M.B.
Damante, G.
Darder, E.
Davidson, R.
de la Hoya, M.
Puppa, L.D.
Dennis, J.
Díez, O.
Ding, Y.C.
Ditsch, N.
Domchek, S.M.
Donaldson, A.
Dworniczak, B.
Easton, D.F.
Eccles, D.M.
Eeles, R.A.
Ehrencrona, H.
Ejlertsen, B.
Engel, C.
Evans, D.G.
Faivre, L.
Faust, U.
Feliubadaló, L.
Foretova, L.
Fostira, F.
Fountzilas, G.
Frost, D.
García-Barberán, V.
Garre, P.
Gauthier-Villars, M.
Géczi, L.
Gehrig, A.
Gerdes, A.-.
Gesta, P.
Giannini, G.
Glendon, G.
Godwin, A.K.
Goldgar, D.E.
Greene, M.H.
Gutierrez-Barrera, A.M.
Hahnen, E.
Hamann, U.
Hauke, J.
Herold, N.
Hogervorst, F.B.
Honisch, E.
Hopper, J.L.
Hulick, P.J.
Investigators, K.
Investigators, H.
Izatt, L.
Jager, A.
James, P.
Janavicius, R.
Jensen, U.B.
Jensen, T.D.
Johannsson, O.T.
John, E.M.
Joseph, V.
Kang, E.
Kast, K.
Kiiski, J.I.
Kim, S.-.
Kim, Z.
Ko, K.-.
Konstantopoulou, I.
Kramer, G.
Krogh, L.
Kruse, T.A.
Kwong, A.
Larsen, M.
Lasset, C.
Lautrup, C.
Lazaro, C.
Lee, J.
Lee, J.W.
Lee, M.H.
Lemke, J.
Lesueur, F.
Liljegren, A.
Lindblom, A.
Llovet, P.
Lopez-Fernández, A.
Lopez-Perolio, I.
Lorca, V.
Loud, J.T.
Ma, E.S.
Mai, P.L.
Manoukian, S.
Mari, V.
Martin, L.
Matricardi, L.
Mebirouk, N.
Medici, V.
Meijers-Heijboer, H.E.
Meindl, A.
Mensenkamp, A.R.
Miller, C.
Gomes, D.M.
Montagna, M.
Mooij, T.M.
Moserle, L.
Mouret-Fourme, E.
Mulligan, A.M.
Nathanson, K.L.
Navratilova, M.
Nevanlinna, H.
Niederacher, D.
Nielsen, F.C.
Nikitina-Zake, L.
Offit, K.
Olah, E.
Olopade, O.I.
Ong, K.-.
Osorio, A.
Ott, C.-.
Palli, D.
Park, S.K.
Parsons, M.T.
Pedersen, I.S.
Peissel, B.
Peixoto, A.
Pérez-Segura, P.
Peterlongo, P.
Petersen, A.H.
Porteous, M.E.
Pujana, M.A.
Radice, P.
Ramser, J.
Rantala, J.
Rashid, M.U.
Rhiem, K.
Rizzolo, P.
Robson, M.E.
Rookus, M.A.
Rossing, C.M.
Ruddy, K.J.
Santos, C.
Saule, C.
Scarpitta, R.
Schmutzler, R.K.
Schuster, H.
Senter, L.
Seynaeve, C.M.
Shah, P.D.
Sharma, P.
Shin, V.Y.
Silvestri, V.
Simard, J.
Singer, C.F.
Skytte, A.-.
Snape, K.
Solano, A.R.
Soucy, P.
Southey, M.C.
Spurdle, A.B.
Steele, L.
Steinemann, D.
Stoppa-Lyonnet, D.
Stradella, A.
Sunde, L.
Sutter, C.
Tan, Y.Y.
Teixeira, M.R.
Teo, S.H.
Thomassen, M.
Tibiletti, M.G.
Tischkowitz, M.
Tognazzo, S.
Toland, A.E.
Tommasi, S.
Torres, D.
Toss, A.
Trainer, A.H.
Tung, N.
van Asperen, C.J.
van der Baan, F.H.
van der Kolk, L.E.
van der Luijt, R.B.
van Hest, L.P.
Varesco, L.
Varon-Mateeva, R.
Viel, A.
Vierstraete, J.
Villa, R.
von Wachenfeldt, A.
Wagner, P.
Wang-Gohrke, S.
Wappenschmidt, B.
Weitzel, J.N.
Wieme, G.
Yadav, S.
Yannoukakos, D.
Yoon, S.-.
Zanzottera, C.
Zorn, K.K.
D'Amico, A.V.
Freedman, M.L.
Pomerantz, M.M.
Chenevix-Trench, G.
Antoniou, A.C.
Neuhausen, S.L.
Ottini, L.
Nielsen, H.R.
Rebbeck, T.R.
(2020). Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness. Cancer res,
Vol.80
(3),
pp. 624-638.
show abstract
full text
Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual..
Fachal, L.
Aschard, H.
Beesley, J.
Barnes, D.R.
Allen, J.
Kar, S.
Pooley, K.A.
Dennis, J.
Michailidou, K.
Turman, C.
Soucy, P.
Lemaçon, A.
Lush, M.
Tyrer, J.P.
Ghoussaini, M.
Moradi Marjaneh, M.
Jiang, X.
Agata, S.
Aittomäki, K.
Alonso, M.R.
Andrulis, I.L.
Anton-Culver, H.
Antonenkova, N.N.
Arason, A.
Arndt, V.
Aronson, K.J.
Arun, B.K.
Auber, B.
Auer, P.L.
Azzollini, J.
Balmaña, J.
Barkardottir, R.B.
Barrowdale, D.
Beeghly-Fadiel, A.
Benitez, J.
Bermisheva, M.
Białkowska, K.
Blanco, A.M.
Blomqvist, C.
Blot, W.
Bogdanova, N.V.
Bojesen, S.E.
Bolla, M.K.
Bonanni, B.
Borg, A.
Bosse, K.
Brauch, H.
Brenner, H.
Briceno, I.
Brock, I.W.
Brooks-Wilson, A.
Brüning, T.
Burwinkel, B.
Buys, S.S.
Cai, Q.
Caldés, T.
Caligo, M.A.
Camp, N.J.
Campbell, I.
Canzian, F.
Carroll, J.S.
Carter, B.D.
Castelao, J.E.
Chiquette, J.
Christiansen, H.
Chung, W.K.
Claes, K.B.
Clarke, C.L.
GEMO Study Collaborators,
EMBRACE Collaborators,
Collée, J.M.
Cornelissen, S.
Couch, F.J.
Cox, A.
Cross, S.S.
Cybulski, C.
Czene, K.
Daly, M.B.
de la Hoya, M.
Devilee, P.
Diez, O.
Ding, Y.C.
Dite, G.S.
Domchek, S.M.
Dörk, T.
Dos-Santos-Silva, I.
Droit, A.
Dubois, S.
Dumont, M.
Duran, M.
Durcan, L.
Dwek, M.
Eccles, D.M.
Engel, C.
Eriksson, M.
Evans, D.G.
Fasching, P.A.
Fletcher, O.
Floris, G.
Flyger, H.
Foretova, L.
Foulkes, W.D.
Friedman, E.
Fritschi, L.
Frost, D.
Gabrielson, M.
Gago-Dominguez, M.
Gambino, G.
Ganz, P.A.
Gapstur, S.M.
Garber, J.
García-Sáenz, J.A.
Gaudet, M.M.
Georgoulias, V.
Giles, G.G.
Glendon, G.
Godwin, A.K.
Goldberg, M.S.
Goldgar, D.E.
González-Neira, A.
Tibiletti, M.G.
Greene, M.H.
Grip, M.
Gronwald, J.
Grundy, A.
Guénel, P.
Hahnen, E.
Haiman, C.A.
Håkansson, N.
Hall, P.
Hamann, U.
Harrington, P.A.
Hartikainen, J.M.
Hartman, M.
He, W.
Healey, C.S.
Heemskerk-Gerritsen, B.A.
Heyworth, J.
Hillemanns, P.
Hogervorst, F.B.
Hollestelle, A.
Hooning, M.J.
Hopper, J.L.
Howell, A.
Huang, G.
Hulick, P.J.
Imyanitov, E.N.
KConFab Investigators,
HEBON Investigators,
ABCTB Investigators,
Isaacs, C.
Iwasaki, M.
Jager, A.
Jakimovska, M.
Jakubowska, A.
James, P.A.
Janavicius, R.
Jankowitz, R.C.
John, E.M.
Johnson, N.
Jones, M.E.
Jukkola-Vuorinen, A.
Jung, A.
Kaaks, R.
Kang, D.
Kapoor, P.M.
Karlan, B.Y.
Keeman, R.
Kerin, M.J.
Khusnutdinova, E.
Kiiski, J.I.
Kirk, J.
Kitahara, C.M.
Ko, Y.-.
Konstantopoulou, I.
Kosma, V.-.
Koutros, S.
Kubelka-Sabit, K.
Kwong, A.
Kyriacou, K.
Laitman, Y.
Lambrechts, D.
Lee, E.
Leslie, G.
Lester, J.
Lesueur, F.
Lindblom, A.
Lo, W.-.
Long, J.
Lophatananon, A.
Loud, J.T.
Lubiński, J.
MacInnis, R.J.
Maishman, T.
Makalic, E.
Mannermaa, A.
Manoochehri, M.
Manoukian, S.
Margolin, S.
Martinez, M.E.
Matsuo, K.
Maurer, T.
Mavroudis, D.
Mayes, R.
McGuffog, L.
McLean, C.
Mebirouk, N.
Meindl, A.
Miller, A.
Miller, N.
Montagna, M.
Moreno, F.
Muir, K.
Mulligan, A.M.
Muñoz-Garzon, V.M.
Muranen, T.A.
Narod, S.A.
Nassir, R.
Nathanson, K.L.
Neuhausen, S.L.
Nevanlinna, H.
Neven, P.
Nielsen, F.C.
Nikitina-Zake, L.
Norman, A.
Offit, K.
Olah, E.
Olopade, O.I.
Olsson, H.
Orr, N.
Osorio, A.
Pankratz, V.S.
Papp, J.
Park, S.K.
Park-Simon, T.-.
Parsons, M.T.
Paul, J.
Pedersen, I.S.
Peissel, B.
Peshkin, B.
Peterlongo, P.
Peto, J.
Plaseska-Karanfilska, D.
Prajzendanc, K.
Prentice, R.
Presneau, N.
Prokofyeva, D.
Pujana, M.A.
Pylkäs, K.
Radice, P.
Ramus, S.J.
Rantala, J.
Rau-Murthy, R.
Rennert, G.
Risch, H.A.
Robson, M.
Romero, A.
Rossing, M.
Saloustros, E.
Sánchez-Herrero, E.
Sandler, D.P.
Santamariña, M.
Saunders, C.
Sawyer, E.J.
Scheuner, M.T.
Schmidt, D.F.
Schmutzler, R.K.
Schneeweiss, A.
Schoemaker, M.J.
Schöttker, B.
Schürmann, P.
Scott, C.
Scott, R.J.
Senter, L.
Seynaeve, C.M.
Shah, M.
Sharma, P.
Shen, C.-.
Shu, X.-.
Singer, C.F.
Slavin, T.P.
Smichkoska, S.
Southey, M.C.
Spinelli, J.J.
Spurdle, A.B.
Stone, J.
Stoppa-Lyonnet, D.
Sutter, C.
Swerdlow, A.J.
Tamimi, R.M.
Tan, Y.Y.
Tapper, W.J.
Taylor, J.A.
Teixeira, M.R.
Tengström, M.
Teo, S.H.
Terry, M.B.
Teulé, A.
Thomassen, M.
Thull, D.L.
Tischkowitz, M.
Toland, A.E.
Tollenaar, R.A.
Tomlinson, I.
Torres, D.
Torres-Mejía, G.
Troester, M.A.
Truong, T.
Tung, N.
Tzardi, M.
Ulmer, H.-.
Vachon, C.M.
van Asperen, C.J.
van der Kolk, L.E.
van Rensburg, E.J.
Vega, A.
Viel, A.
Vijai, J.
Vogel, M.J.
Wang, Q.
Wappenschmidt, B.
Weinberg, C.R.
Weitzel, J.N.
Wendt, C.
Wildiers, H.
Winqvist, R.
Wolk, A.
Wu, A.H.
Yannoukakos, D.
Zhang, Y.
Zheng, W.
Hunter, D.
Pharoah, P.D.
Chang-Claude, J.
García-Closas, M.
Schmidt, M.K.
Milne, R.L.
Kristensen, V.N.
French, J.D.
Edwards, S.L.
Antoniou, A.C.
Chenevix-Trench, G.
Simard, J.
Easton, D.F.
Kraft, P.
Dunning, A.M.
(2020). Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes. Nat genet,
Vol.52
(1),
pp. 56-73.
show abstract
full text
Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes..
ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium,
(2020). Pan-cancer analysis of whole genomes. Nature,
Vol.578
(7793),
pp. 82-93.
show abstract
full text
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1-3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10-18..
Zhang, Y.D.
Hurson, A.N.
Zhang, H.
Choudhury, P.P.
Easton, D.F.
Milne, R.L.
Simard, J.
Hall, P.
Michailidou, K.
Dennis, J.
Schmidt, M.K.
Chang-Claude, J.
Gharahkhani, P.
Whiteman, D.
Campbell, P.T.
Hoffmeister, M.
Jenkins, M.
Peters, U.
Hsu, L.
Gruber, S.B.
Casey, G.
Schmit, S.L.
O'Mara, T.A.
Spurdle, A.B.
Thompson, D.J.
Tomlinson, I.
De Vivo, I.
Landi, M.T.
Law, M.H.
Iles, M.M.
Demenais, F.
Kumar, R.
MacGregor, S.
Bishop, D.T.
Ward, S.V.
Bondy, M.L.
Houlston, R.
Wiencke, J.K.
Melin, B.
Barnholtz-Sloan, J.
Kinnersley, B.
Wrensch, M.R.
Amos, C.I.
Hung, R.J.
Brennan, P.
McKay, J.
Caporaso, N.E.
Berndt, S.I.
Birmann, B.M.
Camp, N.J.
Kraft, P.
Rothman, N.
Slager, S.L.
Berchuck, A.
Pharoah, P.D.
Sellers, T.A.
Gayther, S.A.
Pearce, C.L.
Goode, E.L.
Schildkraut, J.M.
Moysich, K.B.
Amundadottir, L.T.
Jacobs, E.J.
Klein, A.P.
Petersen, G.M.
Risch, H.A.
Stolzenberg-Solomon, R.Z.
Wolpin, B.M.
Li, D.
Eeles, R.A.
Haiman, C.A.
Kote-Jarai, Z.
Schumacher, F.R.
Al Olama, A.A.
Purdue, M.P.
Scelo, G.
Dalgaard, M.D.
Greene, M.H.
Grotmol, T.
Kanetsky, P.A.
McGlynn, K.A.
Nathanson, K.L.
Turnbull, C.
Wiklund, F.
Breast Cancer Association Consortium (BCAC),
Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON),
Colon Cancer Family Registry (CCFR),
Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT),
Endometrial Cancer Association Consortium (ECAC),
Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO),
Melanoma Genetics Consortium (GenoMEL),
Glioma International Case-Control Study (GICC),
International Lung Cancer Consortium (ILCCO),
Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium,
International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph),
Ovarian Cancer Association Consortium (OCAC),
Oral Cancer GWAS,
Pancreatic Cancer Case-Control Consortium (PanC4),
Pancreatic Cancer Cohort Consortium (PanScan),
Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL),
Renal Cancer GWAS,
Testicular Cancer Consortium (TECAC),
Chanock, S.J.
Chatterjee, N.
Garcia-Closas, M.
(2020). Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers. Nat commun,
Vol.11
(1),
p. 3353.
show abstract
full text
Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence..
Bancroft, E.K.
Saya, S.
Brown, E.
Thomas, S.
Taylor, N.
Rothwell, J.
Pope, J.
Chamberlain, A.
Page, E.
Benafif, S.
Hanson, H.
Dias, A.
Mikropoulos, C.
Izatt, L.
Side, L.
Walker, L.
Donaldson, A.
Cook, J.A.
Barwell, J.
Wiles, V.
Limb, L.
Eccles, D.M.
Leach, M.O.
Shanley, S.
Gilbert, F.J.
Gallagher, D.
Rajashanker, B.
Whitehouse, R.W.
Koh, D.-.
Sohaib, S.A.
Evans, D.G.
Eeles, R.A.
Walker, L.G.
(2020). Psychosocial effects of whole-body MRI screening in adult high-risk pathogenic TP53 mutation carriers: a case-controlled study (SIGNIFY). J med genet,
Vol.57
(4),
pp. 226-236.
show abstract
full text
BACKGROUND: Germline TP53 gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is recommended for female TP53 pv carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44 TP53 pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adult TP53 pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms. METHODS: Psychosocial and other assessments were carried out at study enrolment, immediately before MRI, before and after MRI results, and at 12, 26 and 52 weeks' follow-up. RESULTS: WB-MRI was found to be acceptable with high levels of satisfaction and low levels of psychological morbidity throughout. Although their mean levels of cancer worry were not high, carriers had significantly more cancer worry at most time-points than controls. They also reported significantly more clinically significant intrusive and avoidant thoughts about cancer than controls at all time-points. There were no clinically significant adverse psychosocial outcomes in either carriers with a history of cancer or in those requiring further investigations. CONCLUSION: WB-MRI screening can be implemented in TP53 pv carriers without adverse psychosocial outcomes in the short and medium terms. A previous cancer diagnosis may predict a better psychosocial outcome. Some carriers seriously underestimate their risk of cancer. Carriers of pv should have access to a clinician to help them develop adaptive strategies to cope with cancer-related concerns and respond to clinically significant depression and/or anxiety..
Gillessen, S.
Attard, G.
Beer, T.M.
Beltran, H.
Bjartell, A.
Bossi, A.
Briganti, A.
Bristow, R.G.
Chi, K.N.
Clarke, N.
Davis, I.D.
de Bono, J.
Drake, C.G.
Duran, I.
Eeles, R.
Efstathiou, E.
Evans, C.P.
Fanti, S.
Feng, F.Y.
Fizazi, K.
Frydenberg, M.
Gleave, M.
Halabi, S.
Heidenreich, A.
Heinrich, D.
Higano, C.T.
Hofman, M.S.
Hussain, M.
James, N.
Kanesvaran, R.
Kantoff, P.
Khauli, R.B.
Leibowitz, R.
Logothetis, C.
Maluf, F.
Millman, R.
Morgans, A.K.
Morris, M.J.
Mottet, N.
Mrabti, H.
Murphy, D.G.
Murthy, V.
Oh, W.K.
Ost, P.
O'Sullivan, J.M.
Padhani, A.R.
Parker, C.
Poon, D.M.
Pritchard, C.C.
Reiter, R.E.
Roach, M.
Rubin, M.
Ryan, C.J.
Saad, F.
Sade, J.P.
Sartor, O.
Scher, H.I.
Shore, N.
Small, E.
Smith, M.
Soule, H.
Sternberg, C.N.
Steuber, T.
Suzuki, H.
Sweeney, C.
Sydes, M.R.
Taplin, M.-.
Tombal, B.
Türkeri, L.
van Oort, I.
Zapatero, A.
Omlin, A.
(2020). Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019. Eur urol,
Vol.77
(4),
pp. 508-547.
show abstract
full text
BACKGROUND: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence. OBJECTIVE: To present the results from the APCCC 2019. DESIGN, SETTING, AND PARTICIPANTS: Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process. RESULTS AND LIMITATIONS: Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material. CONCLUSIONS: These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making..
Brandão, A.
Paulo, P.
Maia, S.
Pinheiro, M.
Peixoto, A.
Cardoso, M.
Silva, M.P.
Santos, C.
Eeles, R.A.
Kote-Jarai, Z.
Muir, K.
Ukgpcs Collaborators,
Schleutker, J.
Wang, Y.
Pashayan, N.
Batra, J.
Apcb BioResource,
Grönberg, H.
Neal, D.E.
Nordestgaard, B.G.
Tangen, C.M.
Southey, M.C.
Wolk, A.
Albanes, D.
Haiman, C.A.
Travis, R.C.
Stanford, J.L.
Mucci, L.A.
West, C.M.
Nielsen, S.F.
Kibel, A.S.
Cussenot, O.
Berndt, S.I.
Koutros, S.
Sørensen, K.D.
Cybulski, C.
Grindedal, E.M.
Park, J.Y.
Ingles, S.A.
Maier, C.
Hamilton, R.J.
Rosenstein, B.S.
Vega, A.
The Impact Study Steering Committee And Collaborators,
Kogevinas, M.
Wiklund, F.
Penney, K.L.
Brenner, H.
John, E.M.
Kaneva, R.
Logothetis, C.J.
Neuhausen, S.L.
Ruyck, K.D.
Razack, A.
Newcomb, L.F.
Canary Pass Investigators,
Lessel, D.
Usmani, N.
Claessens, F.
Gago-Dominguez, M.
Townsend, P.A.
Roobol, M.J.
The Profile Study Steering Committee,
The Practical Consortium,
Teixeira, M.R.
(2020). The CHEK2 Variant C 349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor. Cancers (basel),
Vol.12
(11).
show abstract
full text
The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families..
Ahmed, M.
Goh, C.
Saunders, E.
Cieza-Borrella, C.
PRACTICAL consortium,
Kote-Jarai, Z.
Schumacher, F.R.
Eeles, R.
(2020). Germline genetic variation in prostate susceptibility does not predict outcomes in the chemoprevention trials PCPT and SELECT. Prostate cancer prostatic dis,
Vol.23
(2),
pp. 333-342.
show abstract
full text
BACKGROUND: The development of prostate cancer can be influenced by genetic and environmental factors. Numerous germline SNPs influence prostate cancer susceptibility. The functional pathways in which these SNPs increase prostate cancer susceptibility are unknown. Finasteride is currently not being used routinely as a chemoprevention agent but the long term outcomes of the PCPT trial are awaited. The outcomes of the SELECT trial have not recommended the use of chemoprevention in preventing prostate cancer. This study investigated whether germline risk SNPs could be used to predict outcomes in the PCPT and SELECT trial. METHODS: Genotyping was performed in European men entered into the PCPT trial (n = 2434) and SELECT (n = 4885). Next generation genotyping was performed using Affymetrix® Eureka™ Genotyping protocols. Logistic regression models were used to test the association of risk scores and the outcomes in the PCPT and SELECT trials. RESULTS: Of the 100 SNPs, 98 designed successfully and genotyping was validated for samples genotyped on other platforms. A number of SNPs predicted for aggressive disease in both trials. Men with a higher polygenic score are more likely to develop prostate cancer in both trials, but the score did not predict for other outcomes in the trial. CONCLUSION: Men with a higher polygenic risk score are more likely to develop prostate cancer. There were no interactions of these germline risk SNPs and the chemoprevention agents in the SELECT and PCPT trials..
Wu, L.
Yang, Y.
Guo, X.
Shu, X.-.
Cai, Q.
Shu, X.
Li, B.
Tao, R.
Wu, C.
Nikas, J.B.
Sun, Y.
Zhu, J.
Roobol, M.J.
Giles, G.G.
Brenner, H.
John, E.M.
Clements, J.
Grindedal, E.M.
Park, J.Y.
Stanford, J.L.
Kote-Jarai, Z.
Haiman, C.A.
Eeles, R.A.
Zheng, W.
Long, J.
PRACTICAL consortium,
CRUK Consortium,
BPC3 Consortium,
CAPS Consortium,
PEGASUS Consortium,
(2020). An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk. Nat commun,
Vol.11
(1),
p. 3905.
show abstract
full text
It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG sites associated with PrCa risk, here we establish genetic models to predict methylation (N = 1,595) and conduct association analyses with PrCa risk (79,194 cases and 61,112 controls). We identify 759 CpG sites showing an association, including 15 located at novel loci. Among those 759 CpG sites, methylation of 42 is associated with expression of 28 adjacent genes. Among 22 genes, 18 show an association with PrCa risk. Overall, 25 CpG sites show consistent association directions for the methylation-gene expression-PrCa pathway. We identify DNA methylation biomarkers associated with PrCa, and our findings suggest that specific CpG sites may influence PrCa via regulating expression of candidate PrCa target genes..
Huynh-Le, M.-.
Fan, C.C.
Karunamuni, R.
Walsh, E.I.
Turner, E.L.
Lane, J.A.
Martin, R.M.
Neal, D.E.
Donovan, J.L.
Hamdy, F.C.
Parsons, J.K.
Eeles, R.A.
Easton, D.F.
Kote-Jarai, Z.
Amin Al Olama, A.
Benlloch Garcia, S.
Muir, K.
Grönberg, H.
Wiklund, F.
Aly, M.
Schleutker, J.
Sipeky, C.
Tammela, T.L.
Nordestgaard, B.G.
Key, T.J.
Travis, R.C.
Pharoah, P.D.
Pashayan, N.
Khaw, K.-.
Thibodeau, S.N.
McDonnell, S.K.
Schaid, D.J.
Maier, C.
Vogel, W.
Luedeke, M.
Herkommer, K.
Kibel, A.S.
Cybulski, C.
Wokolorczyk, D.
Kluzniak, W.
Cannon-Albright, L.A.
Brenner, H.
Schöttker, B.
Holleczek, B.
Park, J.Y.
Sellers, T.A.
Lin, H.-.
Slavov, C.K.
Kaneva, R.P.
Mitev, V.I.
Batra, J.
Clements, J.A.
Spurdle, A.B.
Teixeira, M.R.
Paulo, P.
Maia, S.
Pandha, H.
Michael, A.
Mills, I.G.
Andreassen, O.A.
Dale, A.M.
Seibert, T.M.
Australian Prostate Cancer BioResource (APCB),
PRACTICAL Consortium,
(2020). A Genetic Risk Score to Personalize Prostate Cancer Screening, Applied to Population Data. Cancer epidemiol biomarkers prev,
Vol.29
(9),
pp. 1731-1738.
show abstract
full text
BACKGROUND: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. METHODS: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. RESULTS: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. CONCLUSIONS: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. IMPACT: Personalized genetic risk assessments could inform prostate cancer screening decisions..
Karunamuni, R.A.
Huynh-Le, M.-.
Fan, C.C.
Eeles, R.A.
Easton, D.F.
Kote-Jarai, Z.
Amin Al Olama, A.
Benlloch Garcia, S.
Muir, K.
Gronberg, H.
Wiklund, F.
Aly, M.
Schleutker, J.
Sipeky, C.
Tammela, T.L.
Nordestgaard, B.G.
Key, T.J.
Travis, R.C.
Neal, D.E.
Donovan, J.L.
Hamdy, F.C.
Pharoah, P.
Pashayan, N.
Khaw, K.-.
Thibodeau, S.N.
McDonnell, S.K.
Schaid, D.J.
Maier, C.
Vogel, W.
Luedeke, M.
Herkommer, K.
Kibel, A.S.
Cybulski, C.
Wokolorczyk, D.
Kluzniak, W.
Cannon-Albright, L.
Brenner, H.
Schöttker, B.
Holleczek, B.
Park, J.Y.
Sellers, T.A.
Lin, H.-.
Slavov, C.
Kaneva, R.
Mitev, V.
Batra, J.
Clements, J.A.
Spurdle, A.
Australian Prostate Cancer BioResource (APCB),
Teixeira, M.R.
Paulo, P.
Maia, S.
Pandha, H.
Michael, A.
Mills, I.G.
Andreassen, O.A.
Dale, A.M.
Seibert, T.M.
PRACTICAL Consortium,
(2020). The effect of sample size on polygenic hazard models for prostate cancer. Eur j hum genet,
Vol.28
(10),
pp. 1467-1475.
show abstract
full text
We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models..
Barnes, D.R.
Rookus, M.A.
McGuffog, L.
Leslie, G.
Mooij, T.M.
Dennis, J.
Mavaddat, N.
Adlard, J.
Ahmed, M.
Aittomäki, K.
Andrieu, N.
Andrulis, I.L.
Arnold, N.
Arun, B.K.
Azzollini, J.
Balmaña, J.
Barkardottir, R.B.
Barrowdale, D.
Benitez, J.
Berthet, P.
Białkowska, K.
Blanco, A.M.
Blok, M.J.
Bonanni, B.
Boonen, S.E.
Borg, Å.
Bozsik, A.
Bradbury, A.R.
Brennan, P.
Brewer, C.
Brunet, J.
Buys, S.S.
Caldés, T.
Caligo, M.A.
Campbell, I.
Christensen, L.L.
Chung, W.K.
Claes, K.B.
Colas, C.
GEMO Study Collaborators,
EMBRACE Collaborators,
Collonge-Rame, M.-.
Cook, J.
Daly, M.B.
Davidson, R.
de la Hoya, M.
de Putter, R.
Delnatte, C.
Devilee, P.
Diez, O.
Ding, Y.C.
Domchek, S.M.
Dorfling, C.M.
Dumont, M.
Eeles, R.
Ejlertsen, B.
Engel, C.
Evans, D.G.
Faivre, L.
Foretova, L.
Fostira, F.
Friedlander, M.
Friedman, E.
Frost, D.
Ganz, P.A.
Garber, J.
Gehrig, A.
Gerdes, A.-.
Gesta, P.
Giraud, S.
Glendon, G.
Godwin, A.K.
Goldgar, D.E.
González-Neira, A.
Greene, M.H.
Gschwantler-Kaulich, D.
Hahnen, E.
Hamann, U.
Hanson, H.
Hentschel, J.
Hogervorst, F.B.
Hooning, M.J.
Horvath, J.
Hu, C.
Hulick, P.J.
Imyanitov, E.N.
kConFab Investigators,
HEBON Investigators,
GENEPSO Investigators,
Isaacs, C.
Izatt, L.
Izquierdo, A.
Jakubowska, A.
James, P.A.
Janavicius, R.
John, E.M.
Joseph, V.
Karlan, B.Y.
Kast, K.
Koudijs, M.
Kruse, T.A.
Kwong, A.
Laitman, Y.
Lasset, C.
Lazaro, C.
Lester, J.
Lesueur, F.
Liljegren, A.
Loud, J.T.
Lubiński, J.
Mai, P.L.
Manoukian, S.
Mari, V.
Mebirouk, N.
Meijers-Heijboer, H.E.
Meindl, A.
Mensenkamp, A.R.
Miller, A.
Montagna, M.
Mouret-Fourme, E.
Mukherjee, S.
Mulligan, A.M.
Nathanson, K.L.
Neuhausen, S.L.
Nevanlinna, H.
Niederacher, D.
Nielsen, F.C.
Nikitina-Zake, L.
Noguès, C.
Olah, E.
Olopade, O.I.
Ong, K.-.
O'Shaughnessy-Kirwan, A.
Osorio, A.
Ott, C.-.
Papi, L.
Park, S.K.
Parsons, M.T.
Pedersen, I.S.
Peissel, B.
Peixoto, A.
Peterlongo, P.
Pfeiler, G.
Phillips, K.-.
Prajzendanc, K.
Pujana, M.A.
Radice, P.
Ramser, J.
Ramus, S.J.
Rantala, J.
Rennert, G.
Risch, H.A.
Robson, M.
Rønlund, K.
Salani, R.
Schuster, H.
Senter, L.
Shah, P.D.
Sharma, P.
Side, L.E.
Singer, C.F.
Slavin, T.P.
Soucy, P.
Southey, M.C.
Spurdle, A.B.
Steinemann, D.
Steinsnyder, Z.
Stoppa-Lyonnet, D.
Sutter, C.
Tan, Y.Y.
Teixeira, M.R.
Teo, S.H.
Thull, D.L.
Tischkowitz, M.
Tognazzo, S.
Toland, A.E.
Trainer, A.H.
Tung, N.
van Engelen, K.
van Rensburg, E.J.
Vega, A.
Vierstraete, J.
Wagner, G.
Walker, L.
Wang-Gohrke, S.
Wappenschmidt, B.
Weitzel, J.N.
Yadav, S.
Yang, X.
Yannoukakos, D.
Zimbalatti, D.
Offit, K.
Thomassen, M.
Couch, F.J.
Schmutzler, R.K.
Simard, J.
Easton, D.F.
Chenevix-Trench, G.
Antoniou, A.C.
Consortium of Investigators of Modifiers of BRCA and BRCA2,
(2020). Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants. Genet med,
Vol.22
(10),
pp. 1653-1666.
show abstract
full text
PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes..
Nyberg, T.
Frost, D.
Barrowdale, D.
Evans, D.G.
Bancroft, E.
Adlard, J.
Ahmed, M.
Barwell, J.
Brady, A.F.
Brewer, C.
Cook, J.
Davidson, R.
Donaldson, A.
Eason, J.
Gregory, H.
Henderson, A.
Izatt, L.
Kennedy, M.J.
Miller, C.
Morrison, P.J.
Murray, A.
Ong, K.-.
Porteous, M.
Pottinger, C.
Rogers, M.T.
Side, L.
Snape, K.
Tripathi, V.
Walker, L.
Tischkowitz, M.
Eeles, R.
Easton, D.F.
Antoniou, A.C.
(2020). Prostate Cancer Risk by BRCA2 Genomic Regions. Eur urol,
Vol.78
(4),
pp. 494-497.
show abstract
full text
A BRCA2 prostate cancer cluster region (PCCR) was recently proposed (c.7914 to 3') wherein pathogenic variants (PVs) are associated with higher prostate cancer (PCa) risk than PVs elsewhere in the BRCA2 gene. Using a prospective cohort study of 447 male BRCA2 PV carriers recruited in the UK and Ireland from 1998 to 2016, we estimated standardised incidence ratios (SIRs) compared with population incidences and assessed variation in risk by PV location. Carriers of PVs in the PCCR had a PCa SIR of 8.33 (95% confidence interval [CI] 4.46-15.6) and were at a higher risk of PCa than carriers of other BRCA2 PVs (SIR = 3.31, 95% CI 1.97-5.57; hazard ratio = 2.34, 95% CI 1.09-5.03). PCCR PV carriers had an estimated cumulative PCa risk of 44% (95% CI 23-72%) by the age of 75 yr and 78% (95% CI 54-94%) by the age of 85 yr. Our results corroborate the existence of a PCCR in BRCA2 in a prospective cohort. PATIENT SUMMARY: In this report, we investigated whether the risk of prostate cancer for men with a harmful mutation in the BRCA2 gene differs based on where in the gene the mutation is located. We found that men with mutations in one region of BRCA2 had a higher risk of prostate cancer than men with mutations elsewhere in the gene..
Gilson, C.
Ingleby, F.
Gilbert, D.C.
Parry, M.A.
Atako, N.B.
Ali, A.
Hoyle, A.
Clarke, N.W.
Gannon, M.
Wanstall, C.
Brawley, C.
Mason, M.D.
Malik, Z.
Simmons, A.
Loehr, A.
Parry-Jones, A.
Eeles, R.
Kote-Jarai, Z.
James, N.D.
Amos, C.
Parmar, M.K.
Langley, R.E.
Sydes, M.R.
Attard, G.
Chowdhury, S.
STAMPEDE Investigators,
(2020). Genomic Profiles of De Novo High- and Low-Volume Metastatic Prostate Cancer: Results From a 2-Stage Feasibility and Prevalence Study in the STAMPEDE Trial. Jco precis oncol,
Vol.4,
pp. 882-897.
show abstract
PURPOSE: The STAMPEDE trial recruits men with newly diagnosed, high-risk, hormone-sensitive prostate cancer. To ascertain the feasibility of targeted next-generation sequencing (tNGS) and the prevalence of baseline genomic aberrations, we sequenced tumor and germline DNA from patients with metastatic prostate cancer (mPCa) starting long-term androgen-deprivation therapy (ADT). METHODS: In a 2-stage approach, archival, formalin-fixed, paraffin-embedded (FFPE) prostate tumor core biopsy samples were retrospectively subjected to 2 tNGS assays. Prospective enrollment enabled validation using tNGS in tumor and germline DNA. RESULTS: In stage 1, tNGS data were obtained from 185 tumors from 287 patients (65%); 98% had de novo mPCa. We observed PI3K pathway aberrations in 43%, due to PTEN copy-number loss (34%) and/or activating mutations in PIK3 genes or AKT (18%) and TP53 mutation or loss in 33%. No androgen receptor (AR) aberrations were detected; RB1 loss was observed in < 1%. In stage 2, 93 (92%) of 101 FFPE tumors (biopsy obtained within 8 months) were successfully sequenced prospectively. The prevalence of DNA damage repair (DDR) deficiency was 14% (somatic) and 5% (germline). BRCA2 mutations and mismatch repair gene mutations were exclusive to high-volume disease. Aberrant DDR (22% v 15%), Wnt pathway (16% v 4%), and chromatin remodeling (16% v 8%) were all more common in high-volume compared with low-volume disease, but the small numbers limited statistical comparisons. CONCLUSION: Prospective genomic characterization is feasible using residual diagnostic tumor samples and reveals that the genomic landscapes of de novo high-volume mPCa and advanced metastatic prostate cancer have notable similarities (PI3K pathway, DDR, Wnt, chromatin remodeling) and differences (AR, RB1). These results will inform the design and conduct of biomarker-directed trials in men with metastatic hormone-sensitive prostate cancer..
Mavaddat, N.
Antoniou, A.C.
Mooij, T.M.
Hooning, M.J.
Heemskerk-Gerritsen, B.A.
GENEPSO,
Noguès, C.
Gauthier-Villars, M.
Caron, O.
Gesta, P.
Pujol, P.
Lortholary, A.
EMBRACE,
Barrowdale, D.
Frost, D.
Evans, D.G.
Izatt, L.
Adlard, J.
Eeles, R.
Brewer, C.
Tischkowitz, M.
Henderson, A.
Cook, J.
Eccles, D.
HEBON,
van Engelen, K.
Mourits, M.J.
Ausems, M.G.
Koppert, L.B.
Hopper, J.L.
John, E.M.
Chung, W.K.
Andrulis, I.L.
Daly, M.B.
Buys, S.S.
kConFab Investigators,
Benitez, J.
Caldes, T.
Jakubowska, A.
Simard, J.
Singer, C.F.
Tan, Y.
Olah, E.
Navratilova, M.
Foretova, L.
Gerdes, A.-.
Roos-Blom, M.-.
Van Leeuwen, F.E.
Arver, B.
Olsson, H.
Schmutzler, R.K.
Engel, C.
Kast, K.
Phillips, K.-.
Terry, M.B.
Milne, R.L.
Goldgar, D.E.
Rookus, M.A.
Andrieu, N.
Easton, D.F.
IBCCS,
kConFab,
BCFR,
(2020). Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers. Breast cancer res,
Vol.22
(1),
p. 8.
show abstract
full text
BACKGROUND: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. METHODS: A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. RESULTS: There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. CONCLUSION: We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO..
Hanson, H.
Brady, A.F.
Crawford, G.
Eeles, R.A.
Gibson, S.
Jorgensen, M.
Izatt, L.
Sohaib, A.
Tischkowitz, M.
Evans, D.G.
Consensus Group Members,
(2020). UKCGG Consensus Group guidelines for the management of patients with constitutional TP53 pathogenic variants. J med genet,
Vol.58
(2),
pp. 135-139.
show abstract
full text
Constitutional pathogenic variants in TP53 are associated with Li-Fraumeni syndrome or the more recently described heritable TP53-related cancer syndrome and are associated with increased lifetime risks of a wide spectrum of cancers. Due to the broad tumour spectrum, surveillance for this patient group has been limited. To date, the only recommendation in the UK has been for annual breast MRI in women; however, more recently, a more intensive surveillance protocol including whole-body MRI (WB-MRI) has been recommended by International Expert Groups. To address the gap in surveillance for this patient group in the UK, the UK Cancer Genetics Group facilitated a 1-day consensus meeting to discuss a protocol for the UK. Using a preworkshop survey followed by structured discussion on the day, we achieved consensus for a UK surveillance protocol for TP53 carriers to be adopted by UK Clinical Genetics services. The key recommendations are for annual WB-MRI and dedicated brain MRI from birth, annual breast MRI from 20 years in women and three-four monthly abdominal ultrasound in children along with review in a dedicated clinic..
Aladwani, M.
Lophatananon, A.
Robinson, F.
Rahman, A.
Ollier, W.
Kote-Jarai, Z.
Dearnaley, D.
Koveela, G.
Hussain, N.
Rageevakumar, R.
Keating, D.
Osborne, A.
Dadaev, T.
Brook, M.
British Association of Urological Surgeons’ Section of Oncology,
Eeles, R.
Muir, K.R.
(2020). Relationship of self-reported body size and shape with risk for prostate cancer: A UK case-control study. Plos one,
Vol.15
(9),
p. e0238928.
show abstract
full text
INTRODUCTION: Previous evidence has suggested a relationship between male self-reported body size and the risk of developing prostate cancer. In this UK-wide case-control study, we have explored the possible association of prostate cancer risk with male self-reported body size. We also investigated body shape as a surrogate marker for fat deposition around the body. As obesity and excessive adiposity have been linked with increased risk for developing a number of different cancers, further investigation of self-reported body size and shape and their potential relationship with prostate cancer was considered to be appropriate. OBJECTIVE: The study objective was to investigate whether underlying associations exist between prostate cancer risk and male self-reported body size and shape. METHODS: Data were collected from a large case-control study of men (1928 cases and 2043 controls) using self-administered questionnaires. Data from self-reported pictograms of perceived body size relating to three decades of life (20's, 30's and 40's) were recorded and analysed, including the pattern of change. The associations of self-identified body shape with prostate cancer risk were also explored. RESULTS: Self-reported body size for men in their 20's, 30's and 40's did not appear to be associated with prostate cancer risk. More than half of the subjects reported an increase in self-reported body size throughout these three decades of life. Furthermore, no association was observed between self-reported body size changes and prostate cancer risk. Using 'symmetrical' body shape as a reference group, subjects with an 'apple' shape showed a significant 27% reduction in risk (Odds ratio = 0.73, 95% C.I. 0.57-0.92). CONCLUSIONS: Change in self-reported body size throughout early to mid-adulthood in males is not a significant risk factor for the development of prostate cancer. Body shape indicative of body fat distribution suggested that an 'apple' body shape was protective and inversely associated with prostate cancer risk when compared with 'symmetrical' shape. Further studies which investigate prostate cancer risk and possible relationships with genetic factors known to influence body shape may shed further light on any underlying associations..
Qian, F.
Wang, S.
Mitchell, J.
McGuffog, L.
Barrowdale, D.
Leslie, G.
Oosterwijk, J.C.
Chung, W.K.
Evans, D.G.
Engel, C.
Kast, K.
Aalfs, C.M.
Adank, M.A.
Adlard, J.
Agnarsson, B.A.
Aittomäki, K.
Alducci, E.
Andrulis, I.L.
Arun, B.K.
Ausems, M.G.
Azzollini, J.
Barouk-Simonet, E.
Barwell, J.
Belotti, M.
Benitez, J.
Berger, A.
Borg, A.
Bradbury, A.R.
Brunet, J.
Buys, S.S.
Caldes, T.
Caligo, M.A.
Campbell, I.
Caputo, S.M.
Chiquette, J.
Claes, K.B.
Margriet Collée, J.
Couch, F.J.
Coupier, I.
Daly, M.B.
Davidson, R.
Diez, O.
Domchek, S.M.
Donaldson, A.
Dorfling, C.M.
Eeles, R.
Feliubadaló, L.
Foretova, L.
Fowler, J.
Friedman, E.
Frost, D.
Ganz, P.A.
Garber, J.
Garcia-Barberan, V.
Glendon, G.
Godwin, A.K.
Gómez Garcia, E.B.
Gronwald, J.
Hahnen, E.
Hamann, U.
Henderson, A.
Hendricks, C.B.
Hopper, J.L.
Hulick, P.J.
Imyanitov, E.N.
Isaacs, C.
Izatt, L.
Izquierdo, Á.
Jakubowska, A.
Kaczmarek, K.
Kang, E.
Karlan, B.Y.
Kets, C.M.
Kim, S.-.
Kim, Z.
Kwong, A.
Laitman, Y.
Lasset, C.
Hyuk Lee, M.
Won Lee, J.
Lee, J.
Lester, J.
Lesueur, F.
Loud, J.T.
Lubinski, J.
Mebirouk, N.
Meijers-Heijboer, H.E.
Meindl, A.
Miller, A.
Montagna, M.
Mooij, T.M.
Morrison, P.J.
Mouret-Fourme, E.
Nathanson, K.L.
Neuhausen, S.L.
Nevanlinna, H.
Niederacher, D.
Nielsen, F.C.
Nussbaum, R.L.
Offit, K.
Olah, E.
Ong, K.-.
Ottini, L.
Park, S.K.
Peterlongo, P.
Pfeiler, G.
Phelan, C.M.
Poppe, B.
Pradhan, N.
Radice, P.
Ramus, S.J.
Rantala, J.
Robson, M.
Rodriguez, G.C.
Schmutzler, R.K.
Hutten Selkirk, C.G.
Shah, P.D.
Simard, J.
Singer, C.F.
Sokolowska, J.
Stoppa-Lyonnet, D.
Sutter, C.
Yen Tan, Y.
Teixeira, R.M.
Teo, S.H.
Terry, M.B.
Thomassen, M.
Tischkowitz, M.
Toland, A.E.
Tucker, K.M.
Tung, N.
van Asperen, C.J.
van Engelen, K.
van Rensburg, E.J.
Wang-Gohrke, S.
Wappenschmidt, B.
Weitzel, J.N.
Yannoukakos, D.
GEMO Study Collaborators,
HEBON,
EMBRACE,
Greene, M.H.
Rookus, M.A.
Easton, D.F.
Chenevix-Trench, G.
Antoniou, A.C.
Goldgar, D.E.
Olopade, O.I.
Rebbeck, T.R.
Huo, D.
(2019). Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study. J natl cancer inst,
Vol.111
(4),
pp. 350-364.
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BACKGROUND: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. METHODS: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. RESULTS: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer. CONCLUSION: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management..
Jiang, X.
Dimou, N.L.
Al-Dabhani, K.
Lewis, S.J.
Martin, R.M.
Haycock, P.C.
Gunter, M.J.
Key, T.J.
Eeles, R.A.
Muir, K.
Neal, D.
Giles, G.G.
Giovannucci, E.L.
Stampfer, M.
Pierce, B.L.
Schildkraut, J.M.
Warren Andersen, S.
Thompson, D.
Zheng, W.
Kraft, P.
Tsilidis, K.K.
PRACTICAL, CRUK, BPC3, CAPS and PEGASUS consortia,
(2019). Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study. Int j epidemiol,
Vol.48
(5),
pp. 1416-1424.
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BACKGROUND: Observational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization (MR) analysis comprising 15 748 breast and 22 898 prostate-cancer cases. Demonstrating causality has proven challenging and one common limitation of MR studies is insufficient power. METHODS: We aimed to determine whether circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary-level data from the largest ever genome-wide association studies conducted on vitamin D (N = 73 699), breast cancer (Ncase = 122 977) and prostate cancer (Ncase = 79 148). We constructed a stronger instrument using six common genetic variants (compared with the previous four variants) and applied several two-sample MR methods. RESULTS: We found no evidence to support a causal association between 25(OH)D and risk of breast cancer [OR per 25 nmol/L increase, 1.02 (95% confidence interval: 0.97-1.08), P = 0.47], oestrogen receptor (ER)+ [1.00 (0.94-1.07), P = 0.99] or ER- [1.02 (0.90-1.16), P = 0.75] subsets, prostate cancer [1.00 (0.93-1.07), P = 0.99] or the advanced subtype [1.02 (0.90-1.16), P = 0.72] using the inverse-variance-weighted method. Sensitivity analyses did not reveal any sign of directional pleiotropy. CONCLUSIONS: Despite its almost five-fold augmented sample size and substantially improved statistical power, our MR analysis does not support a causal effect of circulating 25(OH)D concentrations on breast- or prostate-cancer risk. However, we can still not exclude a modest or non-linear effect of vitamin D. Future studies may be designed to understand the effect of vitamin D in subpopulations with a profound deficiency..
Wu, L.
Wang, J.
Cai, Q.
Cavazos, T.B.
Emami, N.C.
Long, J.
Shu, X.-.
Lu, Y.
Guo, X.
Bauer, J.A.
Pasaniuc, B.
Penney, K.L.
Freedman, M.L.
Kote-Jarai, Z.
Witte, J.S.
Haiman, C.A.
Eeles, R.A.
Zheng, W.
PRACTICAL, CRUK, BPC3, CAPS, PEGASUS Consortia,
(2019). Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk: A Transcriptome-Wide Association Study in Over 140,000 European Descendants. Cancer res,
Vol.79
(13),
pp. 3192-3204.
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Genome-wide association study-identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61 × 10-6, a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61 × 10-6 after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology. SIGNIFICANCE: This study identifies novel prostate cancer genetic loci and possible causal genes, advancing our understanding of the molecular mechanisms that drive prostate cancer..
Adams, C.D.
Richmond, R.
Ferreira, D.L.
Spiller, W.
Tan, V.
Zheng, J.
Würtz, P.
Donovan, J.
Hamdy, F.
Neal, D.
Lane, J.A.
Smith, G.D.
Relton, C.
Eeles, R.A.
Haiman, C.A.
Kote-Jarai, Z.
Schumacher, F.R.
Olama, A.A.
Benlloch, S.
Muir, K.
Berndt, S.I.
Conti, D.V.
Wiklund, F.
Chanock, S.J.
Gapstur, S.
Stevens, V.L.
Tangen, C.M.
Batra, J.
Clements, J.A.
Gronberg, H.
Pashayan, N.
Schleutker, J.
Albanes, D.
Wolk, A.
West, C.M.
Mucci, L.A.
Cancel-Tassin, G.
Koutros, S.
Sorensen, K.D.
Maehle, L.
Travis, R.C.
Hamilton, R.J.
Ingles, S.A.
Rosenstein, B.S.
Lu, Y.-.
Giles, G.G.
Kibel, A.S.
Vega, A.
Kogevinas, M.
Penney, K.L.
Park, J.Y.
Stanford, J.L.
Cybulski, C.
Nordestgaard, B.G.
Brenner, H.
Maier, C.
Kim, J.
John, E.M.
Teixeira, M.R.
Neuhausen, S.L.
De Ruyck, K.
Razack, A.
Newcomb, L.F.
Lessel, D.
Kaneva, R.P.
Usmani, N.
Claessens, F.
Townsend, P.A.
Dominguez, M.G.
Roobol, M.J.
Menegaux, F.
Khaw, K.-.
Cannon-Albright, L.A.
Pandha, H.
Thibodeau, S.N.
Martin, R.M.
PRACTICAL consortium,
(2019). Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study. Cancer epidemiol biomarkers prev,
Vol.28
(1),
pp. 208-216.
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BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR). METHODS: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification..
Bancroft, E.K.
Saya, S.
Page, E.C.
Myhill, K.
Thomas, S.
Pope, J.
Chamberlain, A.
Hart, R.
Glover, W.
Cook, J.
Rosario, D.J.
Helfand, B.T.
Hutten Selkirk, C.
Davidson, R.
Longmuir, M.
Eccles, D.M.
Gadea, N.
Brewer, C.
Barwell, J.
Salinas, M.
Greenhalgh, L.
Tischkowitz, M.
Henderson, A.
Evans, D.G.
Buys, S.S.
IMPACT Study Steering Committee,
IMPACT Collaborators,
Eeles, R.A.
Aaronson, N.K.
(2019). Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations. Bju int,
Vol.123
(2),
pp. 284-292.
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OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening..
Nyberg, T.
Govindasami, K.
Leslie, G.
Dadaev, T.
Bancroft, E.
Ni Raghallaigh, H.
Brook, M.N.
Hussain, N.
Keating, D.
Lee, A.
McMahon, R.
Morgan, A.
Mullen, A.
Osborne, A.
Rageevakumar, R.
UK Genetic Prostate Cancer Study Collaborators,
Kote-Jarai, Z.
Eeles, R.
Antoniou, A.C.
(2019). Homeobox B13 G84E Mutation and Prostate Cancer Risk. Eur urol,
Vol.75
(5),
pp. 834-845.
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BACKGROUND: The homeobox B13 (HOXB13) G84E mutation has been recommended for use in genetic counselling for prostate cancer (PCa), but the magnitude of PCa risk conferred by this mutation is uncertain. OBJECTIVE: To obtain precise risk estimates for mutation carriers and information on how these vary by family history and other factors. DESIGN, SETTING, AND PARTICIPANTS: Two-fold: a systematic review and meta-analysis of published risk estimates, and a kin-cohort study comprising pedigree data on 11983 PCa patients enrolled during 1993-2014 from 189 UK hospitals and who had been genotyped for HOXB13 G84E. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relative and absolute PCa risks. Complex segregation analysis with ascertainment adjustment to derive age-specific risks applicable to the population, and to investigate how these vary by family history and birth cohort. RESULTS AND LIMITATIONS: A meta-analysis of case-control studies revealed significant heterogeneity between reported relative risks (RRs; range: 0.95-33.0, p<0.001) and differences by case selection (p=0.007). Based on case-control studies unselected for PCa family history, the pooled RR estimate was 3.43 (95% confidence interval [CI] 2.78-4.23). In the kin-cohort study, PCa risk for mutation carriers varied by family history (p<0.001). There was a suggestion that RRs decrease with age, but this was not significant (p=0.068). We found higher RR estimates for men from more recent birth cohorts (p=0.004): 3.09 (95% CI 2.03-4.71) for men born in 1929 or earlier and 5.96 (95% CI 4.01-8.88) for men born in 1930 or later. The absolute PCa risk by age 85 for a male HOXB13 G84E carrier varied from 60% for those with no PCa family history to 98% for those with two relatives diagnosed at young ages, compared with an average risk of 15% for noncarriers. Limitations include the reliance on self-reported cancer family history. CONCLUSIONS: PCa risks for HOXB13 G84E mutation carriers are heterogeneous. Counselling should not be based on average risk estimates but on age-specific absolute risk estimates tailored to individual mutation carriers' family history and birth cohort. PATIENT SUMMARY: Men who carry a hereditary mutation in the homeobox B13 (HOXB13) gene have a higher than average risk for developing prostate cancer. In our study, we examined a large number of families of men with prostate cancer recruited across UK hospitals, to assess what other factors may contribute to this risk and to assess whether we could create a precise model to help in predicting a man's prostate cancer risk. We found that the risk of developing prostate cancer in men who carry this genetic mutation is also affected by a family history of prostate cancer and their year of birth. This information can be used to assess more personalised prostate cancer risks to men who carry HOXB13 mutations and hence better counsel them on more personalised risk management options, such as tailoring prostate cancer screening frequency..
Qian, F.
Rookus, M.A.
Leslie, G.
Risch, H.A.
Greene, M.H.
Aalfs, C.M.
Adank, M.A.
Adlard, J.
Agnarsson, B.A.
Ahmed, M.
Aittomäki, K.
Andrulis, I.L.
Arnold, N.
Arun, B.K.
Ausems, M.G.
Azzollini, J.
Barrowdale, D.
Barwell, J.
Benitez, J.
Białkowska, K.
Bonadona, V.
Borde, J.
Borg, A.
Bradbury, A.R.
Brunet, J.
Buys, S.S.
Caldés, T.
Caligo, M.A.
Campbell, I.
Carter, J.
Chiquette, J.
Chung, W.K.
Claes, K.B.
Collée, J.M.
Collonge-Rame, M.-.
Couch, F.J.
Daly, M.B.
Delnatte, C.
Diez, O.
Domchek, S.M.
Dorfling, C.M.
Eason, J.
Easton, D.F.
Eeles, R.
Engel, C.
Evans, D.G.
Faivre, L.
Feliubadaló, L.
Foretova, L.
Friedman, E.
Frost, D.
Ganz, P.A.
Garber, J.
Garcia-Barberan, V.
Gehrig, A.
Glendon, G.
Godwin, A.K.
Gómez Garcia, E.B.
Hamann, U.
Hauke, J.
Hopper, J.L.
Hulick, P.J.
Imyanitov, E.N.
Isaacs, C.
Izatt, L.
Jakubowska, A.
Janavicius, R.
John, E.M.
Karlan, B.Y.
Kets, C.M.
Laitman, Y.
Lázaro, C.
Leroux, D.
Lester, J.
Lesueur, F.
Loud, J.T.
Lubiński, J.
Łukomska, A.
McGuffog, L.
Mebirouk, N.
Meijers-Heijboer, H.E.
Meindl, A.
Miller, A.
Montagna, M.
Mooij, T.M.
Mouret-Fourme, E.
Nathanson, K.L.
Nehoray, B.
Neuhausen, S.L.
Nevanlinna, H.
Nielsen, F.C.
Offit, K.
Olah, E.
Ong, K.-.
Oosterwijk, J.C.
Ottini, L.
Parsons, M.T.
Peterlongo, P.
Pfeiler, G.
Pradhan, N.
Radice, P.
Ramus, S.J.
Rantala, J.
Rennert, G.
Robson, M.
Rodriguez, G.C.
Salani, R.
Scheuner, M.T.
Schmutzler, R.K.
Shah, P.D.
Side, L.E.
Simard, J.
Singer, C.F.
Steinemann, D.
Stoppa-Lyonnet, D.
Tan, Y.Y.
Teixeira, M.R.
Terry, M.B.
Thomassen, M.
Tischkowitz, M.
Tognazzo, S.
Toland, A.E.
Tung, N.
van Asperen, C.J.
van Engelen, K.
van Rensburg, E.J.
Venat-Bouvet, L.
Vierstraete, J.
Wagner, G.
Walker, L.
Weitzel, J.N.
Yannoukakos, D.
KConFab Investigators,
HEBON Investigators,
GEMO Study Collaborators,
EMBRACE Collaborators,
Antoniou, A.C.
Goldgar, D.E.
Olopade, O.I.
Chenevix-Trench, G.
Rebbeck, T.R.
Huo, D.
CIMBA,
(2019). Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers. Br j cancer,
Vol.121
(2),
pp. 180-192.
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full text
BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population..
Loveday, C.
Sud, A.
Litchfield, K.
Levy, M.
Holroyd, A.
Broderick, P.
Kote-Jarai, Z.
Dunning, A.M.
Muir, K.
Peto, J.
Eeles, R.
Easton, D.F.
Dudakia, D.
Orr, N.
Pashayan, N.
UK Testicular Cancer Collaboration,
PRACTICAL Consortium,
Reid, A.
Huddart, R.A.
Houlston, R.S.
Turnbull, C.
(2019). Runs of homozygosity and testicular cancer risk. Andrology,
Vol.7
(4),
pp. 555-564.
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BACKGROUND: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. OBJECTIVE: To examine whether RoH are associated with TGCT risk. METHODS: We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. RESULTS: Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology. DISCUSSION AND CONCLUSION: Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls..
Leongamornlert, D.A.
Saunders, E.J.
Wakerell, S.
Whitmore, I.
Dadaev, T.
Cieza-Borrella, C.
Benafif, S.
Brook, M.N.
Donovan, J.L.
Hamdy, F.C.
Neal, D.E.
Muir, K.
Govindasami, K.
Conti, D.V.
Kote-Jarai, Z.
Eeles, R.A.
(2019). Germline DNA Repair Gene Mutations in Young-onset Prostate Cancer Cases in the UK: Evidence for a More Extensive Genetic Panel. Eur urol,
Vol.76
(3),
pp. 329-337.
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BACKGROUND: Rare germline mutations in DNA repair genes are associated with prostate cancer (PCa) predisposition and prognosis. OBJECTIVE: To quantify the frequency of germline DNA repair gene mutations in UK PCa cases and controls, in order to more comprehensively evaluate the contribution of individual genes to overall PCa risk and likelihood of aggressive disease. DESIGN, SETTING, AND PARTICIPANTS: We sequenced 167 DNA repair and eight PCa candidate genes in a UK-based cohort of 1281 young-onset PCa cases (diagnosed at ≤60yr) and 1160 selected controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Gene-level SKAT-O and gene-set adaptive combination of p values (ADA) analyses were performed separately for cases versus controls, and aggressive (Gleason score ≥8, n=201) versus nonaggressive (Gleason score ≤7, n=1048) cases. RESULTS AND LIMITATIONS: We identified 233 unique protein truncating variants (PTVs) with minor allele frequency <0.5% in controls in 97 genes. The total proportion of PTV carriers was higher in cases than in controls (15% vs 12%, odds ratio [OR]=1.29, 95% confidence interval [CI] 1.01-1.64, p=0.036). Gene-level analyses selected NBN (pSKAT-O=2.4×10-4) for overall risk and XPC (pSKAT-O=1.6×10-4) for aggressive disease, both at candidate-level significance (p<3.1×10-4 and p<3.4×10-4, respectively). Gene-set analysis identified a subset of 20 genes associated with increased PCa risk (OR=3.2, 95% CI 2.1-4.8, pADA=4.1×10-3) and four genes that increased risk of aggressive disease (OR=11.2, 95% CI 4.6-27.7, pADA=5.6×10-3), three of which overlap the predisposition gene set. CONCLUSIONS: The union of the gene-level and gene-set-level analyses identified 23 unique DNA repair genes associated with PCa predisposition or risk of aggressive disease. These findings will help facilitate the development of a PCa-specific sequencing panel with both predictive and prognostic potential. PATIENT SUMMARY: This large sequencing study assessed the rate of inherited DNA repair gene mutations between prostate cancer patients and disease-free men. A panel of 23 genes was identified, which may improve risk prediction or treatment pathways in future clinical practice..
Brand, D.H.
Parker, J.I.
Dearnaley, D.P.
Eeles, R.
Huddart, R.
Khoo, V.
Murray, J.
Suh, Y.-.
Tree, A.C.
van As, N.
Parker, C.
(2019). Patterns of recurrence after prostate bed radiotherapy. Radiother oncol,
Vol.141,
pp. 174-180.
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BACKGROUND AND PURPOSE: Prostate bed radiotherapy is a standard treatment after radical prostatectomy. Recent evidence suggests that, for patients with a PSA > 0.34 ng/ml, the radiotherapy treatment volume should include not only the prostate bed but also the pelvic lymph nodes. We describe the patterns of failure after prostate bed radiotherapy, focussing on the proportion of patients with radiologically confirmed pelvic nodal failure only, in the absence of distant disease. MATERIALS AND METHODS: Patients included were men receiving prostate bed radiotherapy at the Royal Marsden Hospital between 1997 and 2013. The key outcome of interest was the pattern of radiologic failure after prostate bed radiotherapy. Baseline characteristics of patients experiencing pelvic nodal failure without distant disease were compared versus all other relapse patterns. Comparisons were by Chi-square test, with multiple testing adjusted p < 0.005 significant. RESULTS: 140 of 322 patients developed biochemical failure after salvage RT. Radiologic failure occurred in 89 patients. 35 of the 89 patients (39%) with radiologic failure had pelvic nodal failure without distant disease, with no significant differences in baseline characteristics when compared to all other patients. The rate of pelvic nodal failure was the same for patients with PSA above or below 0.34 ng/ml (16/149, 95% CI = 6-17% vs 19/171, 95% CI = 7-17%). CONCLUSIONS: Pelvic lymph node disease, without more distant disease, is a common site of failure in men receiving radiotherapy to the prostate bed, including those with PSA < 0.34 ng/ml. This observation informs the case for including the pelvic lymph nodes in the radiotherapy treatment volume..
Callender, T.
Emberton, M.
Morris, S.
Eeles, R.
Kote-Jarai, Z.
Pharoah, P.D.
Pashayan, N.
(2019). Polygenic risk-tailored screening for prostate cancer: A benefit-harm and cost-effectiveness modelling study. Plos med,
Vol.16
(12),
p. e1002998.
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BACKGROUND: The United States Preventive Services Task Force supports individualised decision-making for prostate-specific antigen (PSA)-based screening in men aged 55-69. Knowing how the potential benefits and harms of screening vary by an individual's risk of developing prostate cancer could inform decision-making about screening at both an individual and population level. This modelling study examined the benefit-harm tradeoffs and the cost-effectiveness of a risk-tailored screening programme compared to age-based and no screening. METHODS AND FINDINGS: A life-table model, projecting age-specific prostate cancer incidence and mortality, was developed of a hypothetical cohort of 4.48 million men in England aged 55 to 69 years with follow-up to age 90. Risk thresholds were based on age and polygenic profile. We compared no screening, age-based screening (quadrennial PSA testing from 55 to 69), and risk-tailored screening (men aged 55 to 69 years with a 10-year absolute risk greater than a threshold receive quadrennial PSA testing from the age they reach the risk threshold). The analysis was undertaken from the health service perspective, including direct costs borne by the health system for risk assessment, screening, diagnosis, and treatment. We used probabilistic sensitivity analyses to account for parameter uncertainty and discounted future costs and benefits at 3.5% per year. Our analysis should be considered cautiously in light of limitations related to our model's cohort-based structure and the uncertainty of input parameters in mathematical models. Compared to no screening over 35 years follow-up, age-based screening prevented the most deaths from prostate cancer (39,272, 95% uncertainty interval [UI]: 16,792-59,685) at the expense of 94,831 (95% UI: 84,827-105,630) overdiagnosed cancers. Age-based screening was the least cost-effective strategy studied. The greatest number of quality-adjusted life-years (QALYs) was generated by risk-based screening at a 10-year absolute risk threshold of 4%. At this threshold, risk-based screening led to one-third fewer overdiagnosed cancers (64,384, 95% UI: 57,382-72,050) but averted 6.3% fewer (9,695, 95% UI: 2,853-15,851) deaths from prostate cancer by comparison with age-based screening. Relative to no screening, risk-based screening at a 4% 10-year absolute risk threshold was cost-effective in 48.4% and 57.4% of the simulations at willingness-to-pay thresholds of GBP£20,000 (US$26,000) and £30,000 ($39,386) per QALY, respectively. The cost-effectiveness of risk-tailored screening improved as the threshold rose. CONCLUSIONS: Based on the results of this modelling study, offering screening to men at higher risk could potentially reduce overdiagnosis and improve the benefit-harm tradeoff and the cost-effectiveness of a prostate cancer screening program. The optimal threshold will depend on societal judgements of the appropriate balance of benefits-harms and cost-effectiveness..
Page, E.C.
Bancroft, E.K.
Brook, M.N.
Assel, M.
Hassan Al Battat, M.
Thomas, S.
Taylor, N.
Chamberlain, A.
Pope, J.
Raghallaigh, H.N.
Evans, D.G.
Rothwell, J.
Maehle, L.
Grindedal, E.M.
James, P.
Mascarenhas, L.
McKinley, J.
Side, L.
Thomas, T.
van Asperen, C.
Vasen, H.
Kiemeney, L.A.
Ringelberg, J.
Jensen, T.D.
Osther, P.J.
Helfand, B.T.
Genova, E.
Oldenburg, R.A.
Cybulski, C.
Wokolorczyk, D.
Ong, K.-.
Huber, C.
Lam, J.
Taylor, L.
Salinas, M.
Feliubadaló, L.
Oosterwijk, J.C.
van Zelst-Stams, W.
Cook, J.
Rosario, D.J.
Domchek, S.
Powers, J.
Buys, S.
O'Toole, K.
Ausems, M.G.
Schmutzler, R.K.
Rhiem, K.
Izatt, L.
Tripathi, V.
Teixeira, M.R.
Cardoso, M.
Foulkes, W.D.
Aprikian, A.
van Randeraad, H.
Davidson, R.
Longmuir, M.
Ruijs, M.W.
Helderman van den Enden, A.T.
Adank, M.
Williams, R.
Andrews, L.
Murphy, D.G.
Halliday, D.
Walker, L.
Liljegren, A.
Carlsson, S.
Azzabi, A.
Jobson, I.
Morton, C.
Shackleton, K.
Snape, K.
Hanson, H.
Harris, M.
Tischkowitz, M.
Taylor, A.
Kirk, J.
Susman, R.
Chen-Shtoyerman, R.
Spigelman, A.
Pachter, N.
Ahmed, M.
Ramon Y Cajal, T.
Zgajnar, J.
Brewer, C.
Gadea, N.
Brady, A.F.
van Os, T.
Gallagher, D.
Johannsson, O.
Donaldson, A.
Barwell, J.
Nicolai, N.
Friedman, E.
Obeid, E.
Greenhalgh, L.
Murthy, V.
Copakova, L.
Saya, S.
McGrath, J.
Cooke, P.
Rønlund, K.
Richardson, K.
Henderson, A.
Teo, S.H.
Arun, B.
Kast, K.
Dias, A.
Aaronson, N.K.
Ardern-Jones, A.
Bangma, C.H.
Castro, E.
Dearnaley, D.
Eccles, D.M.
Tricker, K.
Eyfjord, J.
Falconer, A.
Foster, C.
Gronberg, H.
Hamdy, F.C.
Stefansdottir, V.
Khoo, V.
Lindeman, G.J.
Lubinski, J.
Axcrona, K.
Mikropoulos, C.
Mitra, A.
Moynihan, C.
Rennert, G.
Suri, M.
Wilson, P.
Dudderidge, T.
IMPACT Study Collaborators,
Offman, J.
Kote-Jarai, Z.
Vickers, A.
Lilja, H.
Eeles, R.A.
(2019). Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers. Eur urol,
Vol.76
(6),
pp. 831-842.
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BACKGROUND: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations. OBJECTIVE: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status. DESIGN, SETTING, AND PARTICIPANTS: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians. RESULTS AND LIMITATIONS: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65). CONCLUSIONS: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers. PATIENT SUMMARY: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening..
Law, P.J.
Timofeeva, M.
Fernandez-Rozadilla, C.
Broderick, P.
Studd, J.
Fernandez-Tajes, J.
Farrington, S.
Svinti, V.
Palles, C.
Orlando, G.
Sud, A.
Holroyd, A.
Penegar, S.
Theodoratou, E.
Vaughan-Shaw, P.
Campbell, H.
Zgaga, L.
Hayward, C.
Campbell, A.
Harris, S.
Deary, I.J.
Starr, J.
Gatcombe, L.
Pinna, M.
Briggs, S.
Martin, L.
Jaeger, E.
Sharma-Oates, A.
East, J.
Leedham, S.
Arnold, R.
Johnstone, E.
Wang, H.
Kerr, D.
Kerr, R.
Maughan, T.
Kaplan, R.
Al-Tassan, N.
Palin, K.
Hänninen, U.A.
Cajuso, T.
Tanskanen, T.
Kondelin, J.
Kaasinen, E.
Sarin, A.-.
Eriksson, J.G.
Rissanen, H.
Knekt, P.
Pukkala, E.
Jousilahti, P.
Salomaa, V.
Ripatti, S.
Palotie, A.
Renkonen-Sinisalo, L.
Lepistö, A.
Böhm, J.
Mecklin, J.-.
Buchanan, D.D.
Win, A.-.
Hopper, J.
Jenkins, M.E.
Lindor, N.M.
Newcomb, P.A.
Gallinger, S.
Duggan, D.
Casey, G.
Hoffmann, P.
Nöthen, M.M.
Jöckel, K.-.
Easton, D.F.
Pharoah, P.D.
Peto, J.
Canzian, F.
Swerdlow, A.
Eeles, R.A.
Kote-Jarai, Z.
Muir, K.
Pashayan, N.
PRACTICAL consortium,
Harkin, A.
Allan, K.
McQueen, J.
Paul, J.
Iveson, T.
Saunders, M.
Butterbach, K.
Chang-Claude, J.
Hoffmeister, M.
Brenner, H.
Kirac, I.
Matošević, P.
Hofer, P.
Brezina, S.
Gsur, A.
Cheadle, J.P.
Aaltonen, L.A.
Tomlinson, I.
Houlston, R.S.
Dunlop, M.G.
(2019). Association analyses identify 31 new risk loci for colorectal cancer susceptibility. Nat commun,
Vol.10
(1),
p. 2154.
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Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention..
Wu, L.
Shu, X.
Bao, J.
Guo, X.
Kote-Jarai, Z.
Haiman, C.A.
Eeles, R.A.
Zheng, W.
PRACTICAL, CRUK, BPC3, CAPS, PEGASUS Consortia,
(2019). Analysis of Over 140,000 European Descendants Identifies Genetically Predicted Blood Protein Biomarkers Associated with Prostate Cancer Risk. Cancer res,
Vol.79
(18),
pp. 4592-4598.
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full text
Several blood protein biomarkers have been associated with prostate cancer risk. However, most studies assessed only a small number of biomarkers and/or included a small sample size. To identify novel protein biomarkers of prostate cancer risk, we studied 79,194 cases and 61,112 controls of European ancestry, included in the PRACTICAL/ELLIPSE consortia, using genetic instruments of protein quantitative trait loci for 1,478 plasma proteins. A total of 31 proteins were associated with prostate cancer risk including proteins encoded by GSTP1, whose methylation level was shown previously to be associated with prostate cancer risk, and MSMB, SPINT2, IGF2R, and CTSS, which were previously implicated as potential target genes of prostate cancer risk variants identified in genome-wide association studies. A total of 18 proteins inversely correlated and 13 positively correlated with prostate cancer risk. For 28 of the identified proteins, gene somatic changes of short indels, splice site, nonsense, or missense mutations were detected in patients with prostate cancer in The Cancer Genome Atlas. Pathway enrichment analysis showed that relevant genes were significantly enriched in cancer-related pathways. In conclusion, this study identifies 31 candidates of protein biomarkers for prostate cancer risk and provides new insights into the biology and genetics of prostate tumorigenesis. SIGNIFICANCE: Integration of genomics and proteomics data identifies biomarkers associated with prostate cancer risk..
Jiang, X.
Finucane, H.K.
Schumacher, F.R.
Schmit, S.L.
Tyrer, J.P.
Han, Y.
Michailidou, K.
Lesseur, C.
Kuchenbaecker, K.B.
Dennis, J.
Conti, D.V.
Casey, G.
Gaudet, M.M.
Huyghe, J.R.
Albanes, D.
Aldrich, M.C.
Andrew, A.S.
Andrulis, I.L.
Anton-Culver, H.
Antoniou, A.C.
Antonenkova, N.N.
Arnold, S.M.
Aronson, K.J.
Arun, B.K.
Bandera, E.V.
Barkardottir, R.B.
Barnes, D.R.
Batra, J.
Beckmann, M.W.
Benitez, J.
Benlloch, S.
Berchuck, A.
Berndt, S.I.
Bickeböller, H.
Bien, S.A.
Blomqvist, C.
Boccia, S.
Bogdanova, N.V.
Bojesen, S.E.
Bolla, M.K.
Brauch, H.
Brenner, H.
Brenton, J.D.
Brook, M.N.
Brunet, J.
Brunnström, H.
Buchanan, D.D.
Burwinkel, B.
Butzow, R.
Cadoni, G.
Caldés, T.
Caligo, M.A.
Campbell, I.
Campbell, P.T.
Cancel-Tassin, G.
Cannon-Albright, L.
Campa, D.
Caporaso, N.
Carvalho, A.L.
Chan, A.T.
Chang-Claude, J.
Chanock, S.J.
Chen, C.
Christiani, D.C.
Claes, K.B.
Claessens, F.
Clements, J.
Collée, J.M.
Correa, M.C.
Couch, F.J.
Cox, A.
Cunningham, J.M.
Cybulski, C.
Czene, K.
Daly, M.B.
deFazio, A.
Devilee, P.
Diez, O.
Gago-Dominguez, M.
Donovan, J.L.
Dörk, T.
Duell, E.J.
Dunning, A.M.
Dwek, M.
Eccles, D.M.
Edlund, C.K.
Edwards, D.R.
Ellberg, C.
Evans, D.G.
Fasching, P.A.
Ferris, R.L.
Liloglou, T.
Figueiredo, J.C.
Fletcher, O.
Fortner, R.T.
Fostira, F.
Franceschi, S.
Friedman, E.
Gallinger, S.J.
Ganz, P.A.
Garber, J.
García-Sáenz, J.A.
Gayther, S.A.
Giles, G.G.
Godwin, A.K.
Goldberg, M.S.
Goldgar, D.E.
Goode, E.L.
Goodman, M.T.
Goodman, G.
Grankvist, K.
Greene, M.H.
Gronberg, H.
Gronwald, J.
Guénel, P.
Håkansson, N.
Hall, P.
Hamann, U.
Hamdy, F.C.
Hamilton, R.J.
Hampe, J.
Haugen, A.
Heitz, F.
Herrero, R.
Hillemanns, P.
Hoffmeister, M.
Høgdall, E.
Hong, Y.-.
Hopper, J.L.
Houlston, R.
Hulick, P.J.
Hunter, D.J.
Huntsman, D.G.
Idos, G.
Imyanitov, E.N.
Ingles, S.A.
Isaacs, C.
Jakubowska, A.
James, P.
Jenkins, M.A.
Johansson, M.
Johansson, M.
John, E.M.
Joshi, A.D.
Kaneva, R.
Karlan, B.Y.
Kelemen, L.E.
Kühl, T.
Khaw, K.-.
Khusnutdinova, E.
Kibel, A.S.
Kiemeney, L.A.
Kim, J.
Kjaer, S.K.
Knight, J.A.
Kogevinas, M.
Kote-Jarai, Z.
Koutros, S.
Kristensen, V.N.
Kupryjanczyk, J.
Lacko, M.
Lam, S.
Lambrechts, D.
Landi, M.T.
Lazarus, P.
Le, N.D.
Lee, E.
Lejbkowicz, F.
Lenz, H.-.
Leslie, G.
Lessel, D.
Lester, J.
Levine, D.A.
Li, L.
Li, C.I.
Lindblom, A.
Lindor, N.M.
Liu, G.
Loupakis, F.
Lubiński, J.
Maehle, L.
Maier, C.
Mannermaa, A.
Marchand, L.L.
Margolin, S.
May, T.
McGuffog, L.
Meindl, A.
Middha, P.
Miller, A.
Milne, R.L.
MacInnis, R.J.
Modugno, F.
Montagna, M.
Moreno, V.
Moysich, K.B.
Mucci, L.
Muir, K.
Mulligan, A.M.
Nathanson, K.L.
Neal, D.E.
Ness, A.R.
Neuhausen, S.L.
Nevanlinna, H.
Newcomb, P.A.
Newcomb, L.F.
Nielsen, F.C.
Nikitina-Zake, L.
Nordestgaard, B.G.
Nussbaum, R.L.
Offit, K.
Olah, E.
Olama, A.A.
Olopade, O.I.
Olshan, A.F.
Olsson, H.
Osorio, A.
Pandha, H.
Park, J.Y.
Pashayan, N.
Parsons, M.T.
Pejovic, T.
Penney, K.L.
Peters, W.H.
Phelan, C.M.
Phipps, A.I.
Plaseska-Karanfilska, D.
Pring, M.
Prokofyeva, D.
Radice, P.
Stefansson, K.
Ramus, S.J.
Raskin, L.
Rennert, G.
Rennert, H.S.
van Rensburg, E.J.
Riggan, M.J.
Risch, H.A.
Risch, A.
Roobol, M.J.
Rosenstein, B.S.
Rossing, M.A.
De Ruyck, K.
Saloustros, E.
Sandler, D.P.
Sawyer, E.J.
Schabath, M.B.
Schleutker, J.
Schmidt, M.K.
Setiawan, V.W.
Shen, H.
Siegel, E.M.
Sieh, W.
Singer, C.F.
Slattery, M.L.
Sorensen, K.D.
Southey, M.C.
Spurdle, A.B.
Stanford, J.L.
Stevens, V.L.
Stintzing, S.
Stone, J.
Sundfeldt, K.
Sutphen, R.
Swerdlow, A.J.
Tajara, E.H.
Tangen, C.M.
Tardon, A.
Taylor, J.A.
Teare, M.D.
Teixeira, M.R.
Terry, M.B.
Terry, K.L.
Thibodeau, S.N.
Thomassen, M.
Bjørge, L.
Tischkowitz, M.
Toland, A.E.
Torres, D.
Townsend, P.A.
Travis, R.C.
Tung, N.
Tworoger, S.S.
Ulrich, C.M.
Usmani, N.
Vachon, C.M.
Van Nieuwenhuysen, E.
Vega, A.
Aguado-Barrera, M.E.
Wang, Q.
Webb, P.M.
Weinberg, C.R.
Weinstein, S.
Weissler, M.C.
Weitzel, J.N.
West, C.M.
White, E.
Whittemore, A.S.
Wichmann, H.-.
Wiklund, F.
Winqvist, R.
Wolk, A.
Woll, P.
Woods, M.
Wu, A.H.
Wu, X.
Yannoukakos, D.
Zheng, W.
Zienolddiny, S.
Ziogas, A.
Zorn, K.K.
Lane, J.M.
Saxena, R.
Thomas, D.
Hung, R.J.
Diergaarde, B.
McKay, J.
Peters, U.
Hsu, L.
García-Closas, M.
Eeles, R.A.
Chenevix-Trench, G.
Brennan, P.J.
Haiman, C.A.
Simard, J.
Easton, D.F.
Gruber, S.B.
Pharoah, P.D.
Price, A.L.
Pasaniuc, B.
Amos, C.I.
Kraft, P.
Lindström, S.
(2019). Shared heritability and functional enrichment across six solid cancers. Nat commun,
Vol.10
(1),
p. 431.
show abstract
full text
Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis..
Howell, A.
Ashcroft, L.
Fallowfield, L.
Eccles, D.M.
Eeles, R.A.
Ward, A.
Brentnall, A.R.
Dowsett, M.
Cuzick, J.M.
Greenhalgh, R.
Boggis, C.
Motion, J.
Sergeant, J.C.
Adams, J.
Evans, D.G.
(2018). RAZOR: A Phase II Open Randomized Trial of Screening Plus Goserelin and Raloxifene Versus Screening Alone in Premenopausal Women at Increased Risk of Breast Cancer. Cancer epidemiol biomarkers prev,
Vol.27
(1),
pp. 58-66.
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full text
Background: Ovarian suppression in premenopausal women is known to reduce breast cancer risk. This study aimed to assess uptake and compliance with ovarian suppression using the luteinizing hormone releasing hormone (LHRH) analogue, goserelin, with add-back raloxifene, as a potential regimen for breast cancer prevention.Methods: Women at ≥30% lifetime risk breast cancer were approached and randomized to mammographic screening alone (C-Control) or screening in addition to monthly subcutaneous injections of 3.6 mg goserelin and continuous 60 mg raloxifene daily orally (T-Treated) for 2 years. The primary endpoint was therapy adherence. Secondary endpoints were toxicity/quality of life, change in bone density, and mammographic density.Results: A total of 75/950 (7.9%) women approached agreed to randomization. In the T-arm, 20 of 38 (52%) of women completed the 2-year period of study compared with the C-arm (27/37, 73.0%). Dropouts were related to toxicity but also the wish to have established risk-reducing procedures and proven chemoprevention. As relatively few women completed the study, data are limited, but those in the T-arm reported significant increases in toxicity and sexual problems, no change in anxiety, and less cancer worry. Lumbar spine bone density declined by 7.0% and visually assessed mammographic density by 4.7% over the 2-year treatment period.Conclusions: Uptake is somewhat lower than comparable studies with tamoxifen for prevention with higher dropout rates. Raloxifene may preserve bone density, but reduction in mammographic density reversed after treatment was completed.Impact: This study indicates that breast cancer risk reduction may be possible using LHRH agonists, but reducing toxicity and preventing bone changes would make this a more attractive option. Cancer Epidemiol Biomarkers Prev; 27(1); 58-66. ©2017 AACR..
Eeles, R.
Ni Raghallaigh, H.
(2018). Men with a susceptibility to prostate cancer and the role of genetic based screening. Transl androl urol,
Vol.7
(1),
pp. 61-69.
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full text
Prostate cancer is the second most common malignancy affecting men worldwide, and the commonest affecting men of African descent. Significant diagnostic and therapeutic advances have been made in the past decade. Improvements in the accuracy of prostate cancer diagnosis include the uptake of multi-parametric MRI and a shift towards targeted biopsy. We also now have more life-prolonging systemic and hormonal therapies for men with advanced disease at our disposal than ever before. However, the development of robust screening tools and targeted screening programs has not followed at the same pace. Evidence to support population-based screening remains unclear, with the use of PSA as a screening test limiting our ability to discriminate between clinically significant and insignificant disease. Prostate cancer has a large heritable component. Given that most men without risk factors have a low lifetime risk of developing lethal prostate cancer, much work is being done to further our knowledge of how we can best screen men in higher risk categories, such as those with a family history (FH) of the disease or those of African ancestry. These men have been reported to carry upwards of a two-fold increased risk of developing the disease at an earlier age, with evidence suggesting poorer survival outcomes. In men with a FH of prostate cancer, this is felt to be due to rare, high-penetrance mutations and the presence of multiple, common low penetrance alleles, with men carrying specific germline mutations in the BRCA and other DNA repair genes at particularly high risk. To date, large scale genome-wide association studies (GWAS) have led to the discovery of approximately 170 single nucleotide polymorphisms (SNPs) associated with prostate cancer risk, allowing over 30% of prostate cancer risk to be explained. Genomic tests, utilising somatic (prostate biopsy) tissue can also predict the risk of unfavourable pathology, biochemical recurrence and the likelihood of metastatic disease using gene expression. Targeted screening studies are currently under way in men with DNA repair mutations, men with a FH and those of Afro-Caribbean ethnicity which will greater inform our understanding of disease incidence and behaviour in these men, treatment outcomes and developing the most appropriate screening regime for such men. Incorporating a patient's genetic mutation status into risk algorithms allows us an opportunity to develop targeted screening programs for men in whom early cancer detection and treatment will positively influence survival, and in the process offer male family members of affected men the chance to be counselled and screened accordingly..
Copson, E.R.
Maishman, T.C.
Tapper, W.J.
Cutress, R.I.
Greville-Heygate, S.
Altman, D.G.
Eccles, B.
Gerty, S.
Durcan, L.T.
Jones, L.
Evans, D.G.
Thompson, A.M.
Pharoah, P.
Easton, D.F.
Dunning, A.M.
Hanby, A.
Lakhani, S.
Eeles, R.
Gilbert, F.J.
Hamed, H.
Hodgson, S.
Simmonds, P.
Stanton, L.
Eccles, D.M.
(2018). Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet oncol,
Vol.19
(2),
pp. 169-180.
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BACKGROUND: Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer. METHODS: We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing. FINDINGS: Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0-9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5-98·4] vs 96·6% [95·8-97·3]; at 5 years: 83·8% [79·3-87·5] vs 85·0% [83·5-86·4]; at 10 years: 73·4% [67·4-78·5] vs 70·1% [67·7-72·3]; hazard ratio [HR] 0·96 [95% CI 0·76-1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89-97] vs 91% [88-94]; HR 0·59 [95% CI 0·35-0·99]; p=0·047) but not 5 years (81% [73-87] vs 74% [70-78]; HR 1·13 [0·70-1·84]; p=0·62) or 10 years (72% [62-80] vs 69% [63-74]; HR 2·12 [0·82-5·49]; p= 0·12). INTERPRETATION: Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences. FUNDING: Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant..
Gillessen, S.
Attard, G.
Beer, T.M.
Beltran, H.
Bossi, A.
Bristow, R.
Carver, B.
Castellano, D.
Chung, B.H.
Clarke, N.
Daugaard, G.
Davis, I.D.
de Bono, J.
Borges Dos Reis, R.
Drake, C.G.
Eeles, R.
Efstathiou, E.
Evans, C.P.
Fanti, S.
Feng, F.
Fizazi, K.
Frydenberg, M.
Gleave, M.
Halabi, S.
Heidenreich, A.
Higano, C.S.
James, N.
Kantoff, P.
Kellokumpu-Lehtinen, P.-.
Khauli, R.B.
Kramer, G.
Logothetis, C.
Maluf, F.
Morgans, A.K.
Morris, M.J.
Mottet, N.
Murthy, V.
Oh, W.
Ost, P.
Padhani, A.R.
Parker, C.
Pritchard, C.C.
Roach, M.
Rubin, M.A.
Ryan, C.
Saad, F.
Sartor, O.
Scher, H.
Sella, A.
Shore, N.
Smith, M.
Soule, H.
Sternberg, C.N.
Suzuki, H.
Sweeney, C.
Sydes, M.R.
Tannock, I.
Tombal, B.
Valdagni, R.
Wiegel, T.
Omlin, A.
(2018). Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. Eur urol,
Vol.73
(2),
pp. 178-211.
show abstract
full text
BACKGROUND: In advanced prostate cancer (APC), successful drug development as well as advances in imaging and molecular characterisation have resulted in multiple areas where there is lack of evidence or low level of evidence. The Advanced Prostate Cancer Consensus Conference (APCCC) 2017 addressed some of these topics. OBJECTIVE: To present the report of APCCC 2017. DESIGN, SETTING, AND PARTICIPANTS: Ten important areas of controversy in APC management were identified: high-risk localised and locally advanced prostate cancer; "oligometastatic" prostate cancer; castration-naïve and castration-resistant prostate cancer; the role of imaging in APC; osteoclast-targeted therapy; molecular characterisation of blood and tissue; genetic counselling/testing; side effects of systemic treatment(s); global access to prostate cancer drugs. A panel of 60 international prostate cancer experts developed the program and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 150 predefined questions, which have been developed following a modified Delphi process. RESULTS AND LIMITATIONS: Voting is based on panellist opinion, and thus is not based on a standard literature review or meta-analysis. The outcomes of the voting had varying degrees of support, as reflected in the wording of this article, as well as in the detailed voting results recorded in Supplementary data. CONCLUSIONS: The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available, including disease extent and location, prior therapies regardless of type, host factors including comorbidities, as well as patient preferences, current and emerging evidence, and logistical and economic constraints. Inclusion of men with APC in clinical trials should be strongly encouraged. Importantly, APCCC 2017 again identified important areas in need of trials specifically designed to address them. PATIENT SUMMARY: The second Advanced Prostate Cancer Consensus Conference APCCC 2017 did provide a forum for discussion and debates on current treatment options for men with advanced prostate cancer. The aim of the conference is to bring the expertise of world experts to care givers around the world who see less patients with prostate cancer. The conference concluded with a discussion and voting of the expert panel on predefined consensus questions, targeting areas of primary clinical relevance. The results of these expert opinion votes are embedded in the clinical context of current treatment of men with advanced prostate cancer and provide a practical guide to clinicians to assist in the discussions with men with prostate cancer as part of a shared and multidisciplinary decision-making process..
Dias, A.
Kote-Jarai, Z.
Mikropoulos, C.
Eeles, R.
(2018). Prostate Cancer Germline Variations and Implications for Screening and Treatment. Cold spring harb perspect med,
Vol.8
(9).
show abstract
full text
Prostate cancer (PCa) is a highly heritable disease, and rapid evolution of sequencing technologies has enabled marked progression of our understanding of its genetic inheritance. A complex polygenic model that involves common low-penetrance susceptibility alleles causing individually small but cumulatively significant risk and rarer genetic variants causing greater risk represent the current most accepted model. Through genome-wide association studies, more than 100 single-nucleotide polymorphisms (SNPs) associated with PCa risk have been identified. Consistent reports have identified germline mutations in the genes BRCA1, BRCA2, MMR, HOXB13, CHEK2, and NBS1 as conferring moderate risks, with some leading to a more aggressive disease behavior. Considering this knowledge, several research strategies have been developed to determine whether targeted prostate screening using genetic information can overcome the limitations of population-based prostate-specific antigen (PSA) screening. Germline DNA-repair mutations are more frequent in men with metastatic disease than previously thought, and these patients have a more favorable response to therapy with poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors. Genomic information is a practical tool that has the potential to enable the concept of precision medicine to become a reality in all steps of PCa patient care..
Schrijver, L.H.
Olsson, H.
Phillips, K.-.
Terry, M.B.
Goldgar, D.E.
Kast, K.
Engel, C.
Mooij, T.M.
Adlard, J.
Barrowdale, D.
Davidson, R.
Eeles, R.
Ellis, S.
Evans, D.G.
Frost, D.
Izatt, L.
Porteous, M.E.
Side, L.E.
Walker, L.
Berthet, P.
Bonadona, V.
Leroux, D.
Mouret-Fourme, E.
Venat-Bouvet, L.
Buys, S.S.
Southey, M.C.
John, E.M.
Chung, W.K.
Daly, M.B.
Bane, A.
van Asperen, C.J.
Gómez Garcia, E.B.
Mourits, M.J.
van Os, T.A.
Roos-Blom, M.-.
Friedlander, M.L.
McLachlan, S.-.
Singer, C.F.
Tan, Y.Y.
Foretova, L.
Navratilova, M.
Gerdes, A.-.
Caldes, T.
Simard, J.
Olah, E.
Jakubowska, A.
Arver, B.
Osorio, A.
Noguès, C.
Andrieu, N.
Easton, D.F.
van Leeuwen, F.E.
Hopper, J.L.
Milne, R.L.
Antoniou, A.C.
Rookus, M.A.
EMBRACE, GENEPSO, BCFR, HEBON, kConFab, and IBCCS,
(2018). Oral Contraceptive Use and Breast Cancer Risk: Retrospective and Prospective Analyses From a BRCA1 and BRCA2 Mutation Carrier Cohort Study. Jnci cancer spectr,
Vol.2
(2),
p. pky023.
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BACKGROUND: For BRCA1 and BRCA2 mutation carriers, the association between oral contraceptive preparation (OCP) use and breast cancer (BC) risk is still unclear. METHODS: Breast camcer risk associations were estimated from OCP data on 6030 BRCA1 and 3809 BRCA2 mutation carriers using age-dependent Cox regression, stratified by study and birth cohort. Prospective, left-truncated retrospective and full-cohort retrospective analyses were performed. RESULTS: For BRCA1 mutation carriers, OCP use was not associated with BC risk in prospective analyses (hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 0.75 to 1.56), but in the left-truncated and full-cohort retrospective analyses, risks were increased by 26% (95% CI = 6% to 51%) and 39% (95% CI = 23% to 58%), respectively. For BRCA2 mutation carriers, OCP use was associated with BC risk in prospective analyses (HR = 1.75, 95% CI = 1.03 to 2.97), but retrospective analyses were inconsistent (left-truncated: HR = 1.06, 95% CI = 0.85 to 1.33; full cohort: HR = 1.52, 95% CI = 1.28 to 1.81). There was evidence of increasing risk with duration of use, especially before the first full-term pregnancy (BRCA1: both retrospective analyses, P < .001 and P = .001, respectively; BRCA2: full retrospective analysis, P = .002). CONCLUSIONS: Prospective analyses did not show that past use of OCP is associated with an increased BC risk for BRCA1 mutation carriers in young middle-aged women (40-50 years). For BRCA2 mutation carriers, a causal association is also not likely at those ages. Findings between retrospective and prospective analyses were inconsistent and could be due to survival bias or a true association for younger women who were underrepresented in the prospective cohort. Given the uncertain safety of long-term OCP use for BRCA1/2 mutation carriers, indications other than contraception should be avoided and nonhormonal contraceptive methods should be discussed..
Mancuso, N.
Gayther, S.
Gusev, A.
Zheng, W.
Penney, K.L.
Kote-Jarai, Z.
Eeles, R.
Freedman, M.
Haiman, C.
Pasaniuc, B.
PRACTICAL consortium,
(2018). Large-scale transcriptome-wide association study identifies new prostate cancer risk regions. Nat commun,
Vol.9
(1),
p. 4079.
show abstract
full text
Although genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here we integrate the largest PrCa GWAS (N = 142,392) with gene expression measured in 45 tissues (N = 4458), including normal and tumor prostate, to perform a multi-tissue transcriptome-wide association study (TWAS) for PrCa. We identify 217 genes at 84 independent 1 Mb regions associated with PrCa risk, 9 of which are regions with no genome-wide significant SNP within 2 Mb. 23 genes are significant in TWAS only for alternative splicing models in prostate tumor thus supporting the hypothesis of splicing driving risk for continued oncogenesis. Finally, we use a Bayesian probabilistic approach to estimate credible sets of genes containing the causal gene at a pre-defined level; this reduced the list of 217 associations to 109 genes in the 90% credible set. Overall, our findings highlight the power of integrating expression with PrCa GWAS to identify novel risk loci and prioritize putative causal genes at known risk loci..
Rebbeck, T.R.
Friebel, T.M.
Friedman, E.
Hamann, U.
Huo, D.
Kwong, A.
Olah, E.
Olopade, O.I.
Solano, A.R.
Teo, S.-.
Thomassen, M.
Weitzel, J.N.
Chan, T.L.
Couch, F.J.
Goldgar, D.E.
Kruse, T.A.
Palmero, E.I.
Park, S.K.
Torres, D.
van Rensburg, E.J.
McGuffog, L.
Parsons, M.T.
Leslie, G.
Aalfs, C.M.
Abugattas, J.
Adlard, J.
Agata, S.
Aittomäki, K.
Andrews, L.
Andrulis, I.L.
Arason, A.
Arnold, N.
Arun, B.K.
Asseryanis, E.
Auerbach, L.
Azzollini, J.
Balmaña, J.
Barile, M.
Barkardottir, R.B.
Barrowdale, D.
Benitez, J.
Berger, A.
Berger, R.
Blanco, A.M.
Blazer, K.R.
Blok, M.J.
Bonadona, V.
Bonanni, B.
Bradbury, A.R.
Brewer, C.
Buecher, B.
Buys, S.S.
Caldes, T.
Caliebe, A.
Caligo, M.A.
Campbell, I.
Caputo, S.M.
Chiquette, J.
Chung, W.K.
Claes, K.B.
Collée, J.M.
Cook, J.
Davidson, R.
de la Hoya, M.
De Leeneer, K.
de Pauw, A.
Delnatte, C.
Diez, O.
Ding, Y.C.
Ditsch, N.
Domchek, S.M.
Dorfling, C.M.
Velazquez, C.
Dworniczak, B.
Eason, J.
Easton, D.F.
Eeles, R.
Ehrencrona, H.
Ejlertsen, B.
EMBRACE,
Engel, C.
Engert, S.
Evans, D.G.
Faivre, L.
Feliubadaló, L.
Ferrer, S.F.
Foretova, L.
Fowler, J.
Frost, D.
Galvão, H.C.
Ganz, P.A.
Garber, J.
Gauthier-Villars, M.
Gehrig, A.
GEMO Study Collaborators,
Gerdes, A.-.
Gesta, P.
Giannini, G.
Giraud, S.
Glendon, G.
Godwin, A.K.
Greene, M.H.
Gronwald, J.
Gutierrez-Barrera, A.
Hahnen, E.
Hauke, J.
HEBON,
Henderson, A.
Hentschel, J.
Hogervorst, F.B.
Honisch, E.
Imyanitov, E.N.
Isaacs, C.
Izatt, L.
Izquierdo, A.
Jakubowska, A.
James, P.
Janavicius, R.
Jensen, U.B.
John, E.M.
Vijai, J.
Kaczmarek, K.
Karlan, B.Y.
Kast, K.
Investigators, K.
Kim, S.-.
Konstantopoulou, I.
Korach, J.
Laitman, Y.
Lasa, A.
Lasset, C.
Lázaro, C.
Lee, A.
Lee, M.H.
Lester, J.
Lesueur, F.
Liljegren, A.
Lindor, N.M.
Longy, M.
Loud, J.T.
Lu, K.H.
Lubinski, J.
Machackova, E.
Manoukian, S.
Mari, V.
Martínez-Bouzas, C.
Matrai, Z.
Mebirouk, N.
Meijers-Heijboer, H.E.
Meindl, A.
Mensenkamp, A.R.
Mickys, U.
Miller, A.
Montagna, M.
Moysich, K.B.
Mulligan, A.M.
Musinsky, J.
Neuhausen, S.L.
Nevanlinna, H.
Ngeow, J.
Nguyen, H.P.
Niederacher, D.
Nielsen, H.R.
Nielsen, F.C.
Nussbaum, R.L.
Offit, K.
Öfverholm, A.
Ong, K.-.
Osorio, A.
Papi, L.
Papp, J.
Pasini, B.
Pedersen, I.S.
Peixoto, A.
Peruga, N.
Peterlongo, P.
Pohl, E.
Pradhan, N.
Prajzendanc, K.
Prieur, F.
Pujol, P.
Radice, P.
Ramus, S.J.
Rantala, J.
Rashid, M.U.
Rhiem, K.
Robson, M.
Rodriguez, G.C.
Rogers, M.T.
Rudaitis, V.
Schmidt, A.Y.
Schmutzler, R.K.
Senter, L.
Shah, P.D.
Sharma, P.
Side, L.E.
Simard, J.
Singer, C.F.
Skytte, A.-.
Slavin, T.P.
Snape, K.
Sobol, H.
Southey, M.
Steele, L.
Steinemann, D.
Sukiennicki, G.
Sutter, C.
Szabo, C.I.
Tan, Y.Y.
Teixeira, M.R.
Terry, M.B.
Teulé, A.
Thomas, A.
Thull, D.L.
Tischkowitz, M.
Tognazzo, S.
Toland, A.E.
Topka, S.
Trainer, A.H.
Tung, N.
van Asperen, C.J.
van der Hout, A.H.
van der Kolk, L.E.
van der Luijt, R.B.
Van Heetvelde, M.
Varesco, L.
Varon-Mateeva, R.
Vega, A.
Villarreal-Garza, C.
von Wachenfeldt, A.
Walker, L.
Wang-Gohrke, S.
Wappenschmidt, B.
Weber, B.H.
Yannoukakos, D.
Yoon, S.-.
Zanzottera, C.
Zidan, J.
Zorn, K.K.
Hutten Selkirk, C.G.
Hulick, P.J.
Chenevix-Trench, G.
Spurdle, A.B.
Antoniou, A.C.
Nathanson, K.L.
(2018). Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum mutat,
Vol.39
(5),
pp. 593-620.
show abstract
full text
The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations..
Wedge, D.C.
Gundem, G.
Mitchell, T.
Woodcock, D.J.
Martincorena, I.
Ghori, M.
Zamora, J.
Butler, A.
Whitaker, H.
Kote-Jarai, Z.
Alexandrov, L.B.
Van Loo, P.
Massie, C.E.
Dentro, S.
Warren, A.Y.
Verrill, C.
Berney, D.M.
Dennis, N.
Merson, S.
Hawkins, S.
Howat, W.
Lu, Y.-.
Lambert, A.
Kay, J.
Kremeyer, B.
Karaszi, K.
Luxton, H.
Camacho, N.
Marsden, L.
Edwards, S.
Matthews, L.
Bo, V.
Leongamornlert, D.
McLaren, S.
Ng, A.
Yu, Y.
Zhang, H.
Dadaev, T.
Thomas, S.
Easton, D.F.
Ahmed, M.
Bancroft, E.
Fisher, C.
Livni, N.
Nicol, D.
Tavaré, S.
Gill, P.
Greenman, C.
Khoo, V.
Van As, N.
Kumar, P.
Ogden, C.
Cahill, D.
Thompson, A.
Mayer, E.
Rowe, E.
Dudderidge, T.
Gnanapragasam, V.
Shah, N.C.
Raine, K.
Jones, D.
Menzies, A.
Stebbings, L.
Teague, J.
Hazell, S.
Corbishley, C.
CAMCAP Study Group,
de Bono, J.
Attard, G.
Isaacs, W.
Visakorpi, T.
Fraser, M.
Boutros, P.C.
Bristow, R.G.
Workman, P.
Sander, C.
TCGA Consortium,
Hamdy, F.C.
Futreal, A.
McDermott, U.
Al-Lazikani, B.
Lynch, A.G.
Bova, G.S.
Foster, C.S.
Brewer, D.S.
Neal, D.E.
Cooper, C.S.
Eeles, R.A.
(2018). Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets. Nat genet,
Vol.50
(5),
pp. 682-692.
show abstract
full text
Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials..
Matejcic, M.
Saunders, E.J.
Dadaev, T.
Brook, M.N.
Wang, K.
Sheng, X.
Olama, A.A.
Schumacher, F.R.
Ingles, S.A.
Govindasami, K.
Benlloch, S.
Berndt, S.I.
Albanes, D.
Koutros, S.
Muir, K.
Stevens, V.L.
Gapstur, S.M.
Tangen, C.M.
Batra, J.
Clements, J.
Gronberg, H.
Pashayan, N.
Schleutker, J.
Wolk, A.
West, C.
Mucci, L.
Kraft, P.
Cancel-Tassin, G.
Sorensen, K.D.
Maehle, L.
Grindedal, E.M.
Strom, S.S.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Travis, R.C.
Hamilton, R.J.
Rosenstein, B.
Lu, Y.-.
Giles, G.G.
Kibel, A.S.
Vega, A.
Bensen, J.T.
Kogevinas, M.
Penney, K.L.
Park, J.Y.
Stanford, J.L.
Cybulski, C.
Nordestgaard, B.G.
Brenner, H.
Maier, C.
Kim, J.
Teixeira, M.R.
Neuhausen, S.L.
De Ruyck, K.
Razack, A.
Newcomb, L.F.
Lessel, D.
Kaneva, R.
Usmani, N.
Claessens, F.
Townsend, P.A.
Gago-Dominguez, M.
Roobol, M.J.
Menegaux, F.
Khaw, K.-.
Cannon-Albright, L.A.
Pandha, H.
Thibodeau, S.N.
Schaid, D.J.
PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium,
Wiklund, F.
Chanock, S.J.
Easton, D.F.
Eeles, R.A.
Kote-Jarai, Z.
Conti, D.V.
Haiman, C.A.
(2018). Germline variation at 8q24 and prostate cancer risk in men of European ancestry. Nat commun,
Vol.9
(1),
p. 4616.
show abstract
full text
Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification..
FitzGerald, L.M.
Zhao, S.
Leonardson, A.
Geybels, M.S.
Kolb, S.
Lin, D.W.
Wright, J.L.
Eeles, R.
Kote-Jarai, Z.
Govindasami, K.
Giles, G.G.
Southey, M.C.
Schleutker, J.
Tammela, T.L.
Sipeky, C.
Penney, K.L.
Stampfer, M.J.
Gronberg, H.
Wiklund, F.
Stattin, P.
Hugosson, J.
Karyadi, D.M.
Ostrander, E.A.
Feng, Z.
Stanford, J.L.
(2018). Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases. Prostate cancer prostatic dis,
Vol.21
(2),
pp. 228-237.
show abstract
full text
BACKGROUND: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. METHODS: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. RESULTS: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). CONCLUSIONS: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness..
Mijuskovic, M.
Saunders, E.J.
Leongamornlert, D.A.
Wakerell, S.
Whitmore, I.
Dadaev, T.
Cieza-Borrella, C.
Govindasami, K.
Brook, M.N.
Haiman, C.A.
Conti, D.V.
Eeles, R.A.
Kote-Jarai, Z.
(2018). Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease. Br j cancer,
Vol.119
(1),
pp. 96-104.
show abstract
full text
BACKGROUND: Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes. METHODS: We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants. RESULTS: Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects. CONCLUSIONS: Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application..
Schumacher, F.R.
Al Olama, A.A.
Berndt, S.I.
Benlloch, S.
Ahmed, M.
Saunders, E.J.
Dadaev, T.
Leongamornlert, D.
Anokian, E.
Cieza-Borrella, C.
Goh, C.
Brook, M.N.
Sheng, X.
Fachal, L.
Dennis, J.
Tyrer, J.
Muir, K.
Lophatananon, A.
Stevens, V.L.
Gapstur, S.M.
Carter, B.D.
Tangen, C.M.
Goodman, P.J.
Thompson, I.M.
Batra, J.
Chambers, S.
Moya, L.
Clements, J.
Horvath, L.
Tilley, W.
Risbridger, G.P.
Gronberg, H.
Aly, M.
Nordström, T.
Pharoah, P.
Pashayan, N.
Schleutker, J.
Tammela, T.L.
Sipeky, C.
Auvinen, A.
Albanes, D.
Weinstein, S.
Wolk, A.
Håkansson, N.
West, C.M.
Dunning, A.M.
Burnet, N.
Mucci, L.A.
Giovannucci, E.
Andriole, G.L.
Cussenot, O.
Cancel-Tassin, G.
Koutros, S.
Beane Freeman, L.E.
Sorensen, K.D.
Orntoft, T.F.
Borre, M.
Maehle, L.
Grindedal, E.M.
Neal, D.E.
Donovan, J.L.
Hamdy, F.C.
Martin, R.M.
Travis, R.C.
Key, T.J.
Hamilton, R.J.
Fleshner, N.E.
Finelli, A.
Ingles, S.A.
Stern, M.C.
Rosenstein, B.S.
Kerns, S.L.
Ostrer, H.
Lu, Y.-.
Zhang, H.-.
Feng, N.
Mao, X.
Guo, X.
Wang, G.
Sun, Z.
Giles, G.G.
Southey, M.C.
MacInnis, R.J.
FitzGerald, L.M.
Kibel, A.S.
Drake, B.F.
Vega, A.
Gómez-Caamaño, A.
Szulkin, R.
Eklund, M.
Kogevinas, M.
Llorca, J.
Castaño-Vinyals, G.
Penney, K.L.
Stampfer, M.
Park, J.Y.
Sellers, T.A.
Lin, H.-.
Stanford, J.L.
Cybulski, C.
Wokolorczyk, D.
Lubinski, J.
Ostrander, E.A.
Geybels, M.S.
Nordestgaard, B.G.
Nielsen, S.F.
Weischer, M.
Bisbjerg, R.
Røder, M.A.
Iversen, P.
Brenner, H.
Cuk, K.
Holleczek, B.
Maier, C.
Luedeke, M.
Schnoeller, T.
Kim, J.
Logothetis, C.J.
John, E.M.
Teixeira, M.R.
Paulo, P.
Cardoso, M.
Neuhausen, S.L.
Steele, L.
Ding, Y.C.
De Ruyck, K.
De Meerleer, G.
Ost, P.
Razack, A.
Lim, J.
Teo, S.-.
Lin, D.W.
Newcomb, L.F.
Lessel, D.
Gamulin, M.
Kulis, T.
Kaneva, R.
Usmani, N.
Singhal, S.
Slavov, C.
Mitev, V.
Parliament, M.
Claessens, F.
Joniau, S.
Van den Broeck, T.
Larkin, S.
Townsend, P.A.
Aukim-Hastie, C.
Gago-Dominguez, M.
Castelao, J.E.
Martinez, M.E.
Roobol, M.J.
Jenster, G.
van Schaik, R.H.
Menegaux, F.
Truong, T.
Koudou, Y.A.
Xu, J.
Khaw, K.-.
Cannon-Albright, L.
Pandha, H.
Michael, A.
Thibodeau, S.N.
McDonnell, S.K.
Schaid, D.J.
Lindstrom, S.
Turman, C.
Ma, J.
Hunter, D.J.
Riboli, E.
Siddiq, A.
Canzian, F.
Kolonel, L.N.
Le Marchand, L.
Hoover, R.N.
Machiela, M.J.
Cui, Z.
Kraft, P.
Amos, C.I.
Conti, D.V.
Easton, D.F.
Wiklund, F.
Chanock, S.J.
Henderson, B.E.
Kote-Jarai, Z.
Haiman, C.A.
Eeles, R.A.
Profile Study,
Australian Prostate Cancer BioResource (APCB),
IMPACT Study,
Canary PASS Investigators,
Breast and Prostate Cancer Cohort Consortium (BPC3),
PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium,
Cancer of the Prostate in Sweden (CAPS),
Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci (PEGASUS),
Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium,
(2018). Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nat genet,
Vol.50
(7),
pp. 928-936.
show abstract
full text
Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1..
Benafif, S.
Kote-Jarai, Z.
Eeles, R.A.
PRACTICAL Consortium,
(2018). A Review of Prostate Cancer Genome-Wide Association Studies (GWAS). Cancer epidemiol biomarkers prev,
Vol.27
(8),
pp. 845-857.
show abstract
full text
Prostate cancer is the most common cancer in men in Europe and the United States. The genetic heritability of prostate cancer is contributed to by both rarely occurring genetic variants with higher penetrance and moderate to commonly occurring variants conferring lower risks. The number of identified variants belonging to the latter category has increased dramatically in the last 10 years with the development of the genome-wide association study (GWAS) and the collaboration of international consortia that have led to the sharing of large-scale genotyping data. Over 40 prostate cancer GWAS have been reported, with approximately 170 common variants now identified. Clinical utility of these variants could include strategies for population-based risk stratification to target prostate cancer screening to men with an increased genetic risk of disease development, while for those who develop prostate cancer, identifying genetic variants could allow treatment to be tailored based on a genetic profile in the early disease setting. Functional studies of identified variants are needed to fully understand underlying mechanisms of disease and identify novel targets for treatment. This review will outline the GWAS carried out in prostate cancer and the common variants identified so far, and how these may be utilized clinically in the screening for and management of prostate cancer. Cancer Epidemiol Biomarkers Prev; 27(8); 845-57. ©2018 AACR..
Sud, A.
Thomsen, H.
Orlando, G.
Försti, A.
Law, P.J.
Broderick, P.
Cooke, R.
Hariri, F.
Pastinen, T.
Easton, D.F.
Pharoah, P.D.
Dunning, A.M.
Peto, J.
Canzian, F.
Eeles, R.
Kote-Jarai, Z.
Muir, K.
Pashayan, N.
Campa, D.
PRACTICAL Consortium,
Hoffmann, P.
Nöthen, M.M.
Jöckel, K.-.
von Strandmann, E.P.
Swerdlow, A.J.
Engert, A.
Orr, N.
Hemminki, K.
Houlston, R.S.
(2018). Genome-wide association study implicates immune dysfunction in the development of Hodgkin lymphoma. Blood,
Vol.132
(19),
pp. 2040-2052.
show abstract
full text
To further our understanding of inherited susceptibility to Hodgkin lymphoma (HL), we performed a meta-analysis of 7 genome-wide association studies totaling 5325 HL cases and 22 423 control patients. We identify 5 new HL risk loci at 6p21.31 (rs649775; P = 2.11 × 10-10), 6q23.3 (rs1002658; P = 2.97 × 10-8), 11q23.1 (rs7111520; P = 1.44 × 10-11), 16p11.2 (rs6565176; P = 4.00 × 10-8), and 20q13.12 (rs2425752; P = 2.01 × 10-8). Integration of gene expression, histone modification, and in situ promoter capture Hi-C data at the 5 new and 13 known risk loci implicates dysfunction of the germinal center reaction, disrupted T-cell differentiation and function, and constitutive NF-κB activation as mechanisms of predisposition. These data provide further insights into the genetic susceptibility and biology of HL..
Loveday, C.
Law, P.
Litchfield, K.
Levy, M.
Holroyd, A.
Broderick, P.
Kote-Jarai, Z.
Dunning, A.M.
Muir, K.
Peto, J.
Eeles, R.
Easton, D.F.
Dudakia, D.
Orr, N.
Pashayan, N.
UK Testicular Cancer Collaboration, The PRACTICAL Consortium,
Reid, A.
Huddart, R.A.
Houlston, R.S.
Turnbull, C.
(2018). Large-scale Analysis Demonstrates Familial Testicular Cancer to have Polygenic Aetiology. Eur urol,
Vol.74
(3),
pp. 248-252.
show abstract
full text
UNLABELLED: Testicular germ cell tumour (TGCT) is the most common cancer in young men. Multiplex TGCT families have been well reported and analyses of population cancer registries have demonstrated a four- to eightfold risk to male relatives of TGCT patients. Early linkage analysis and recent large-scale germline exome analysis in TGCT cases demonstrate absence of major high-penetrance TGCT susceptibility gene(s). Serial genome-wide association study analyses in sporadic TGCT have in total reported 49 independent risk loci. To date, it has not been demonstrated whether familial TGCT arises due to enrichment of the same common variants underpinning susceptibility to sporadic TGCT or is due to shared environmental/lifestyle factors or disparate rare genetic TGCT susceptibility factors. Here we present polygenic risk score analysis of 37 TGCT susceptibility single-nucleotide polymorphisms in 236 familial and 3931 sporadic TGCT cases, and 12 368 controls, which demonstrates clear enrichment for TGCT susceptibility alleles in familial compared to sporadic cases (p=0.0001), with the majority of familial cases (84-100%) being attributable to polygenic enrichment. These analyses reveal TGCT as the first rare malignancy of early adulthood in which familial clustering is driven by the aggregate effects of polygenic variation in the absence of a major high-penetrance susceptibility gene. PATIENT SUMMARY: To date, it has been unclear whether familial clusters of testicular germ cell tumour (TGCT) arise due to genetics or shared environmental or lifestyle factors. We present large-scale genetic analyses comparing 236 familial TGCT cases, 3931 isolated TGCT cases, and 12 368 controls. We show that familial TGCT is caused, at least in part, by presence of a higher dose of the same common genetic variants that cause susceptibility to TGCT in general..
Vijayakrishnan, J.
Studd, J.
Broderick, P.
Kinnersley, B.
Holroyd, A.
Law, P.J.
Kumar, R.
Allan, J.M.
Harrison, C.J.
Moorman, A.V.
Vora, A.
Roman, E.
Rachakonda, S.
Kinsey, S.E.
Sheridan, E.
Thompson, P.D.
Irving, J.A.
Koehler, R.
Hoffmann, P.
Nöthen, M.M.
Heilmann-Heimbach, S.
Jöckel, K.-.
Easton, D.F.
Pharaoh, P.D.
Dunning, A.M.
Peto, J.
Canzian, F.
Swerdlow, A.
Eeles, R.A.
Kote-Jarai, Z.
Muir, K.
Pashayan, N.
PRACTICAL Consortium,
Greaves, M.
Zimmerman, M.
Bartram, C.R.
Schrappe, M.
Stanulla, M.
Hemminki, K.
Houlston, R.S.
(2018). Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia. Nat commun,
Vol.9
(1),
p. 1340.
show abstract
full text
Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology..
Seibert, T.M.
Fan, C.C.
Wang, Y.
Zuber, V.
Karunamuni, R.
Parsons, J.K.
Eeles, R.A.
Easton, D.F.
Kote-Jarai, Z.
Al Olama, A.A.
Garcia, S.B.
Muir, K.
Grönberg, H.
Wiklund, F.
Aly, M.
Schleutker, J.
Sipeky, C.
Tammela, T.L.
Nordestgaard, B.G.
Nielsen, S.F.
Weischer, M.
Bisbjerg, R.
Røder, M.A.
Iversen, P.
Key, T.J.
Travis, R.C.
Neal, D.E.
Donovan, J.L.
Hamdy, F.C.
Pharoah, P.
Pashayan, N.
Khaw, K.-.
Maier, C.
Vogel, W.
Luedeke, M.
Herkommer, K.
Kibel, A.S.
Cybulski, C.
Wokolorczyk, D.
Kluzniak, W.
Cannon-Albright, L.
Brenner, H.
Cuk, K.
Saum, K.-.
Park, J.Y.
Sellers, T.A.
Slavov, C.
Kaneva, R.
Mitev, V.
Batra, J.
Clements, J.A.
Spurdle, A.
Teixeira, M.R.
Paulo, P.
Maia, S.
Pandha, H.
Michael, A.
Kierzek, A.
Karow, D.S.
Mills, I.G.
Andreassen, O.A.
Dale, A.M.
PRACTICAL Consortium*,
(2018). Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts. Bmj,
Vol.360,
pp. j5757-j5757.
show abstract
full text
OBJECTIVES: To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. DESIGN: Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. SETTING: Multiple institutions that were members of international PRACTICAL consortium. PARTICIPANTS: All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. MAIN OUTCOME MEASURES: Prediction with hazard score of age of onset of aggressive cancer in validation set. RESULTS: In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10-16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. CONCLUSIONS: Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa..
Dadaev, T.
Saunders, E.J.
Newcombe, P.J.
Anokian, E.
Leongamornlert, D.A.
Brook, M.N.
Cieza-Borrella, C.
Mijuskovic, M.
Wakerell, S.
Olama, A.A.
Schumacher, F.R.
Berndt, S.I.
Benlloch, S.
Ahmed, M.
Goh, C.
Sheng, X.
Zhang, Z.
Muir, K.
Govindasami, K.
Lophatananon, A.
Stevens, V.L.
Gapstur, S.M.
Carter, B.D.
Tangen, C.M.
Goodman, P.
Thompson, I.M.
Batra, J.
Chambers, S.
Moya, L.
Clements, J.
Horvath, L.
Tilley, W.
Risbridger, G.
Gronberg, H.
Aly, M.
Nordström, T.
Pharoah, P.
Pashayan, N.
Schleutker, J.
Tammela, T.L.
Sipeky, C.
Auvinen, A.
Albanes, D.
Weinstein, S.
Wolk, A.
Hakansson, N.
West, C.
Dunning, A.M.
Burnet, N.
Mucci, L.
Giovannucci, E.
Andriole, G.
Cussenot, O.
Cancel-Tassin, G.
Koutros, S.
Freeman, L.E.
Sorensen, K.D.
Orntoft, T.F.
Borre, M.
Maehle, L.
Grindedal, E.M.
Neal, D.E.
Donovan, J.L.
Hamdy, F.C.
Martin, R.M.
Travis, R.C.
Key, T.J.
Hamilton, R.J.
Fleshner, N.E.
Finelli, A.
Ingles, S.A.
Stern, M.C.
Rosenstein, B.
Kerns, S.
Ostrer, H.
Lu, Y.-.
Zhang, H.-.
Feng, N.
Mao, X.
Guo, X.
Wang, G.
Sun, Z.
Giles, G.G.
Southey, M.C.
MacInnis, R.J.
FitzGerald, L.M.
Kibel, A.S.
Drake, B.F.
Vega, A.
Gómez-Caamaño, A.
Fachal, L.
Szulkin, R.
Eklund, M.
Kogevinas, M.
Llorca, J.
Castaño-Vinyals, G.
Penney, K.L.
Stampfer, M.
Park, J.Y.
Sellers, T.A.
Lin, H.-.
Stanford, J.L.
Cybulski, C.
Wokolorczyk, D.
Lubinski, J.
Ostrander, E.A.
Geybels, M.S.
Nordestgaard, B.G.
Nielsen, S.F.
Weisher, M.
Bisbjerg, R.
Røder, M.A.
Iversen, P.
Brenner, H.
Cuk, K.
Holleczek, B.
Maier, C.
Luedeke, M.
Schnoeller, T.
Kim, J.
Logothetis, C.J.
John, E.M.
Teixeira, M.R.
Paulo, P.
Cardoso, M.
Neuhausen, S.L.
Steele, L.
Ding, Y.C.
De Ruyck, K.
De Meerleer, G.
Ost, P.
Razack, A.
Lim, J.
Teo, S.-.
Lin, D.W.
Newcomb, L.F.
Lessel, D.
Gamulin, M.
Kulis, T.
Kaneva, R.
Usmani, N.
Slavov, C.
Mitev, V.
Parliament, M.
Singhal, S.
Claessens, F.
Joniau, S.
Van den Broeck, T.
Larkin, S.
Townsend, P.A.
Aukim-Hastie, C.
Gago-Dominguez, M.
Castelao, J.E.
Martinez, M.E.
Roobol, M.J.
Jenster, G.
van Schaik, R.H.
Menegaux, F.
Truong, T.
Koudou, Y.A.
Xu, J.
Khaw, K.-.
Cannon-Albright, L.
Pandha, H.
Michael, A.
Kierzek, A.
Thibodeau, S.N.
McDonnell, S.K.
Schaid, D.J.
Lindstrom, S.
Turman, C.
Ma, J.
Hunter, D.J.
Riboli, E.
Siddiq, A.
Canzian, F.
Kolonel, L.N.
Le Marchand, L.
Hoover, R.N.
Machiela, M.J.
Kraft, P.
PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium,
Freedman, M.
Wiklund, F.
Chanock, S.
Henderson, B.E.
Easton, D.F.
Haiman, C.A.
Eeles, R.A.
Conti, D.V.
Kote-Jarai, Z.
(2018). Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants. Nat commun,
Vol.9
(1),
p. 2256.
show abstract
full text
Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling..
Girardi, F.
Barnes, D.R.
Barrowdale, D.
Frost, D.
Brady, A.F.
Miller, C.
Henderson, A.
Donaldson, A.
Murray, A.
Brewer, C.
Pottinger, C.
Evans, D.G.
Eccles, D.
EMBRACE,
Lalloo, F.
Gregory, H.
Cook, J.
Eason, J.
Adlard, J.
Barwell, J.
Ong, K.R.
Walker, L.
Izatt, L.
Side, L.E.
Kennedy, M.J.
Tischkowitz, M.
Rogers, M.T.
Porteous, M.E.
Morrison, P.J.
Eeles, R.
Davidson, R.
Snape, K.
Easton, D.F.
Antoniou, A.C.
(2018). Risks of breast or ovarian cancer in BRCA1 or BRCA2 predictive test negatives: findings from the EMBRACE study. Genet med,
Vol.20
(12),
pp. 1575-1582.
show abstract
full text
PURPOSE: BRCA1/BRCA2 predictive test negatives are proven noncarriers of a BRCA1/BRCA2 mutation that is carried by their relatives. The risk of developing breast cancer (BC) or epithelial ovarian cancer (EOC) in these women is uncertain. The study aimed to estimate risks of invasive BC and EOC in a large cohort of BRCA1/BRCA2 predictive test negatives. METHODS: We used cohort analysis to estimate incidences, cumulative risks, and standardized incidence ratios (SIRs). RESULTS: A total of 1,895 unaffected women were eligible for inclusion in the BC risk analysis and 1,736 in the EOC risk analysis. There were 23 incident invasive BCs and 2 EOCs. The cumulative risk of invasive BC was 9.4% (95% confidence interval (CI) 5.9-15%) by age 85 years and the corresponding risk of EOC was 0.6% (95% CI 0.2-2.6%). The SIR for invasive BC was 0.93 (95% CI 0.62-1.40) in the overall cohort, 0.85 (95% CI 0.48-1.50) in noncarriers from BRCA1 families, and 1.03 (95% CI 0.57-1.87) in noncarriers from BRCA2 families. The SIR for EOC was 0.79 (95% CI 0.20-3.17) in the overall cohort. CONCLUSION: Our results did not provide evidence for elevated risks of invasive BC or EOC in BRCA1/BRCA2 predictive test negatives..
Luca, B.-.
Brewer, D.S.
Edwards, D.R.
Edwards, S.
Whitaker, H.C.
Merson, S.
Dennis, N.
Cooper, R.A.
Hazell, S.
Warren, A.Y.
CancerMap Group,
Eeles, R.
Lynch, A.G.
Ross-Adams, H.
Lamb, A.D.
Neal, D.E.
Sethia, K.
Mills, R.D.
Ball, R.Y.
Curley, H.
Clark, J.
Moulton, V.
Cooper, C.S.
(2018). DESNT: A Poor Prognosis Category of Human Prostate Cancer. Eur urol focus,
Vol.4
(6),
pp. 842-850.
show abstract
full text
BACKGROUND: A critical problem in the clinical management of prostate cancer is that it is highly heterogeneous. Accurate prediction of individual cancer behaviour is therefore not achievable at the time of diagnosis leading to substantial overtreatment. It remains an enigma that, in contrast to breast cancer, unsupervised analyses of global expression profiles have not currently defined robust categories of prostate cancer with distinct clinical outcomes. OBJECTIVE: To devise a novel classification framework for human prostate cancer based on unsupervised mathematical approaches. DESIGN, SETTING, AND PARTICIPANTS: Our analyses are based on the hypothesis that previous attempts to classify prostate cancer have been unsuccessful because individual samples of prostate cancer frequently have heterogeneous compositions. To address this issue, we applied an unsupervised Bayesian procedure called Latent Process Decomposition to four independent prostate cancer transcriptome datasets obtained using samples from prostatectomy patients and containing between 78 and 182 participants. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical failure was assessed using log-rank analysis and Cox regression analysis. RESULTS AND LIMITATIONS: Application of Latent Process Decomposition identified a common process in all four independent datasets examined. Cancers assigned to this process (designated DESNT cancers) are characterized by low expression of a core set of 45 genes, many encoding proteins involved in the cytoskeleton machinery, ion transport, and cell adhesion. For the three datasets with linked prostate-specific antigen failure data following prostatectomy, patients with DESNT cancer exhibited poor outcome relative to other patients (p=2.65×10-5, p=4.28×10-5, and p=2.98×10-8). When these three datasets were combined the independent predictive value of DESNT membership was p=1.61×10-7 compared with p=1.00×10-5 for Gleason sum. A limitation of the study is that only prediction of prostate-specific antigen failure was examined. CONCLUSIONS: Our results demonstrate the existence of a novel poor prognosis category of human prostate cancer and will assist in the targeting of therapy, helping avoid treatment-associated morbidity in men with indolent disease. PATIENT SUMMARY: Prostate cancer, unlike breast cancer, does not have a robust classification framework. We propose that this failure has occurred because prostate cancer samples selected for analysis frequently have heterozygous compositions (individual samples are made up of many different parts that each have different characteristics). Applying a mathematical approach that can overcome this problem we identify a novel poor prognosis category of human prostate cancer called DESNT..
Terry, M.B.
Liao, Y.
Kast, K.
Antoniou, A.C.
McDonald, J.A.
Mooij, T.M.
Engel, C.
Nogues, C.
Buecher, B.
Mari, V.
Moretta-Serra, J.
Gladieff, L.
Luporsi, E.
Barrowdale, D.
Frost, D.
Henderson, A.
Brewer, C.
Evans, D.G.
Eccles, D.
Cook, J.
Ong, K.-.
Izatt, L.
Ahmed, M.
Morrison, P.J.
Dommering, C.J.
Oosterwijk, J.C.
Ausems, M.G.
Kriege, M.
Buys, S.S.
Andrulis, I.L.
John, E.M.
Daly, M.
Friedlander, M.
McLachlan, S.A.
Osorio, A.
Caldes, T.
Jakubowska, A.
Simard, J.
Singer, C.F.
Tan, Y.
Olah, E.
Navratilova, M.
Foretova, L.
Gerdes, A.-.
Roos-Blom, M.-.
Arver, B.
Olsson, H.
Schmutzler, R.K.
Hopper, J.L.
van Leeuwen, F.E.
Goldgar, D.
Milne, R.L.
Easton, D.F.
Rookus, M.A.
Andrieu, N.
EMBRACE, GENEPSO, BCFR, HEBON, kConFab and IBCCS,
(2018). The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations. Jnci cancer spectr,
Vol.2
(4),
p. pky078.
show abstract
BACKGROUND: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers. METHODS: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort. RESULTS: For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98). CONCLUSIONS: These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers..
Went, M.
Sud, A.
Försti, A.
Halvarsson, B.-.
Weinhold, N.
Kimber, S.
van Duin, M.
Thorleifsson, G.
Holroyd, A.
Johnson, D.C.
Li, N.
Orlando, G.
Law, P.J.
Ali, M.
Chen, B.
Mitchell, J.S.
Gudbjartsson, D.F.
Kuiper, R.
Stephens, O.W.
Bertsch, U.
Broderick, P.
Campo, C.
Bandapalli, O.R.
Einsele, H.
Gregory, W.A.
Gullberg, U.
Hillengass, J.
Hoffmann, P.
Jackson, G.H.
Jöckel, K.-.
Johnsson, E.
Kristinsson, S.Y.
Mellqvist, U.-.
Nahi, H.
Easton, D.
Pharoah, P.
Dunning, A.
Peto, J.
Canzian, F.
Swerdlow, A.
Eeles, R.A.
Kote-Jarai, Z.
Muir, K.
Pashayan, N.
Nickel, J.
Nöthen, M.M.
Rafnar, T.
Ross, F.M.
da Silva Filho, M.I.
Thomsen, H.
Turesson, I.
Vangsted, A.
Andersen, N.F.
Waage, A.
Walker, B.A.
Wihlborg, A.-.
Broyl, A.
Davies, F.E.
Thorsteinsdottir, U.
Langer, C.
Hansson, M.
Goldschmidt, H.
Kaiser, M.
Sonneveld, P.
Stefansson, K.
Morgan, G.J.
Hemminki, K.
Nilsson, B.
Houlston, R.S.
PRACTICAL consortium,
(2018). Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nat commun,
Vol.9
(1),
p. 3707.
show abstract
full text
Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM..
Lin, H.-.
Huang, P.-.
Chen, D.-.
Tung, H.-.
Sellers, T.A.
Pow-Sang, J.M.
Eeles, R.
Easton, D.
Kote-Jarai, Z.
Amin Al Olama, A.
Benlloch, S.
Muir, K.
Giles, G.G.
Wiklund, F.
Gronberg, H.
Haiman, C.A.
Schleutker, J.
Nordestgaard, B.G.
Travis, R.C.
Hamdy, F.
Neal, D.E.
Pashayan, N.
Khaw, K.-.
Stanford, J.L.
Blot, W.J.
Thibodeau, S.N.
Maier, C.
Kibel, A.S.
Cybulski, C.
Cannon-Albright, L.
Brenner, H.
Kaneva, R.
Batra, J.
Teixeira, M.R.
Pandha, H.
Lu, Y.-.
PRACTICAL Consortium,
Park, J.Y.
(2018). AA9int: SNP interaction pattern search using non-hierarchical additive model set. Bioinformatics,
Vol.34
(24),
pp. 4141-4150.
show abstract
MOTIVATION: The use of single nucleotide polymorphism (SNP) interactions to predict complex diseases is getting more attention during the past decade, but related statistical methods are still immature. We previously proposed the SNP Interaction Pattern Identifier (SIPI) approach to evaluate 45 SNP interaction patterns/patterns. SIPI is statistically powerful but suffers from a large computation burden. For large-scale studies, it is necessary to use a powerful and computation-efficient method. The objective of this study is to develop an evidence-based mini-version of SIPI as the screening tool or solitary use and to evaluate the impact of inheritance mode and model structure on detecting SNP-SNP interactions. RESULTS: We tested two candidate approaches: the 'Five-Full' and 'AA9int' method. The Five-Full approach is composed of the five full interaction models considering three inheritance modes (additive, dominant and recessive). The AA9int approach is composed of nine interaction models by considering non-hierarchical model structure and the additive mode. Our simulation results show that AA9int has similar statistical power compared to SIPI and is superior to the Five-Full approach, and the impact of the non-hierarchical model structure is greater than that of the inheritance mode in detecting SNP-SNP interactions. In summary, it is recommended that AA9int is a powerful tool to be used either alone or as the screening stage of a two-stage approach (AA9int+SIPI) for detecting SNP-SNP interactions in large-scale studies. AVAILABILITY AND IMPLEMENTATION: The 'AA9int' and 'parAA9int' functions (standard and parallel computing version) are added in the SIPI R package, which is freely available at https://linhuiyi.github.io/LinHY_Software/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online..
Mikropoulos, C.
Hutten Selkirk, C.G.
Saya, S.
Bancroft, E.
Vertosick, E.
Dadaev, T.
Brendler, C.
Page, E.
Dias, A.
Evans, D.G.
Rothwell, J.
Maehle, L.
Axcrona, K.
Richardson, K.
Eccles, D.
Jensen, T.
Osther, P.J.
van Asperen, C.J.
Vasen, H.
Kiemeney, L.A.
Ringelberg, J.
Cybulski, C.
Wokolorczyk, D.
Hart, R.
Glover, W.
Lam, J.
Taylor, L.
Salinas, M.
Feliubadaló, L.
Oldenburg, R.
Cremers, R.
Verhaegh, G.
van Zelst-Stams, W.A.
Oosterwijk, J.C.
Cook, J.
Rosario, D.J.
Buys, S.S.
Conner, T.
Domchek, S.
Powers, J.
Ausems, M.G.
Teixeira, M.R.
Maia, S.
Izatt, L.
Schmutzler, R.
Rhiem, K.
Foulkes, W.D.
Boshari, T.
Davidson, R.
Ruijs, M.
Helderman-van den Enden, A.T.
Andrews, L.
Walker, L.
Snape, K.
Henderson, A.
Jobson, I.
Lindeman, G.J.
Liljegren, A.
Harris, M.
Adank, M.A.
Kirk, J.
Taylor, A.
Susman, R.
Chen-Shtoyerman, R.
Pachter, N.
Spigelman, A.
Side, L.
Zgajnar, J.
Mora, J.
Brewer, C.
Gadea, N.
Brady, A.F.
Gallagher, D.
van Os, T.
Donaldson, A.
Stefansdottir, V.
Barwell, J.
James, P.A.
Murphy, D.
Friedman, E.
Nicolai, N.
Greenhalgh, L.
Obeid, E.
Murthy, V.
Copakova, L.
McGrath, J.
Teo, S.-.
Strom, S.
Kast, K.
Leongamornlert, D.A.
Chamberlain, A.
Pope, J.
Newlin, A.C.
Aaronson, N.
Ardern-Jones, A.
Bangma, C.
Castro, E.
Dearnaley, D.
Eyfjord, J.
Falconer, A.
Foster, C.S.
Gronberg, H.
Hamdy, F.C.
Johannsson, O.
Khoo, V.
Lubinski, J.
Grindedal, E.M.
McKinley, J.
Shackleton, K.
Mitra, A.V.
Moynihan, C.
Rennert, G.
Suri, M.
Tricker, K.
IMPACT study collaborators,
Moss, S.
Kote-Jarai, Z.
Vickers, A.
Lilja, H.
Helfand, B.T.
Eeles, R.A.
(2018). Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition. Br j cancer,
Vol.118
(6),
pp. e17-e17.
show abstract
full text
This corrects the article DOI: 10.1038/bjc.2017.429..
Loveday, C.
Litchfield, K.
Levy, M.
Holroyd, A.
Broderick, P.
Kote-Jarai, Z.
Dunning, A.M.
Muir, K.
Peto, J.
Eeles, R.
Easton, D.F.
Dudakia, D.
Orr, N.
Pashayan, N.
Reid, A.
Huddart, R.A.
Houlston, R.S.
Turnbull, C.
(2018). Validation of loci at 2q14 2 and 15q21 3 as risk factors for testicular cancer. Oncotarget,
Vol.9
(16),
pp. 12630-12638.
show abstract
full text
Testicular germ cell tumor (TGCT), the most common cancer in men aged 18 to 45 years, has a strong heritable basis. Genome-wide association studies (GWAS) have proposed single nucleotide polymorphisms (SNPs) at a number of loci influencing TGCT risk. To further evaluate the association of recently proposed risk SNPs with TGCT at 2q14.2, 3q26.2, 7q36.3, 10q26.13 and 15q21.3, we analyzed genotype data on 3,206 cases and 7,422 controls. Our analysis provides independent replication of the associations for risk SNPs at 2q14.2 (rs2713206 at P = 3.03 × 10-2; P-meta = 3.92 × 10-8; nearest gene, TFCP2L1) and rs12912292 at 15q21.3 (P = 7.96 × 10-11; P-meta = 1.55 × 10-19; nearest gene PRTG). Case-only analyses did not reveal specific associations with TGCT histology. TFCP2L1 joins the growing list of genes located within TGCT risk loci with biologically plausible roles in developmental transcriptional regulation, further highlighting the importance of this phenomenon in TGCT oncogenesis..
Nielsen, S.M.
Eccles, D.M.
Romero, I.L.
Al-Mulla, F.
Balmaña, J.
Biancolella, M.
Bslok, R.
Caligo, M.A.
Calvello, M.
Capone, G.L.
Cavalli, P.
Chan, T.L.
Claes, K.B.
Cortesi, L.
Couch, F.J.
de la Hoya, M.
De Toffol, S.
Diez, O.
Domchek, S.M.
Eeles, R.
Efremidis, A.
Fostira, F.
Goldgar, D.
Hadjisavvas, A.
Hansen, T.V.
Hirasawa, A.
Houdayer, C.
Kleiblova, P.
Krieger, S.
Lázaro, C.
Loizidou, M.
Manoukian, S.
Mensenkamp, A.R.
Moghadasi, S.
Monteiro, A.N.
Mori, L.
Morrow, A.
Naldi, N.
Nielsen, H.R.
Olopade, O.I.
Pachter, N.S.
Palmero, E.I.
Pedersen, I.S.
Piane, M.
Puzzo, M.
Robson, M.
Rossing, M.
Sini, M.C.
Solano, A.
Soukupova, J.
Tedaldi, G.
Teixeira, M.
Thomassen, M.
Tibiletti, M.G.
Toland, A.
Törngren, T.
Vaccari, E.
Varesco, L.
Vega, A.
Wallis, Y.
Wappenschmidt, B.
Weitzel, J.
Spurdle, A.B.
De Nicolo, A.
Gómez-García, E.B.
(2018). Genetic Testing and Clinical Management Practices for Variants in Non-BRCA1/2 Breast (and Breast/Ovarian) Cancer Susceptibility Genes: An International Survey by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Clinical Working Group. Jco precis oncol,
Vol.2.
show abstract
full text
Purpose: To describe a snapshot of international genetic testing practices, specifically regarding the use of multigene panels, for hereditary breast/ovarian cancers. We conducted a survey through the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, covering questions about 16 non-BRCA1/2 genes. Methods: Data were collected via in-person and paper/electronic surveys. ENIGMA members from around the world were invited to participate. Additional information was collected via country networks in the United Kingdom and in Italy. Results: Responses from 61 cancer genetics practices across 20 countries showed that 16 genes were tested by > 50% of the centers, but only six (PALB2, TP53, PTEN, CHEK2, ATM, and BRIP1) were tested regularly. US centers tested the genes most often, whereas United Kingdom and Italian centers with no direct ENIGMA affiliation at the time of the survey were the least likely to regularly test them. Most centers tested the 16 genes through multigene panels; some centers tested TP53, PTEN, and other cancer syndrome-associated genes individually. Most centers reported (likely) pathogenic variants to patients and would test family members for such variants. Gene-specific guidelines for breast and ovarian cancer risk management were limited and differed among countries, especially with regard to starting age and type of imaging and risk-reducing surgery recommendations. Conclusion: Currently, a small number of genes beyond BRCA1/2 are routinely analyzed worldwide, and management guidelines are limited and largely based on expert opinion. To attain clinical implementation of multigene panel testing through evidence-based management practices, it is paramount that clinicians (and patients) participate in international initiatives that share panel testing data, interpret sequence variants, and collect prospective data to underpin risk estimates and evaluate the outcome of risk intervention strategies..
Telomeres Mendelian Randomization Collaboration,
Haycock, P.C.
Burgess, S.
Nounu, A.
Zheng, J.
Okoli, G.N.
Bowden, J.
Wade, K.H.
Timpson, N.J.
Evans, D.M.
Willeit, P.
Aviv, A.
Gaunt, T.R.
Hemani, G.
Mangino, M.
Ellis, H.P.
Kurian, K.M.
Pooley, K.A.
Eeles, R.A.
Lee, J.E.
Fang, S.
Chen, W.V.
Law, M.H.
Bowdler, L.M.
Iles, M.M.
Yang, Q.
Worrall, B.B.
Markus, H.S.
Hung, R.J.
Amos, C.I.
Spurdle, A.B.
Thompson, D.J.
O'Mara, T.A.
Wolpin, B.
Amundadottir, L.
Stolzenberg-Solomon, R.
Trichopoulou, A.
Onland-Moret, N.C.
Lund, E.
Duell, E.J.
Canzian, F.
Severi, G.
Overvad, K.
Gunter, M.J.
Tumino, R.
Svenson, U.
van Rij, A.
Baas, A.F.
Bown, M.J.
Samani, N.J.
van t'Hof, F.N.
Tromp, G.
Jones, G.T.
Kuivaniemi, H.
Elmore, J.R.
Johansson, M.
Mckay, J.
Scelo, G.
Carreras-Torres, R.
Gaborieau, V.
Brennan, P.
Bracci, P.M.
Neale, R.E.
Olson, S.H.
Gallinger, S.
Li, D.
Petersen, G.M.
Risch, H.A.
Klein, A.P.
Han, J.
Abnet, C.C.
Freedman, N.D.
Taylor, P.R.
Maris, J.M.
Aben, K.K.
Kiemeney, L.A.
Vermeulen, S.H.
Wiencke, J.K.
Walsh, K.M.
Wrensch, M.
Rice, T.
Turnbull, C.
Litchfield, K.
Paternoster, L.
Standl, M.
Abecasis, G.R.
SanGiovanni, J.P.
Li, Y.
Mijatovic, V.
Sapkota, Y.
Low, S.-.
Zondervan, K.T.
Montgomery, G.W.
Nyholt, D.R.
van Heel, D.A.
Hunt, K.
Arking, D.E.
Ashar, F.N.
Sotoodehnia, N.
Woo, D.
Rosand, J.
Comeau, M.E.
Brown, W.M.
Silverman, E.K.
Hokanson, J.E.
Cho, M.H.
Hui, J.
Ferreira, M.A.
Thompson, P.J.
Morrison, A.C.
Felix, J.F.
Smith, N.L.
Christiano, A.M.
Petukhova, L.
Betz, R.C.
Fan, X.
Zhang, X.
Zhu, C.
Langefeld, C.D.
Thompson, S.D.
Wang, F.
Lin, X.
Schwartz, D.A.
Fingerlin, T.
Rotter, J.I.
Cotch, M.F.
Jensen, R.A.
Munz, M.
Dommisch, H.
Schaefer, A.S.
Han, F.
Ollila, H.M.
Hillary, R.P.
Albagha, O.
Ralston, S.H.
Zeng, C.
Zheng, W.
Shu, X.-.
Reis, A.
Uebe, S.
Hüffmeier, U.
Kawamura, Y.
Otowa, T.
Sasaki, T.
Hibberd, M.L.
Davila, S.
Xie, G.
Siminovitch, K.
Bei, J.-.
Zeng, Y.-.
Försti, A.
Chen, B.
Landi, S.
Franke, A.
Fischer, A.
Ellinghaus, D.
Flores, C.
Noth, I.
Ma, S.-.
Foo, J.N.
Liu, J.
Kim, J.-.
Cox, D.G.
Delattre, O.
Mirabeau, O.
Skibola, C.F.
Tang, C.S.
Garcia-Barcelo, M.
Chang, K.-.
Su, W.-.
Chang, Y.-.
Martin, N.G.
Gordon, S.
Wade, T.D.
Lee, C.
Kubo, M.
Cha, P.-.
Nakamura, Y.
Levy, D.
Kimura, M.
Hwang, S.-.
Hunt, S.
Spector, T.
Soranzo, N.
Manichaikul, A.W.
Barr, R.G.
Kahali, B.
Speliotes, E.
Yerges-Armstrong, L.M.
Cheng, C.-.
Jonas, J.B.
Wong, T.Y.
Fogh, I.
Lin, K.
Powell, J.F.
Rice, K.
Relton, C.L.
Martin, R.M.
Davey Smith, G.
(2017). Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study. Jama oncol,
Vol.3
(5),
pp. 636-651.
show abstract
full text
Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015. Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases..
Reis Ferreira, M.
Khan, A.
Thomas, K.
Truelove, L.
McNair, H.
Gao, A.
Parker, C.C.
Huddart, R.
Bidmead, M.
Eeles, R.
Khoo, V.
van As, N.J.
Hansen, V.N.
Dearnaley, D.P.
(2017). Phase 1/2 Dose-Escalation Study of the Use of Intensity Modulated Radiation Therapy to Treat the Prostate and Pelvic Nodes in Patients With Prostate Cancer. Int j radiat oncol biol phys,
Vol.99
(5),
pp. 1234-1242.
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full text
PURPOSE: To investigate the feasibility of dose escalation and hypofractionation of pelvic lymph node intensity modulated radiation therapy (PLN-IMRT) in prostate cancer (PCa). METHODS AND MATERIALS: In a phase 1/2 study, patients with advanced localized PCa were sequentially treated with 70 to 74 Gy to the prostate and dose-escalating PLN-IMRT at doses of 50 Gy (cohort 1), 55 Gy (cohort 2), and 60 Gy (cohort 3) in 35 to 37 fractions. Two hypofractionated cohorts received 60 Gy to the prostate and 47 Gy to PLN in 20 fractions over 4 weeks (cohort 4) and 5 weeks (cohort 5). All patients received long-course androgen deprivation therapy. Primary outcome was late Radiation Therapy Oncology Group toxicity at 2 years after radiation therapy for all cohorts. Secondary outcomes were acute and late toxicity using other clinician/patient-reported instruments and treatment efficacy. RESULTS: Between August 9, 2000, and June 9, 2010, 447 patients were enrolled. Median follow-up was 90 months. The 2-year rates of grade 2+ bowel/bladder toxicity were as follows: cohort 1, 8.3%/4.2% (95% confidence interval 2.2%-29.4%/0.6%-26.1%); cohort 2, 8.9%/5.9% (4.1%-18.7%/2.3%-15.0%); cohort 3, 13.2%/2.9% (8.6%-20.2%/1.1%-7.7%); cohort 4, 16.4%/4.8% (9.2%-28.4%/1.6%-14.3%); cohort 5, 12.2%/7.3% (7.6%-19.5%/3.9%-13.6%). Prevalence of bowel and bladder toxicity seemed to be stable over time. Other scales mirrored these results. The biochemical/clinical failure-free rate was 71% (66%-75%) at 5 years for the whole group, with pelvic lymph node control in 94% of patients. CONCLUSIONS: This study shows the safety and tolerability of PLN-IMRT. Ongoing and planned phase 3 studies will need to demonstrate an increase in efficacy using PLN-IMRT to offset the small increase in bowel side effects compared with prostate-only IMRT..
Ballinger, M.L.
Best, A.
Mai, P.L.
Khincha, P.P.
Loud, J.T.
Peters, J.A.
Achatz, M.I.
Chojniak, R.
Balieiro da Costa, A.
Santiago, K.M.
Garber, J.
O'Neill, A.F.
Eeles, R.A.
Evans, D.G.
Bleiker, E.
Sonke, G.S.
Ruijs, M.
Loo, C.
Schiffman, J.
Naumer, A.
Kohlmann, W.
Strong, L.C.
Bojadzieva, J.
Malkin, D.
Rednam, S.P.
Stoffel, E.M.
Koeppe, E.
Weitzel, J.N.
Slavin, T.P.
Nehoray, B.
Robson, M.
Walsh, M.
Manelli, L.
Villani, A.
Thomas, D.M.
Savage, S.A.
(2017). Baseline Surveillance in Li-Fraumeni Syndrome Using Whole-Body Magnetic Resonance Imaging: A Meta-analysis. Jama oncol,
Vol.3
(12),
pp. 1634-1639.
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full text
Importance: Guidelines for clinical management in Li-Fraumeni syndrome, a multiple-organ cancer predisposition condition, are limited. Whole-body magnetic resonance imaging (WBMRI) may play a role in surveillance of this high-risk population. Objective: To assess the clinical utility of WBMRI in germline TP53 mutation carriers at baseline. Data Sources: Clinical and research surveillance cohorts were identified through the Li-Fraumeni Exploration Research Consortium. Study Selection: Cohorts that incorporated WBMRI for individuals with germline TP53 mutations from January 1, 2004, through October 1, 2016, were included. Data Extraction and Synthesis: Data were extracted by investigators from each cohort independently and synthesized by 2 investigators. Random-effects meta-analysis methods were used to estimate proportions. Main Outcomes and Measures: The proportions of participants at baseline in whom a lesion was detected that required follow-up and in whom a new primary malignant neoplasm was detected. Results: A total of 578 participants (376 female [65.1%] and 202 male [34.9%]; mean [SD] age, 33.2 [17.1] years) from 13 cohorts in 6 countries were included in the analysis. Two hundred twenty-five lesions requiring clinical follow-up were detected by WBMRI in 173 participants. Sixty-one lesions were diagnosed in 54 individuals as benign or malignant neoplasms. Overall, 42 cancers were identified in 39 individuals, with 35 new localized cancers treated with curative intent. The overall estimated detection rate for new, localized primary cancers was 7% (95% CI, 5%-9%). Conclusions and Relevance: These data suggest clinical utility of baseline WBMRI in TP53 germline mutation carriers and may form an integral part of baseline clinical risk management in this high-risk population..
Sud, A.
Thomsen, H.
Law, P.J.
Försti, A.
Filho, M.I.
Holroyd, A.
Broderick, P.
Orlando, G.
Lenive, O.
Wright, L.
Cooke, R.
Easton, D.
Pharoah, P.
Dunning, A.
Peto, J.
Canzian, F.
Eeles, R.
Kote-Jarai, Z.
Muir, K.
Pashayan, N.
PRACTICAL consortium,
Hoffmann, P.
Nöthen, M.M.
Jöckel, K.-.
Strandmann, E.P.
Lightfoot, T.
Kane, E.
Roman, E.
Lake, A.
Montgomery, D.
Jarrett, R.F.
Swerdlow, A.J.
Engert, A.
Orr, N.
Hemminki, K.
Houlston, R.S.
(2017). Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility. Nat commun,
Vol.8
(1),
p. 1892.
show abstract
full text
Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10-8) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P = 9.43 × 10-17), 6q23.3 (rs6928977, P = 4.62 × 10-11), 10p14 (rs3781093, P = 9.49 × 10-13), 13q34 (rs112998813, P = 4.58 × 10-8) and 16p13.13 (rs34972832, P = 2.12 × 10-8). Additionally, independent loci within the HLA region are observed for nodular sclerosis Hodgkin lymphoma (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity Hodgkin lymphoma (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response..
Conti, D.V.
Wang, K.
Sheng, X.
Bensen, J.T.
Hazelett, D.J.
Cook, M.B.
Ingles, S.A.
Kittles, R.A.
Strom, S.S.
Rybicki, B.A.
Nemesure, B.
Isaacs, W.B.
Stanford, J.L.
Zheng, W.
Sanderson, M.
John, E.M.
Park, J.Y.
Xu, J.
Stevens, V.L.
Berndt, S.I.
Huff, C.D.
Wang, Z.
Yeboah, E.D.
Tettey, Y.
Biritwum, R.B.
Adjei, A.A.
Tay, E.
Truelove, A.
Niwa, S.
Sellers, T.A.
Yamoah, K.
Murphy, A.B.
Crawford, D.C.
Gapstur, S.M.
Bush, W.S.
Aldrich, M.C.
Cussenot, O.
Petrovics, G.
Cullen, J.
Neslund-Dudas, C.
Stern, M.C.
Jarai, Z.-.
Govindasami, K.
Chokkalingam, A.P.
Hsing, A.W.
Goodman, P.J.
Hoffmann, T.
Drake, B.F.
Hu, J.J.
Clark, P.E.
Van Den Eeden, S.K.
Blanchet, P.
Fowke, J.H.
Casey, G.
Hennis, A.J.
Han, Y.
Lubwama, A.
Thompson, I.M.
Leach, R.
Easton, D.F.
Schumacher, F.
Van den Berg, D.J.
Gundell, S.M.
Stram, A.
Wan, P.
Xia, L.
Pooler, L.C.
Mohler, J.L.
Fontham, E.T.
Smith, G.J.
Taylor, J.A.
Srivastava, S.
Eeles, R.A.
Carpten, J.
Kibel, A.S.
Multigner, L.
Parent, M.-.
Menegaux, F.
Cancel-Tassin, G.
Klein, E.A.
Brureau, L.
Stram, D.O.
Watya, S.
Chanock, S.J.
Witte, J.S.
Blot, W.J.
Henderson, B.E.
Haiman, C.A.
PRACTICAL/ELLIPSE Consortium,
(2017). Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry. J natl cancer inst,
Vol.109
(8).
show abstract
full text
Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10 × 10-12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 × 10-10). At 13q34, the signal is located 5' of the gene IRS2 and 3' of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk..
Amos, C.I.
Dennis, J.
Wang, Z.
Byun, J.
Schumacher, F.R.
Gayther, S.A.
Casey, G.
Hunter, D.J.
Sellers, T.A.
Gruber, S.B.
Dunning, A.M.
Michailidou, K.
Fachal, L.
Doheny, K.
Spurdle, A.B.
Li, Y.
Xiao, X.
Romm, J.
Pugh, E.
Coetzee, G.A.
Hazelett, D.J.
Bojesen, S.E.
Caga-Anan, C.
Haiman, C.A.
Kamal, A.
Luccarini, C.
Tessier, D.
Vincent, D.
Bacot, F.
Van Den Berg, D.J.
Nelson, S.
Demetriades, S.
Goldgar, D.E.
Couch, F.J.
Forman, J.L.
Giles, G.G.
Conti, D.V.
Bickeböller, H.
Risch, A.
Waldenberger, M.
Brüske-Hohlfeld, I.
Hicks, B.D.
Ling, H.
McGuffog, L.
Lee, A.
Kuchenbaecker, K.
Soucy, P.
Manz, J.
Cunningham, J.M.
Butterbach, K.
Kote-Jarai, Z.
Kraft, P.
FitzGerald, L.
Lindström, S.
Adams, M.
McKay, J.D.
Phelan, C.M.
Benlloch, S.
Kelemen, L.E.
Brennan, P.
Riggan, M.
O'Mara, T.A.
Shen, H.
Shi, Y.
Thompson, D.J.
Goodman, M.T.
Nielsen, S.F.
Berchuck, A.
Laboissiere, S.
Schmit, S.L.
Shelford, T.
Edlund, C.K.
Taylor, J.A.
Field, J.K.
Park, S.K.
Offit, K.
Thomassen, M.
Schmutzler, R.
Ottini, L.
Hung, R.J.
Marchini, J.
Amin Al Olama, A.
Peters, U.
Eeles, R.A.
Seldin, M.F.
Gillanders, E.
Seminara, D.
Antoniou, A.C.
Pharoah, P.D.
Chenevix-Trench, G.
Chanock, S.J.
Simard, J.
Easton, D.F.
(2017). The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers. Cancer epidemiol biomarkers prev,
Vol.26
(1),
pp. 126-135.
show abstract
full text
BACKGROUND: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits. METHODS: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. RESULTS: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. CONCLUSIONS: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures. IMPACT: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126-35. ©2016 AACR..
Hamdi, Y.
Soucy, P.
Kuchenbaeker, K.B.
Pastinen, T.
Droit, A.
Lemaçon, A.
Adlard, J.
Aittomäki, K.
Andrulis, I.L.
Arason, A.
Arnold, N.
Arun, B.K.
Azzollini, J.
Bane, A.
Barjhoux, L.
Barrowdale, D.
Benitez, J.
Berthet, P.
Blok, M.J.
Bobolis, K.
Bonadona, V.
Bonanni, B.
Bradbury, A.R.
Brewer, C.
Buecher, B.
Buys, S.S.
Caligo, M.A.
Chiquette, J.
Chung, W.K.
Claes, K.B.
Daly, M.B.
Damiola, F.
Davidson, R.
De la Hoya, M.
De Leeneer, K.
Diez, O.
Ding, Y.C.
Dolcetti, R.
Domchek, S.M.
Dorfling, C.M.
Eccles, D.
Eeles, R.
Einbeigi, Z.
Ejlertsen, B.
EMBRACE,
Engel, C.
Gareth Evans, D.
Feliubadalo, L.
Foretova, L.
Fostira, F.
Foulkes, W.D.
Fountzilas, G.
Friedman, E.
Frost, D.
Ganschow, P.
Ganz, P.A.
Garber, J.
Gayther, S.A.
GEMO Study Collaborators,
Gerdes, A.-.
Glendon, G.
Godwin, A.K.
Goldgar, D.E.
Greene, M.H.
Gronwald, J.
Hahnen, E.
Hamann, U.
Hansen, T.V.
Hart, S.
Hays, J.L.
HEBON,
Hogervorst, F.B.
Hulick, P.J.
Imyanitov, E.N.
Isaacs, C.
Izatt, L.
Jakubowska, A.
James, P.
Janavicius, R.
Jensen, U.B.
John, E.M.
Joseph, V.
Just, W.
Kaczmarek, K.
Karlan, B.Y.
KConFab Investigators,
Kets, C.M.
Kirk, J.
Kriege, M.
Laitman, Y.
Laurent, M.
Lazaro, C.
Leslie, G.
Lester, J.
Lesueur, F.
Liljegren, A.
Loman, N.
Loud, J.T.
Manoukian, S.
Mariani, M.
Mazoyer, S.
McGuffog, L.
Meijers-Heijboer, H.E.
Meindl, A.
Miller, A.
Montagna, M.
Mulligan, A.M.
Nathanson, K.L.
Neuhausen, S.L.
Nevanlinna, H.
Nussbaum, R.L.
Olah, E.
Olopade, O.I.
Ong, K.-.
Oosterwijk, J.C.
Osorio, A.
Papi, L.
Park, S.K.
Pedersen, I.S.
Peissel, B.
Segura, P.P.
Peterlongo, P.
Phelan, C.M.
Radice, P.
Rantala, J.
Rappaport-Fuerhauser, C.
Rennert, G.
Richardson, A.
Robson, M.
Rodriguez, G.C.
Rookus, M.A.
Schmutzler, R.K.
Sevenet, N.
Shah, P.D.
Singer, C.F.
Slavin, T.P.
Snape, K.
Sokolowska, J.
Sønderstrup, I.M.
Southey, M.
Spurdle, A.B.
Stadler, Z.
Stoppa-Lyonnet, D.
Sukiennicki, G.
Sutter, C.
Tan, Y.
Tea, M.-.
Teixeira, M.R.
Teulé, A.
Teo, S.-.
Terry, M.B.
Thomassen, M.
Tihomirova, L.
Tischkowitz, M.
Tognazzo, S.
Toland, A.E.
Tung, N.
van den Ouweland, A.M.
van der Luijt, R.B.
van Engelen, K.
van Rensburg, E.J.
Varon-Mateeva, R.
Wappenschmidt, B.
Wijnen, J.T.
Rebbeck, T.
Chenevix-Trench, G.
Offit, K.
Couch, F.J.
Nord, S.
Easton, D.F.
Antoniou, A.C.
Simard, J.
(2017). Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22 3. Breast cancer res treat,
Vol.161
(1),
pp. 117-134.
show abstract
full text
PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk..
Brunner, C.
Davies, N.M.
Martin, R.M.
Eeles, R.
Easton, D.
Kote-Jarai, Z.
Al Olama, A.A.
Benlloch, S.
Muir, K.
Giles, G.
Wiklund, F.
Gronberg, H.
Haiman, C.A.
Schleutker, J.
Nordestgaard, B.G.
Travis, R.C.
Neal, D.
Donovan, J.
Hamdy, F.C.
Pashayan, N.
Khaw, K.-.
Stanford, J.L.
Blot, W.J.
Thibodeau, S.
Maier, C.
Kibel, A.S.
Cybulski, C.
Cannon-Albright, L.
Brenner, H.
Park, J.
Kaneva, R.
Batra, J.
Teixeira, M.R.
Pandha, H.
PRACTICAL Consortium,,
Zuccolo, L.
(2017). Alcohol consumption and prostate cancer incidence and progression: A Mendelian randomisation study. Int j cancer,
Vol.140
(1),
pp. 75-85.
show abstract
full text
Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study-specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol-metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer-specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta-analysed using fixed-effect and random-effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed-effect meta-analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed = 0.78; 95% confidence interval (95%CI):0.66,0.91; p values = 0.002); rs12910509, HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.003); and rs8041922 (HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed = 1.43; 95%CI:1.14,1.79; p values = 0.002) was associated with prostate cancer mortality in men with low-grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression..
Larson, N.B.
McDonnell, S.
Cannon Albright, L.
Teerlink, C.
Stanford, J.
Ostrander, E.A.
Isaacs, W.B.
Xu, J.
Cooney, K.A.
Lange, E.
Schleutker, J.
Carpten, J.D.
Powell, I.
Bailey-Wilson, J.E.
Cussenot, O.
Cancel-Tassin, G.
Giles, G.G.
MacInnis, R.J.
Maier, C.
Whittemore, A.S.
Hsieh, C.-.
Wiklund, F.
Catalona, W.J.
Foulkes, W.
Mandal, D.
Eeles, R.
Kote-Jarai, Z.
Ackerman, M.J.
Olson, T.M.
Klein, C.J.
Thibodeau, S.N.
Schaid, D.J.
(2017). gsSKAT: Rapid gene set analysis and multiple testing correction for rare-variant association studies using weighted linear kernels. Genet epidemiol,
Vol.41
(4),
pp. 297-308.
show abstract
full text
Next-generation sequencing technologies have afforded unprecedented characterization of low-frequency and rare genetic variation. Due to low power for single-variant testing, aggregative methods are commonly used to combine observed rare variation within a single gene. Causal variation may also aggregate across multiple genes within relevant biomolecular pathways. Kernel-machine regression and adaptive testing methods for aggregative rare-variant association testing have been demonstrated to be powerful approaches for pathway-level analysis, although these methods tend to be computationally intensive at high-variant dimensionality and require access to complete data. An additional analytical issue in scans of large pathway definition sets is multiple testing correction. Gene set definitions may exhibit substantial genic overlap, and the impact of the resultant correlation in test statistics on Type I error rate control for large agnostic gene set scans has not been fully explored. Herein, we first outline a statistical strategy for aggregative rare-variant analysis using component gene-level linear kernel score test summary statistics as well as derive simple estimators of the effective number of tests for family-wise error rate control. We then conduct extensive simulation studies to characterize the behavior of our approach relative to direct application of kernel and adaptive methods under a variety of conditions. We also apply our method to two case-control studies, respectively, evaluating rare variation in hereditary prostate cancer and schizophrenia. Finally, we provide open-source R code for public use to facilitate easy application of our methods to existing rare-variant analysis results..
Phelan, C.M.
Kuchenbaecker, K.B.
Tyrer, J.P.
Kar, S.P.
Lawrenson, K.
Winham, S.J.
Dennis, J.
Pirie, A.
Riggan, M.J.
Chornokur, G.
Earp, M.A.
Lyra, P.C.
Lee, J.M.
Coetzee, S.
Beesley, J.
McGuffog, L.
Soucy, P.
Dicks, E.
Lee, A.
Barrowdale, D.
Lecarpentier, J.
Leslie, G.
Aalfs, C.M.
Aben, K.K.
Adams, M.
Adlard, J.
Andrulis, I.L.
Anton-Culver, H.
Antonenkova, N.
AOCS study group,
Aravantinos, G.
Arnold, N.
Arun, B.K.
Arver, B.
Azzollini, J.
Balmaña, J.
Banerjee, S.N.
Barjhoux, L.
Barkardottir, R.B.
Bean, Y.
Beckmann, M.W.
Beeghly-Fadiel, A.
Benitez, J.
Bermisheva, M.
Bernardini, M.Q.
Birrer, M.J.
Bjorge, L.
Black, A.
Blankstein, K.
Blok, M.J.
Bodelon, C.
Bogdanova, N.
Bojesen, A.
Bonanni, B.
Borg, Å.
Bradbury, A.R.
Brenton, J.D.
Brewer, C.
Brinton, L.
Broberg, P.
Brooks-Wilson, A.
Bruinsma, F.
Brunet, J.
Buecher, B.
Butzow, R.
Buys, S.S.
Caldes, T.
Caligo, M.A.
Campbell, I.
Cannioto, R.
Carney, M.E.
Cescon, T.
Chan, S.B.
Chang-Claude, J.
Chanock, S.
Chen, X.Q.
Chiew, Y.-.
Chiquette, J.
Chung, W.K.
Claes, K.B.
Conner, T.
Cook, L.S.
Cook, J.
Cramer, D.W.
Cunningham, J.M.
D'Aloisio, A.A.
Daly, M.B.
Damiola, F.
Damirovna, S.D.
Dansonka-Mieszkowska, A.
Dao, F.
Davidson, R.
DeFazio, A.
Delnatte, C.
Doheny, K.F.
Diez, O.
Ding, Y.C.
Doherty, J.A.
Domchek, S.M.
Dorfling, C.M.
Dörk, T.
Dossus, L.
Duran, M.
Dürst, M.
Dworniczak, B.
Eccles, D.
Edwards, T.
Eeles, R.
Eilber, U.
Ejlertsen, B.
Ekici, A.B.
Ellis, S.
Elvira, M.
EMBRACE Study,
Eng, K.H.
Engel, C.
Evans, D.G.
Fasching, P.A.
Ferguson, S.
Ferrer, S.F.
Flanagan, J.M.
Fogarty, Z.C.
Fortner, R.T.
Fostira, F.
Foulkes, W.D.
Fountzilas, G.
Fridley, B.L.
Friebel, T.M.
Friedman, E.
Frost, D.
Ganz, P.A.
Garber, J.
García, M.J.
Garcia-Barberan, V.
Gehrig, A.
GEMO Study Collaborators,
Gentry-Maharaj, A.
Gerdes, A.-.
Giles, G.G.
Glasspool, R.
Glendon, G.
Godwin, A.K.
Goldgar, D.E.
Goranova, T.
Gore, M.
Greene, M.H.
Gronwald, J.
Gruber, S.
Hahnen, E.
Haiman, C.A.
Håkansson, N.
Hamann, U.
Hansen, T.V.
Harrington, P.A.
Harris, H.R.
Hauke, J.
HEBON Study,
Hein, A.
Henderson, A.
Hildebrandt, M.A.
Hillemanns, P.
Hodgson, S.
Høgdall, C.K.
Høgdall, E.
Hogervorst, F.B.
Holland, H.
Hooning, M.J.
Hosking, K.
Huang, R.-.
Hulick, P.J.
Hung, J.
Hunter, D.J.
Huntsman, D.G.
Huzarski, T.
Imyanitov, E.N.
Isaacs, C.
Iversen, E.S.
Izatt, L.
Izquierdo, A.
Jakubowska, A.
James, P.
Janavicius, R.
Jernetz, M.
Jensen, A.
Jensen, U.B.
John, E.M.
Johnatty, S.
Jones, M.E.
Kannisto, P.
Karlan, B.Y.
Karnezis, A.
Kast, K.
KConFab Investigators,
Kennedy, C.J.
Khusnutdinova, E.
Kiemeney, L.A.
Kiiski, J.I.
Kim, S.-.
Kjaer, S.K.
Köbel, M.
Kopperud, R.K.
Kruse, T.A.
Kupryjanczyk, J.
Kwong, A.
Laitman, Y.
Lambrechts, D.
Larrañaga, N.
Larson, M.C.
Lazaro, C.
Le, N.D.
Le Marchand, L.
Lee, J.W.
Lele, S.B.
Leminen, A.
Leroux, D.
Lester, J.
Lesueur, F.
Levine, D.A.
Liang, D.
Liebrich, C.
Lilyquist, J.
Lipworth, L.
Lissowska, J.
Lu, K.H.
Lubinński, J.
Luccarini, C.
Lundvall, L.
Mai, P.L.
Mendoza-Fandiño, G.
Manoukian, S.
Massuger, L.F.
May, T.
Mazoyer, S.
McAlpine, J.N.
McGuire, V.
McLaughlin, J.R.
McNeish, I.
Meijers-Heijboer, H.
Meindl, A.
Menon, U.
Mensenkamp, A.R.
Merritt, M.A.
Milne, R.L.
Mitchell, G.
Modugno, F.
Moes-Sosnowska, J.
Moffitt, M.
Montagna, M.
Moysich, K.B.
Mulligan, A.M.
Musinsky, J.
Nathanson, K.L.
Nedergaard, L.
Ness, R.B.
Neuhausen, S.L.
Nevanlinna, H.
Niederacher, D.
Nussbaum, R.L.
Odunsi, K.
Olah, E.
Olopade, O.I.
Olsson, H.
Olswold, C.
O'Malley, D.M.
Ong, K.-.
Onland-Moret, N.C.
OPAL study group,
Orr, N.
Orsulic, S.
Osorio, A.
Palli, D.
Papi, L.
Park-Simon, T.-.
Paul, J.
Pearce, C.L.
Pedersen, I.S.
Peeters, P.H.
Peissel, B.
Peixoto, A.
Pejovic, T.
Pelttari, L.M.
Permuth, J.B.
Peterlongo, P.
Pezzani, L.
Pfeiler, G.
Phillips, K.-.
Piedmonte, M.
Pike, M.C.
Piskorz, A.M.
Poblete, S.R.
Pocza, T.
Poole, E.M.
Poppe, B.
Porteous, M.E.
Prieur, F.
Prokofyeva, D.
Pugh, E.
Pujana, M.A.
Pujol, P.
Radice, P.
Rantala, J.
Rappaport-Fuerhauser, C.
Rennert, G.
Rhiem, K.
Rice, P.
Richardson, A.
Robson, M.
Rodriguez, G.C.
Rodríguez-Antona, C.
Romm, J.
Rookus, M.A.
Rossing, M.A.
Rothstein, J.H.
Rudolph, A.
Runnebaum, I.B.
Salvesen, H.B.
Sandler, D.P.
Schoemaker, M.J.
Senter, L.
Setiawan, V.W.
Severi, G.
Sharma, P.
Shelford, T.
Siddiqui, N.
Side, L.E.
Sieh, W.
Singer, C.F.
Sobol, H.
Song, H.
Southey, M.C.
Spurdle, A.B.
Stadler, Z.
Steinemann, D.
Stoppa-Lyonnet, D.
Sucheston-Campbell, L.E.
Sukiennicki, G.
Sutphen, R.
Sutter, C.
Swerdlow, A.J.
Szabo, C.I.
Szafron, L.
Tan, Y.Y.
Taylor, J.A.
Tea, M.-.
Teixeira, M.R.
Teo, S.-.
Terry, K.L.
Thompson, P.J.
Thomsen, L.C.
Thull, D.L.
Tihomirova, L.
Tinker, A.V.
Tischkowitz, M.
Tognazzo, S.
Toland, A.E.
Tone, A.
Trabert, B.
Travis, R.C.
Trichopoulou, A.
Tung, N.
Tworoger, S.S.
van Altena, A.M.
Van Den Berg, D.
van der Hout, A.H.
van der Luijt, R.B.
Van Heetvelde, M.
Van Nieuwenhuysen, E.
van Rensburg, E.J.
Vanderstichele, A.
Varon-Mateeva, R.
Vega, A.
Edwards, D.V.
Vergote, I.
Vierkant, R.A.
Vijai, J.
Vratimos, A.
Walker, L.
Walsh, C.
Wand, D.
Wang-Gohrke, S.
Wappenschmidt, B.
Webb, P.M.
Weinberg, C.R.
Weitzel, J.N.
Wentzensen, N.
Whittemore, A.S.
Wijnen, J.T.
Wilkens, L.R.
Wolk, A.
Woo, M.
Wu, X.
Wu, A.H.
Yang, H.
Yannoukakos, D.
Ziogas, A.
Zorn, K.K.
Narod, S.A.
Easton, D.F.
Amos, C.I.
Schildkraut, J.M.
Ramus, S.J.
Ottini, L.
Goodman, M.T.
Park, S.K.
Kelemen, L.E.
Risch, H.A.
Thomassen, M.
Offit, K.
Simard, J.
Schmutzler, R.K.
Hazelett, D.
Monteiro, A.N.
Couch, F.J.
Berchuck, A.
Chenevix-Trench, G.
Goode, E.L.
Sellers, T.A.
Gayther, S.A.
Antoniou, A.C.
Pharoah, P.D.
(2017). Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer. Nat genet,
Vol.49
(5),
pp. 680-691.
show abstract
full text
To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC..
Toth, R.
Scherer, D.
Kelemen, L.E.
Risch, A.
Hazra, A.
Balavarca, Y.
Issa, J.-.
Moreno, V.
Eeles, R.A.
Ogino, S.
Wu, X.
Ye, Y.
Hung, R.J.
Goode, E.L.
Ulrich, C.M.
OCAC, CORECT, TRICL, ELLIPSE, DRIVE, and GAME-ON consortia,
(2017). Genetic Variants in Epigenetic Pathways and Risks of Multiple Cancers in the GAME-ON Consortium. Cancer epidemiol biomarkers prev,
Vol.26
(6),
pp. 816-825.
show abstract
full text
Background: Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background.Methods: In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate-corrected P values (q values < 0.05) were considered statistically significant.Results: Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants in BABAM1 were confirmed as a susceptibility locus for squamous cell lung, overall breast, estrogen receptor (ER)-negative breast, and overall prostate, and overall serous ovarian cancer; the most significant variant was rs4808076 [OR = 1.14; 95% confidence interval (CI) = 1.10-1.19; q = 6.87 × 10-5]. DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, and overall and aggressive prostate cancer risk (OR = 0.93; 95% CI = 0.91-0.96; q = 0.005). Variants in L3MBTL3 were associated with colorectal, overall breast, ER-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g., rs9388766: OR = 1.06; 95% CI = 1.03-1.08; q = 0.02). Variants in TET2 were significantly associated with overall breast, overall prostate, overall ovarian, and endometrioid ovarian cancer risk, with rs62331150 showing bidirectional effects. Analyses of subpathways did not reveal gene subsets that contributed disproportionately to susceptibility.Conclusions: Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology.Impact: This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes. Cancer Epidemiol Biomarkers Prev; 26(6); 816-25. ©2017 AACR..
Litchfield, K.
Levy, M.
Orlando, G.
Loveday, C.
Law, P.J.
Migliorini, G.
Holroyd, A.
Broderick, P.
Karlsson, R.
Haugen, T.B.
Kristiansen, W.
Nsengimana, J.
Fenwick, K.
Assiotis, I.
Kote-Jarai, Z.
Dunning, A.M.
Muir, K.
Peto, J.
Eeles, R.
Easton, D.F.
Dudakia, D.
Orr, N.
Pashayan, N.
UK Testicular Cancer Collaboration,
PRACTICAL Consortium,
Bishop, D.T.
Reid, A.
Huddart, R.A.
Shipley, J.
Grotmol, T.
Wiklund, F.
Houlston, R.S.
Turnbull, C.
(2017). Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor. Nat genet,
Vol.49
(7),
pp. 1133-1140.
show abstract
full text
Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT..
McBride, K.A.
Ballinger, M.L.
Schlub, T.E.
Young, M.-.
Tattersall, M.H.
Kirk, J.
Eeles, R.
Killick, E.
Walker, L.G.
Shanley, S.
Thomas, D.M.
Mitchell, G.
(2017). Psychosocial morbidity in TP53 mutation carriers: is whole-body cancer screening beneficial?. Fam cancer,
Vol.16
(3),
pp. 423-432.
show abstract
full text
Germline TP53 mutation carriers are at high risk of developing a range of cancers. Effective cancer risk management is an important issue for these individuals. We assessed the psychosocial impact in TP53 mutation carriers of WB-MRI screening as part of the Surveillance in Multi-Organ Cancer (SMOC+) protocol, measuring their unmet needs, anxiety and depression levels as well as cancer worry using psychological questionnaires and in-depth interviews about their experiences of screening. We present preliminary psychosocial findings from 17 participants during their first 12 months on the trial. We found a significant reduction in participants' mean anxiety from baseline to two weeks post WB-MRI (1.2, 95% CI 0.17 to 2.23 p = 0.025), indicative of some benefit. Emerging qualitative themes show most participants are emotionally supported and contained by the screening program and are motivated by their immediate concern about staying alive, despite being informed about the current lack of evidence around efficacy of screening for people with TP53 mutations in terms of cancer morbidity or mortality. For those that do gain emotional reassurance from participating in the screening study, feelings of abandonment by the research team are a risk when the study ends. For others, screening was seen as a burden, consistent with the relentless nature of cancer risk associated with Li-Fraumeni syndrome, though these patients still declared they wished to participate due to their concern with staying alive. Families with TP53 mutations need ongoing support due to the impact on the whole family system. These findings suggest a comprehensive multi-organ screening program for people with TP53 mutations provides psychological benefit independent of an impact on cancer morbidity and mortality associated with the syndrome. The benefits of a multi-organ screening program will be greater still if the screening tests additionally reduce the cancer morbidity and mortality associated with the syndrome. These findings may also inform the care of individuals and families with other multi-organ cancer predisposition syndromes..
Saya, S.
Killick, E.
Thomas, S.
Taylor, N.
Bancroft, E.K.
Rothwell, J.
Benafif, S.
Dias, A.
Mikropoulos, C.
Pope, J.
Chamberlain, A.
Gunapala, R.
SIGNIFY Study Steering Committee,
Izatt, L.
Side, L.
Walker, L.
Tomkins, S.
Cook, J.
Barwell, J.
Wiles, V.
Limb, L.
Eccles, D.
Leach, M.O.
Shanley, S.
Gilbert, F.J.
Hanson, H.
Gallagher, D.
Rajashanker, B.
Whitehouse, R.W.
Koh, D.-.
Sohaib, S.A.
Evans, D.G.
Eeles, R.A.
(2017). Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls. Fam cancer,
Vol.16
(3),
pp. 433-440.
show abstract
full text
In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers. 44 TP53 mutation carriers and 44 population controls were recruited. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. In TP53 mutation carriers, 6 of 44 (13.6, 95% CI 5.2-27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1, 95% CI 20.5-49.9%) and seven controls (15.9, 95% CI 6.7-30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. This should be adopted into national guidelines for management of adult TP53 mutation carriers in addition to the current practice of contrast enhanced breast MRI imaging..
Lindström, S.
Finucane, H.
Bulik-Sullivan, B.
Schumacher, F.R.
Amos, C.I.
Hung, R.J.
Rand, K.
Gruber, S.B.
Conti, D.
Permuth, J.B.
Lin, H.-.
Goode, E.L.
Sellers, T.A.
Amundadottir, L.T.
Stolzenberg-Solomon, R.
Klein, A.
Petersen, G.
Risch, H.
Wolpin, B.
Hsu, L.
Huyghe, J.R.
Chang-Claude, J.
Chan, A.
Berndt, S.
Eeles, R.
Easton, D.
Haiman, C.A.
Hunter, D.J.
Neale, B.
Price, A.L.
Kraft, P.
PanScan, GECCO and the GAME-ON Network: CORECT, DRIVE, ELLIPSE, FOCI, and TRICL-ILCCO,
(2017). Quantifying the Genetic Correlation between Multiple Cancer Types. Cancer epidemiol biomarkers prev,
Vol.26
(9),
pp. 1427-1435.
show abstract
full text
Background: Many cancers share specific genetic risk factors, including both rare high-penetrance mutations and common SNPs identified through genome-wide association studies (GWAS). However, little is known about the overall shared heritability across cancers. Quantifying the extent to which two distinct cancers share genetic origin will give insights to shared biological mechanisms underlying cancer and inform design for future genetic association studies.Methods: In this study, we estimated the pair-wise genetic correlation between six cancer types (breast, colorectal, lung, ovarian, pancreatic, and prostate) using cancer-specific GWAS summary statistics data based on 66,958 case and 70,665 control subjects of European ancestry. We also estimated genetic correlations between cancers and 14 noncancer diseases and traits.Results: After adjusting for 15 pair-wise genetic correlation tests between cancers, we found significant (P < 0.003) genetic correlations between pancreatic and colorectal cancer (rg = 0.55, P = 0.003), lung and colorectal cancer (rg = 0.31, P = 0.001). We also found suggestive genetic correlations between lung and breast cancer (rg = 0.27, P = 0.009), and colorectal and breast cancer (rg = 0.22, P = 0.01). In contrast, we found no evidence that prostate cancer shared an appreciable proportion of heritability with other cancers. After adjusting for 84 tests studying genetic correlations between cancer types and other traits (Bonferroni-corrected P value: 0.0006), only the genetic correlation between lung cancer and smoking remained significant (rg = 0.41, P = 1.03 × 10-6). We also observed nominally significant genetic correlations between body mass index and all cancers except ovarian cancer.Conclusions: Our results highlight novel genetic correlations and lend support to previous observational studies that have observed links between cancers and risk factors.Impact: This study demonstrates modest genetic correlations between cancers; in particular, breast, colorectal, and lung cancer share some degree of genetic basis. Cancer Epidemiol Biomarkers Prev; 26(9); 1427-35. ©2017 AACR..
Camacho, N.
Van Loo, P.
Edwards, S.
Kay, J.D.
Matthews, L.
Haase, K.
Clark, J.
Dennis, N.
Thomas, S.
Kremeyer, B.
Zamora, J.
Butler, A.P.
Gundem, G.
Merson, S.
Luxton, H.
Hawkins, S.
Ghori, M.
Marsden, L.
Lambert, A.
Karaszi, K.
Pelvender, G.
Massie, C.E.
Kote-Jarai, Z.
Raine, K.
Jones, D.
Howat, W.J.
Hazell, S.
Livni, N.
Fisher, C.
Ogden, C.
Kumar, P.
Thompson, A.
Nicol, D.
Mayer, E.
Dudderidge, T.
Yu, Y.
Zhang, H.
Shah, N.C.
Gnanapragasam, V.J.
CRUK-ICGC Prostate Group,
Isaacs, W.
Visakorpi, T.
Hamdy, F.
Berney, D.
Verrill, C.
Warren, A.Y.
Wedge, D.C.
Lynch, A.G.
Foster, C.S.
Lu, Y.J.
Bova, G.S.
Whitaker, H.C.
McDermott, U.
Neal, D.E.
Eeles, R.
Cooper, C.S.
Brewer, D.S.
(2017). Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data. Plos genet,
Vol.13
(9),
p. e1007001.
show abstract
full text
A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses..
Patrikidou, A.
Uccello, M.
Tree, A.
Parker, C.
Attard, G.
Eeles, R.
Khoo, V.
van As, N.
Huddart, R.
Dearnaley, D.
Reid, A.
(2017). Upfront Docetaxel in the Post-STAMPEDE World: Lessons from an Early Evaluation of Non-trial Usage in Hormone-Sensitive Prostate Cancer. Clin oncol (r coll radiol),
Vol.29
(10),
pp. e174-e175.
full text
Bianchini, D.
Lorente, D.
Rescigno, P.
Zafeiriou, Z.
Psychopaida, E.
O'Sullivan, H.
Alaras, M.
Kolinsky, M.
Sumanasuriya, S.
Sousa Fontes, M.
Mateo, J.
Perez Lopez, R.
Tunariu, N.
Fotiadis, N.
Kumar, P.
Tree, A.
Van As, N.
Khoo, V.
Parker, C.
Eeles, R.
Thompson, A.
Dearnaley, D.
de Bono, J.S.
(2017). Effect on Overall Survival of Locoregional Treatment in a Cohort of De Novo Metastatic Prostate Cancer Patients: A Single Institution Retrospective Analysis From the Royal Marsden Hospital. Clin genitourin cancer,
Vol.15
(5),
pp. e801-e807.
show abstract
full text
BACKGROUND: The optimal management of the primary tumor in metastatic at diagnosis (M1) prostate cancer (PCa) patients is not yet established. We retrospectively evaluated the effect of locoregional treatment (LRT) on overall survival (OS) hypothesizing that this could improve outcome through better local disease control and the induction of an antitumor immune response (abscopal effect). PATIENTS AND METHODS: M1 at diagnosis PCa patients referred to the Prostate Targeted Therapy Group at the Royal Marsden between June 2003 and December 2013 were identified. LRT was defined as either surgery, radiotherapy (RT) or transurethral prostatectomy (TURP) administered to the primary tumor at any time point from diagnosis to death. Kaplan-Meier analyses generated OS data. The association between LRT and OS was evaluated in univariate (UV) and multivariate (MV) Cox regression models. RESULTS: Overall 300 patients were identified; 192 patients (64%) experienced local symptoms at some point during their disease course; 72 patients received LRT (56.9% TURP, 52.7% RT). None of the patients were treated with prostatectomy. LRT was more frequently performed in patients with low volume disease (35.4% vs. 16.2%; P < .001), lower prostate-specific antigen (PSA) level at diagnosis (median PSA: 75 vs. 184 ng/mL; P = .005) and local symptoms (34.2% vs. 4.8%; P < .001). LRT was associated in UV and MV analysis with longer OS (62.1 vs. 55.8 months; hazard ratio [HR], 0.74; P = .044), which remained significant for RT (69.4 vs. 55.1 months; HR, 0.54; P = .002) but not for TURP. RT was associated with better OS independent of disease volume at diagnosis. CONCLUSION: These data support the conduct of randomized phase III trials to evaluate the benefit of local control in patients with M1 disease at diagnosis..
Lecarpentier, J.
Silvestri, V.
Kuchenbaecker, K.B.
Barrowdale, D.
Dennis, J.
McGuffog, L.
Soucy, P.
Leslie, G.
Rizzolo, P.
Navazio, A.S.
Valentini, V.
Zelli, V.
Lee, A.
Amin Al Olama, A.
Tyrer, J.P.
Southey, M.
John, E.M.
Conner, T.A.
Goldgar, D.E.
Buys, S.S.
Janavicius, R.
Steele, L.
Ding, Y.C.
Neuhausen, S.L.
Hansen, T.V.
Osorio, A.
Weitzel, J.N.
Toss, A.
Medici, V.
Cortesi, L.
Zanna, I.
Palli, D.
Radice, P.
Manoukian, S.
Peissel, B.
Azzollini, J.
Viel, A.
Cini, G.
Damante, G.
Tommasi, S.
Peterlongo, P.
Fostira, F.
Hamann, U.
Evans, D.G.
Henderson, A.
Brewer, C.
Eccles, D.
Cook, J.
Ong, K.-.
Walker, L.
Side, L.E.
Porteous, M.E.
Davidson, R.
Hodgson, S.
Frost, D.
Adlard, J.
Izatt, L.
Eeles, R.
Ellis, S.
Tischkowitz, M.
EMBRACE,
Godwin, A.K.
Meindl, A.
Gehrig, A.
Dworniczak, B.
Sutter, C.
Engel, C.
Niederacher, D.
Steinemann, D.
Hahnen, E.
Hauke, J.
Rhiem, K.
Kast, K.
Arnold, N.
Ditsch, N.
Wang-Gohrke, S.
Wappenschmidt, B.
Wand, D.
Lasset, C.
Stoppa-Lyonnet, D.
Belotti, M.
Damiola, F.
Barjhoux, L.
Mazoyer, S.
GEMO Study Collaborators,
Van Heetvelde, M.
Poppe, B.
De Leeneer, K.
Claes, K.B.
de la Hoya, M.
Garcia-Barberan, V.
Caldes, T.
Perez Segura, P.
Kiiski, J.I.
Aittomäki, K.
Khan, S.
Nevanlinna, H.
van Asperen, C.J.
HEBON,
Vaszko, T.
Kasler, M.
Olah, E.
Balmaña, J.
Gutiérrez-Enríquez, S.
Diez, O.
Teulé, A.
Izquierdo, A.
Darder, E.
Brunet, J.
Del Valle, J.
Feliubadalo, L.
Pujana, M.A.
Lazaro, C.
Arason, A.
Agnarsson, B.A.
Johannsson, O.T.
Barkardottir, R.B.
Alducci, E.
Tognazzo, S.
Montagna, M.
Teixeira, M.R.
Pinto, P.
Spurdle, A.B.
Holland, H.
KConFab Investigators,
Lee, J.W.
Lee, M.H.
Lee, J.
Kim, S.-.
Kang, E.
Kim, Z.
Sharma, P.
Rebbeck, T.R.
Vijai, J.
Robson, M.
Lincoln, A.
Musinsky, J.
Gaddam, P.
Tan, Y.Y.
Berger, A.
Singer, C.F.
Loud, J.T.
Greene, M.H.
Mulligan, A.M.
Glendon, G.
Andrulis, I.L.
Toland, A.E.
Senter, L.
Bojesen, A.
Nielsen, H.R.
Skytte, A.-.
Sunde, L.
Jensen, U.B.
Pedersen, I.S.
Krogh, L.
Kruse, T.A.
Caligo, M.A.
Yoon, S.-.
Teo, S.-.
von Wachenfeldt, A.
Huo, D.
Nielsen, S.M.
Olopade, O.I.
Nathanson, K.L.
Domchek, S.M.
Lorenchick, C.
Jankowitz, R.C.
Campbell, I.
James, P.
Mitchell, G.
Orr, N.
Park, S.K.
Thomassen, M.
Offit, K.
Couch, F.J.
Simard, J.
Easton, D.F.
Chenevix-Trench, G.
Schmutzler, R.K.
Antoniou, A.C.
Ottini, L.
(2017). Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores. J clin oncol,
Vol.35
(20),
pp. 2240-2250.
show abstract
full text
Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management..
Moynihan, C.
Bancroft, E.K.
Mitra, A.
Ardern-Jones, A.
Castro, E.
Page, E.C.
Eeles, R.A.
(2017). Ambiguity in a masculine world: Being a BRCA1/2 mutation carrier and a man with prostate cancer. Psychooncology,
Vol.26
(11),
pp. 1987-1993.
show abstract
full text
OBJECTIVE: Increased risk of prostate cancer (PCa) is observed in men with BRCA1/BRCA2 mutations. Sex and gender are key determinants of health and disease although unequal care exists between the sexes. Stereotypical male attitudes are shown to lead to poor health outcomes. METHODS: Men with BRCA1/2 mutations and diagnosed with PCa were identified and invited to participate in a qualitative interview study. Data were analysed using a framework approach. "Masculinity theory" was used to report the impact of having both a BRCA1/2 mutation and PCa. RESULTS: Eleven of 15 eligible men were interviewed. The umbrella concept of "Ambiguity in a Masculine World" was evident. Men's responses often matched those of women in a genetic context. Men's BRCA experience was described, as "on the back burner" but "a bonus" enabling familial detection and early diagnosis of PCa. Embodiment of PCa took precedence as men revealed stereotypical "ideal" masculine responses such as stoicism and control while creating new "masculinities" when faced with the vicissitudes of having 2 gendered conditions. CONCLUSION: Health workers are urged to take a reflexive approach, void of masculine ideals, a belief in which obfuscates men's experience. Research is required regarding men's support needs in the name of equality of care..
Milne, R.L.
Kuchenbaecker, K.B.
Michailidou, K.
Beesley, J.
Kar, S.
Lindström, S.
Hui, S.
Lemaçon, A.
Soucy, P.
Dennis, J.
Jiang, X.
Rostamianfar, A.
Finucane, H.
Bolla, M.K.
McGuffog, L.
Wang, Q.
Aalfs, C.M.
ABCTB Investigators,
Adams, M.
Adlard, J.
Agata, S.
Ahmed, S.
Ahsan, H.
Aittomäki, K.
Al-Ejeh, F.
Allen, J.
Ambrosone, C.B.
Amos, C.I.
Andrulis, I.L.
Anton-Culver, H.
Antonenkova, N.N.
Arndt, V.
Arnold, N.
Aronson, K.J.
Auber, B.
Auer, P.L.
Ausems, M.G.
Azzollini, J.
Bacot, F.
Balmaña, J.
Barile, M.
Barjhoux, L.
Barkardottir, R.B.
Barrdahl, M.
Barnes, D.
Barrowdale, D.
Baynes, C.
Beckmann, M.W.
Benitez, J.
Bermisheva, M.
Bernstein, L.
Bignon, Y.-.
Blazer, K.R.
Blok, M.J.
Blomqvist, C.
Blot, W.
Bobolis, K.
Boeckx, B.
Bogdanova, N.V.
Bojesen, A.
Bojesen, S.E.
Bonanni, B.
Børresen-Dale, A.-.
Bozsik, A.
Bradbury, A.R.
Brand, J.S.
Brauch, H.
Brenner, H.
Bressac-de Paillerets, B.
Brewer, C.
Brinton, L.
Broberg, P.
Brooks-Wilson, A.
Brunet, J.
Brüning, T.
Burwinkel, B.
Buys, S.S.
Byun, J.
Cai, Q.
Caldés, T.
Caligo, M.A.
Campbell, I.
Canzian, F.
Caron, O.
Carracedo, A.
Carter, B.D.
Castelao, J.E.
Castera, L.
Caux-Moncoutier, V.
Chan, S.B.
Chang-Claude, J.
Chanock, S.J.
Chen, X.
Cheng, T.-.
Chiquette, J.
Christiansen, H.
Claes, K.B.
Clarke, C.L.
Conner, T.
Conroy, D.M.
Cook, J.
Cordina-Duverger, E.
Cornelissen, S.
Coupier, I.
Cox, A.
Cox, D.G.
Cross, S.S.
Cuk, K.
Cunningham, J.M.
Czene, K.
Daly, M.B.
Damiola, F.
Darabi, H.
Davidson, R.
De Leeneer, K.
Devilee, P.
Dicks, E.
Diez, O.
Ding, Y.C.
Ditsch, N.
Doheny, K.F.
Domchek, S.M.
Dorfling, C.M.
Dörk, T.
Dos-Santos-Silva, I.
Dubois, S.
Dugué, P.-.
Dumont, M.
Dunning, A.M.
Durcan, L.
Dwek, M.
Dworniczak, B.
Eccles, D.
Eeles, R.
Ehrencrona, H.
Eilber, U.
Ejlertsen, B.
Ekici, A.B.
Eliassen, A.H.
EMBRACE,
Engel, C.
Eriksson, M.
Fachal, L.
Faivre, L.
Fasching, P.A.
Faust, U.
Figueroa, J.
Flesch-Janys, D.
Fletcher, O.
Flyger, H.
Foulkes, W.D.
Friedman, E.
Fritschi, L.
Frost, D.
Gabrielson, M.
Gaddam, P.
Gammon, M.D.
Ganz, P.A.
Gapstur, S.M.
Garber, J.
Garcia-Barberan, V.
García-Sáenz, J.A.
Gaudet, M.M.
Gauthier-Villars, M.
Gehrig, A.
GEMO Study Collaborators,
Georgoulias, V.
Gerdes, A.-.
Giles, G.G.
Glendon, G.
Godwin, A.K.
Goldberg, M.S.
Goldgar, D.E.
González-Neira, A.
Goodfellow, P.
Greene, M.H.
Alnæs, G.I.
Grip, M.
Gronwald, J.
Grundy, A.
Gschwantler-Kaulich, D.
Guénel, P.
Guo, Q.
Haeberle, L.
Hahnen, E.
Haiman, C.A.
Håkansson, N.
Hallberg, E.
Hamann, U.
Hamel, N.
Hankinson, S.
Hansen, T.V.
Harrington, P.
Hart, S.N.
Hartikainen, J.M.
Healey, C.S.
HEBON,
Hein, A.
Helbig, S.
Henderson, A.
Heyworth, J.
Hicks, B.
Hillemanns, P.
Hodgson, S.
Hogervorst, F.B.
Hollestelle, A.
Hooning, M.J.
Hoover, B.
Hopper, J.L.
Hu, C.
Huang, G.
Hulick, P.J.
Humphreys, K.
Hunter, D.J.
Imyanitov, E.N.
Isaacs, C.
Iwasaki, M.
Izatt, L.
Jakubowska, A.
James, P.
Janavicius, R.
Janni, W.
Jensen, U.B.
John, E.M.
Johnson, N.
Jones, K.
Jones, M.
Jukkola-Vuorinen, A.
Kaaks, R.
Kabisch, M.
Kaczmarek, K.
Kang, D.
Kast, K.
kConFab/AOCS Investigators,
Keeman, R.
Kerin, M.J.
Kets, C.M.
Keupers, M.
Khan, S.
Khusnutdinova, E.
Kiiski, J.I.
Kim, S.-.
Knight, J.A.
Konstantopoulou, I.
Kosma, V.-.
Kristensen, V.N.
Kruse, T.A.
Kwong, A.
Lænkholm, A.-.
Laitman, Y.
Lalloo, F.
Lambrechts, D.
Landsman, K.
Lasset, C.
Lazaro, C.
Le Marchand, L.
Lecarpentier, J.
Lee, A.
Lee, E.
Lee, J.W.
Lee, M.H.
Lejbkowicz, F.
Lesueur, F.
Li, J.
Lilyquist, J.
Lincoln, A.
Lindblom, A.
Lissowska, J.
Lo, W.-.
Loibl, S.
Long, J.
Loud, J.T.
Lubinski, J.
Luccarini, C.
Lush, M.
MacInnis, R.J.
Maishman, T.
Makalic, E.
Kostovska, I.M.
Malone, K.E.
Manoukian, S.
Manson, J.E.
Margolin, S.
Martens, J.W.
Martinez, M.E.
Matsuo, K.
Mavroudis, D.
Mazoyer, S.
McLean, C.
Meijers-Heijboer, H.
Menéndez, P.
Meyer, J.
Miao, H.
Miller, A.
Miller, N.
Mitchell, G.
Montagna, M.
Muir, K.
Mulligan, A.M.
Mulot, C.
Nadesan, S.
Nathanson, K.L.
NBSC Collaborators,
Neuhausen, S.L.
Nevanlinna, H.
Nevelsteen, I.
Niederacher, D.
Nielsen, S.F.
Nordestgaard, B.G.
Norman, A.
Nussbaum, R.L.
Olah, E.
Olopade, O.I.
Olson, J.E.
Olswold, C.
Ong, K.-.
Oosterwijk, J.C.
Orr, N.
Osorio, A.
Pankratz, V.S.
Papi, L.
Park-Simon, T.-.
Paulsson-Karlsson, Y.
Lloyd, R.
Pedersen, I.S.
Peissel, B.
Peixoto, A.
Perez, J.I.
Peterlongo, P.
Peto, J.
Pfeiler, G.
Phelan, C.M.
Pinchev, M.
Plaseska-Karanfilska, D.
Poppe, B.
Porteous, M.E.
Prentice, R.
Presneau, N.
Prokofieva, D.
Pugh, E.
Pujana, M.A.
Pylkäs, K.
Rack, B.
Radice, P.
Rahman, N.
Rantala, J.
Rappaport-Fuerhauser, C.
Rennert, G.
Rennert, H.S.
Rhenius, V.
Rhiem, K.
Richardson, A.
Rodriguez, G.C.
Romero, A.
Romm, J.
Rookus, M.A.
Rudolph, A.
Ruediger, T.
Saloustros, E.
Sanders, J.
Sandler, D.P.
Sangrajrang, S.
Sawyer, E.J.
Schmidt, D.F.
Schoemaker, M.J.
Schumacher, F.
Schürmann, P.
Schwentner, L.
Scott, C.
Scott, R.J.
Seal, S.
Senter, L.
Seynaeve, C.
Shah, M.
Sharma, P.
Shen, C.-.
Sheng, X.
Shimelis, H.
Shrubsole, M.J.
Shu, X.-.
Side, L.E.
Singer, C.F.
Sohn, C.
Southey, M.C.
Spinelli, J.J.
Spurdle, A.B.
Stegmaier, C.
Stoppa-Lyonnet, D.
Sukiennicki, G.
Surowy, H.
Sutter, C.
Swerdlow, A.
Szabo, C.I.
Tamimi, R.M.
Tan, Y.Y.
Taylor, J.A.
Tejada, M.-.
Tengström, M.
Teo, S.H.
Terry, M.B.
Tessier, D.C.
Teulé, A.
Thöne, K.
Thull, D.L.
Tibiletti, M.G.
Tihomirova, L.
Tischkowitz, M.
Toland, A.E.
Tollenaar, R.A.
Tomlinson, I.
Tong, L.
Torres, D.
Tranchant, M.
Truong, T.
Tucker, K.
Tung, N.
Tyrer, J.
Ulmer, H.-.
Vachon, C.
van Asperen, C.J.
Van Den Berg, D.
van den Ouweland, A.M.
van Rensburg, E.J.
Varesco, L.
Varon-Mateeva, R.
Vega, A.
Viel, A.
Vijai, J.
Vincent, D.
Vollenweider, J.
Walker, L.
Wang, Z.
Wang-Gohrke, S.
Wappenschmidt, B.
Weinberg, C.R.
Weitzel, J.N.
Wendt, C.
Wesseling, J.
Whittemore, A.S.
Wijnen, J.T.
Willett, W.
Winqvist, R.
Wolk, A.
Wu, A.H.
Xia, L.
Yang, X.R.
Yannoukakos, D.
Zaffaroni, D.
Zheng, W.
Zhu, B.
Ziogas, A.
Ziv, E.
Zorn, K.K.
Gago-Dominguez, M.
Mannermaa, A.
Olsson, H.
Teixeira, M.R.
Stone, J.
Offit, K.
Ottini, L.
Park, S.K.
Thomassen, M.
Hall, P.
Meindl, A.
Schmutzler, R.K.
Droit, A.
Bader, G.D.
Pharoah, P.D.
Couch, F.J.
Easton, D.F.
Kraft, P.
Chenevix-Trench, G.
García-Closas, M.
Schmidt, M.K.
Antoniou, A.C.
Simard, J.
(2017). Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat genet,
Vol.49
(12),
pp. 1767-1778.
show abstract
full text
Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer..
Qian, D.C.
Busam, J.A.
Xiao, X.
O'Mara, T.A.
Eeles, R.A.
Schumacher, F.R.
Phelan, C.M.
Amos, C.I.
(2017). seXY: a tool for sex inference from genotype arrays. Bioinformatics,
Vol.33
(4),
pp. 561-563.
show abstract
full text
MOTIVATION: Checking concordance between reported sex and genotype-inferred sex is a crucial quality control measure in genome-wide association studies (GWAS). However, limited insights exist regarding the true accuracy of software that infer sex from genotype array data. RESULTS: We present seXY, a logistic regression model trained on both X chromosome heterozygosity and Y chromosome missingness, that consistently demonstrated >99.5% sex inference accuracy in cross-validation for 889 males and 5,361 females enrolled in prostate cancer and ovarian cancer GWAS. Compared to PLINK, one of the most popular tools for sex inference in GWAS that assesses only X chromosome heterozygosity, seXY achieved marginally better male classification and 3% more accurate female classification. AVAILABILITY AND IMPLEMENTATION: https://github.com/Christopher-Amos-Lab/seXY. CONTACT: [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online..
Lin, H.-.
Chen, D.-.
Huang, P.-.
Liu, Y.-.
Ochoa, A.
Zabaleta, J.
Mercante, D.E.
Fang, Z.
Sellers, T.A.
Pow-Sang, J.M.
Cheng, C.-.
Eeles, R.
Easton, D.
Kote-Jarai, Z.
Amin Al Olama, A.
Benlloch, S.
Muir, K.
Giles, G.G.
Wiklund, F.
Gronberg, H.
Haiman, C.A.
Schleutker, J.
Nordestgaard, B.G.
Travis, R.C.
Hamdy, F.
Pashayan, N.
Khaw, K.-.
Stanford, J.L.
Blot, W.J.
Thibodeau, S.N.
Maier, C.
Kibel, A.S.
Cybulski, C.
Cannon-Albright, L.
Brenner, H.
Kaneva, R.
Batra, J.
Teixeira, M.R.
Pandha, H.
Lu, Y.-.
PRACTICAL Consortium,
Park, J.Y.
(2017). SNP interaction pattern identifier (SIPI): an intensive search for SNP-SNP interaction patterns. Bioinformatics,
Vol.33
(6),
pp. 822-833.
show abstract
full text
MOTIVATION: Testing SNP-SNP interactions is considered as a key for overcoming bottlenecks of genetic association studies. However, related statistical methods for testing SNP-SNP interactions are underdeveloped. RESULTS: We propose the SNP Interaction Pattern Identifier (SIPI), which tests 45 biologically meaningful interaction patterns for a binary outcome. SIPI takes non-hierarchical models, inheritance modes and mode coding direction into consideration. The simulation results show that SIPI has higher power than MDR (Multifactor Dimensionality Reduction), AA_Full, Geno_Full (full interaction model with additive or genotypic mode) and SNPassoc in detecting interactions. Applying SIPI to the prostate cancer PRACTICAL consortium data with approximately 21 000 patients, the four SNP pairs in EGFR-EGFR , EGFR-MMP16 and EGFR-CSF1 were found to be associated with prostate cancer aggressiveness with the exact or similar pattern in the discovery and validation sets. A similar match for external validation of SNP-SNP interaction studies is suggested. We demonstrated that SIPI not only searches for more meaningful interaction patterns but can also overcome the unstable nature of interaction patterns. AVAILABILITY AND IMPLEMENTATION: The SIPI software is freely available at http://publichealth.lsuhsc.edu/LinSoftware/ . CONTACT: [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online..
Taylor, A.E.
Martin, R.M.
Geybels, M.S.
Stanford, J.L.
Shui, I.
Eeles, R.
Easton, D.
Kote-Jarai, Z.
Amin Al Olama, A.
Benlloch, S.
Muir, K.
Giles, G.G.
Wiklund, F.
Gronberg, H.
Haiman, C.A.
Schleutker, J.
Nordestgaard, B.G.
Travis, R.C.
Neal, D.
Pashayan, N.
Khaw, K.-.
Blot, W.
Thibodeau, S.
Maier, C.
Kibel, A.S.
Cybulski, C.
Cannon-Albright, L.
Brenner, H.
Park, J.
Kaneva, R.
Batra, J.
Teixeira, M.R.
Pandha, H.
PRACTICAL Consortium,
Donovan, J.
Munafò, M.R.
(2017). Investigating the possible causal role of coffee consumption with prostate cancer risk and progression using Mendelian randomization analysis. Int j cancer,
Vol.140
(2),
pp. 322-328.
show abstract
full text
Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic variants and prostate cancer case status, stage and grade were assessed by logistic regression and with all-cause and prostate cancer-specific mortality using Cox proportional hazards regression. There was no clear evidence that a genetic risk score combining rs4410790 and rs2472297 was associated with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high-grade compared to low-grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage disease (OR: 1.03, 95% CI: 1.01, 1.06). Amongst men with prostate cancer, there was no clear association between the genetic risk score and all-cause mortality (HR: 1.00, 95% CI: 0.97,1.04) or prostate cancer-specific mortality (HR: 1.03, 95% CI: 0.98,1.08). These results, which should have less bias from confounding than observational estimates, are not consistent with a substantial effect of coffee consumption on reducing prostate cancer incidence or progression..
Kuchenbaecker, K.B.
Hopper, J.L.
Barnes, D.R.
Phillips, K.-.
Mooij, T.M.
Roos-Blom, M.-.
Jervis, S.
van Leeuwen, F.E.
Milne, R.L.
Andrieu, N.
Goldgar, D.E.
Terry, M.B.
Rookus, M.A.
Easton, D.F.
Antoniou, A.C.
BRCA1 and BRCA2 Cohort Consortium,
McGuffog, L.
Evans, D.G.
Barrowdale, D.
Frost, D.
Adlard, J.
Ong, K.-.
Izatt, L.
Tischkowitz, M.
Eeles, R.
Davidson, R.
Hodgson, S.
Ellis, S.
Nogues, C.
Lasset, C.
Stoppa-Lyonnet, D.
Fricker, J.-.
Faivre, L.
Berthet, P.
Hooning, M.J.
van der Kolk, L.E.
Kets, C.M.
Adank, M.A.
John, E.M.
Chung, W.K.
Andrulis, I.L.
Southey, M.
Daly, M.B.
Buys, S.S.
Osorio, A.
Engel, C.
Kast, K.
Schmutzler, R.K.
Caldes, T.
Jakubowska, A.
Simard, J.
Friedlander, M.L.
McLachlan, S.-.
Machackova, E.
Foretova, L.
Tan, Y.Y.
Singer, C.F.
Olah, E.
Gerdes, A.-.
Arver, B.
Olsson, H.
(2017). Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. Jama,
Vol.317
(23),
pp. 2402-2416.
show abstract
full text
Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures: BRCA1/2 mutations, family cancer history, and mutation location. Main Outcomes and Measures: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results: Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). Conclusions and Relevance: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment..
Lophatananon, A.
Stewart-Brown, S.
Kote-Jarai, Z.
Olama, A.A.
Garcia, S.B.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Giles, G.G.
Fitzgerald, L.M.
Southey, M.C.
Pharoah, P.
Pashayan, N.
Gronberg, H.
Wiklund, F.
Aly, M.
Stanford, J.L.
Brenner, H.
Dieffenbach, A.K.
Arndt, V.
Park, J.Y.
Lin, H.-.
Sellers, T.
Slavov, C.
Kaneva, R.
Mitev, V.
Batra, J.
Spurdle, A.
Clements, J.A.
APCB BioResource,
PRACTICAL consortium,
Easton, D.
Eeles, R.A.
Muir, K.
(2017). Height, selected genetic markers and prostate cancer risk: results from the PRACTICAL consortium. Br j cancer,
Vol.117
(5),
pp. 734-743.
show abstract
full text
BACKGROUND: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer. METHODS: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects and their possible interactions. RESULTS: The results suggest that height is associated with high-grade prostate cancer risk. Men with height >180 cm are at a 22% increased risk as compared to men with height <173 cm (OR 1.22, 95% CI 1.01-1.48). Genetic variants in the growth pathway gene showed an association with prostate cancer risk. The aggregate scores of the selected variants identified a significantly increased risk of overall prostate cancer and high-grade prostate cancer by 13% and 15%, respectively, in the highest score group as compared to lowest score group. CONCLUSIONS: There was no evidence of gene-environment interaction between height and the selected candidate SNPs.Our findings suggest a role of height in high-grade prostate cancer. The effect of genetic variants in the genes related to growth is seen in all cases and high-grade prostate cancer. There is no interaction between these two exposures..
Dimitrakopoulou, V.I.
Tsilidis, K.K.
Haycock, P.C.
Dimou, N.L.
Al-Dabhani, K.
Martin, R.M.
Lewis, S.J.
Gunter, M.J.
Mondul, A.
Shui, I.M.
Theodoratou, E.
Nimptsch, K.
Lindström, S.
Albanes, D.
Kühn, T.
Key, T.J.
Travis, R.C.
Vimaleswaran, K.S.
GECCO Consortium,
PRACTICAL Consortium,
GAME-ON Network (CORECT, DRIVE, ELLIPSE, FOCI-OCAC, TRICL-ILCCO),
Kraft, P.
Pierce, B.L.
Schildkraut, J.M.
(2017). Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study. Bmj,
Vol.359,
pp. j4761-j4761.
show abstract
full text
Objective To determine if circulating concentrations of vitamin D are causally associated with risk of cancer.Design Mendelian randomisation study.Setting Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform).Participants 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls.Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations.Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined.Results There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated.Conclusions There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not currently be recommended as a strategy for primary cancer prevention..
Zuber, V.
Bettella, F.
Witoelar, A.
PRACTICAL Consortium,
CRUK GWAS,
BCAC Consortium,
TRICL Consortium,
Andreassen, O.A.
Mills, I.G.
Urbanucci, A.
(2017). Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer. Bmc genomics,
Vol.18
(1),
p. 270.
show abstract
full text
BACKGROUND: Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs. RESULTS: Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia. CONCLUSIONS: This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation..
Fehringer, G.
Kraft, P.
Pharoah, P.D.
Eeles, R.A.
Chatterjee, N.
Schumacher, F.R.
Schildkraut, J.M.
Lindström, S.
Brennan, P.
Bickeböller, H.
Houlston, R.S.
Landi, M.T.
Caporaso, N.
Risch, A.
Amin Al Olama, A.
Berndt, S.I.
Giovannucci, E.L.
Grönberg, H.
Kote-Jarai, Z.
Ma, J.
Muir, K.
Stampfer, M.J.
Stevens, V.L.
Wiklund, F.
Willett, W.C.
Goode, E.L.
Permuth, J.B.
Risch, H.A.
Reid, B.M.
Bezieau, S.
Brenner, H.
Chan, A.T.
Chang-Claude, J.
Hudson, T.J.
Kocarnik, J.K.
Newcomb, P.A.
Schoen, R.E.
Slattery, M.L.
White, E.
Adank, M.A.
Ahsan, H.
Aittomäki, K.
Baglietto, L.
Blomquist, C.
Canzian, F.
Czene, K.
Dos-Santos-Silva, I.
Eliassen, A.H.
Figueroa, J.D.
Flesch-Janys, D.
Fletcher, O.
Garcia-Closas, M.
Gaudet, M.M.
Johnson, N.
Hall, P.
Hazra, A.
Hein, R.
Hofman, A.
Hopper, J.L.
Irwanto, A.
Johansson, M.
Kaaks, R.
Kibriya, M.G.
Lichtner, P.
Liu, J.
Lund, E.
Makalic, E.
Meindl, A.
Müller-Myhsok, B.
Muranen, T.A.
Nevanlinna, H.
Peeters, P.H.
Peto, J.
Prentice, R.L.
Rahman, N.
Sanchez, M.J.
Schmidt, D.F.
Schmutzler, R.K.
Southey, M.C.
Tamimi, R.
Travis, R.C.
Turnbull, C.
Uitterlinden, A.G.
Wang, Z.
Whittemore, A.S.
Yang, X.R.
Zheng, W.
Buchanan, D.D.
Casey, G.
Conti, D.V.
Edlund, C.K.
Gallinger, S.
Haile, R.W.
Jenkins, M.
Le Marchand, L.
Li, L.
Lindor, N.M.
Schmit, S.L.
Thibodeau, S.N.
Woods, M.O.
Rafnar, T.
Gudmundsson, J.
Stacey, S.N.
Stefansson, K.
Sulem, P.
Chen, Y.A.
Tyrer, J.P.
Christiani, D.C.
Wei, Y.
Shen, H.
Hu, Z.
Shu, X.-.
Shiraishi, K.
Takahashi, A.
Bossé, Y.
Obeidat, M.
Nickle, D.
Timens, W.
Freedman, M.L.
Li, Q.
Seminara, D.
Chanock, S.J.
Gong, J.
Peters, U.
Gruber, S.B.
Amos, C.I.
Sellers, T.A.
Easton, D.F.
Hunter, D.J.
Haiman, C.A.
Henderson, B.E.
Hung, R.J.
Ovarian Cancer Association Consortium (OCAC),
PRACTICAL Consortium,
Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON),
Colorectal Transdisciplinary (CORECT) Study,
African American Breast Cancer Consortium (AABC) and African Ancestry Prostate Cancer Consortium (AAPC),
(2016). Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations. Cancer res,
Vol.76
(17),
pp. 5103-5114.
show abstract
full text
Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR..
Shu, C.A.
Pike, M.C.
Jotwani, A.R.
Friebel, T.M.
Soslow, R.A.
Levine, D.A.
Nathanson, K.L.
Konner, J.A.
Arnold, A.G.
Bogomolniy, F.
Dao, F.
Olvera, N.
Bancroft, E.K.
Goldfrank, D.J.
Stadler, Z.K.
Robson, M.E.
Brown, C.L.
Leitao, M.M.
Abu-Rustum, N.R.
Aghajanian, C.A.
Blum, J.L.
Neuhausen, S.L.
Garber, J.E.
Daly, M.B.
Isaacs, C.
Eeles, R.A.
Ganz, P.A.
Barakat, R.R.
Offit, K.
Domchek, S.M.
Rebbeck, T.R.
Kauff, N.D.
(2016). Uterine Cancer After Risk-Reducing Salpingo-oophorectomy Without Hysterectomy in Women With BRCA Mutations. Jama oncol,
Vol.2
(11),
pp. 1434-1440.
show abstract
full text
Importance: The link between BRCA mutations and uterine cancer is unclear. Therefore, although risk-reducing salpingo-oophorectomy (RRSO) is standard treatment among women with BRCA mutations (BRCA+ women), the role of concomitant hysterectomy is controversial. Objective: To determine the risk for uterine cancer and distribution of specific histologic subtypes in BRCA+ women after RRSO without hysterectomy. Design, Setting, and Participants: This multicenter prospective cohort study included 1083 women with a deleterious BRCA1 or BRCA2 mutation identified from January 1, 1995, to December 31, 2011, at 9 academic medical centers in the United States and the United Kingdom who underwent RRSO without a prior or concomitant hysterectomy. Of these, 627 participants were BRCA1+; 453, BRCA2+; and 3, both. Participants were prospectively followed up for a median 5.1 (interquartile range [IQR], 3.0-8.4) years after ascertainment, BRCA testing, or RRSO (whichever occurred last). Follow up data available through October 14, 2014, were included in the analyses. Censoring occurred at uterine cancer diagnosis, hysterectomy, last follow-up, or death. New cancers were categorized by histologic subtype, and available tumors were analyzed for loss of the wild-type BRCA gene and/or protein expression. Main Outcomes and Measures: Incidence of uterine corpus cancer in BRCA+ women who underwent RRSO without hysterectomy compared with rates expected from the Surveillance, Epidemiology, and End Results database. Results: Among the 1083 women women who underwent RRSO without hysterectomy at a median age 45.6 (IQR: 40.9 - 52.5), 8 incident uterine cancers were observed (4.3 expected; observed to expected [O:E] ratio, 1.9; 95% CI, 0.8-3.7; P = .09). No increased risk for endometrioid endometrial carcinoma or sarcoma was found after stratifying by subtype. Five serous and/or serous-like (serous/serous-like) endometrial carcinomas were observed (4 BRCA1+ and 1 BRCA2+) 7.2 to 12.9 years after RRSO (BRCA1: 0.18 expected [O:E ratio, 22.2; 95% CI, 6.1-56.9; P < .001]; BRCA2: 0.16 expected [O:E ratio, 6.4; 95% CI, 0.2-35.5; P = .15]). Tumor analyses confirmed loss of the wild-type BRCA1 gene and/or protein expression in all 3 available serous/serous-like BRCA1+ tumors. Conclusions and Relevance: Although the overall risk for uterine cancer after RRSO was not increased, the risk for serous/serous-like endometrial carcinoma was increased in BRCA1+ women. This risk should be considered when discussing the advantages and risks of hysterectomy at the time of RRSO in BRCA1+ women..
Scarbrough, P.M.
Weber, R.P.
Iversen, E.S.
Brhane, Y.
Amos, C.I.
Kraft, P.
Hung, R.J.
Sellers, T.A.
Witte, J.S.
Pharoah, P.
Henderson, B.E.
Gruber, S.B.
Hunter, D.J.
Garber, J.E.
Joshi, A.D.
McDonnell, K.
Easton, D.F.
Eeles, R.
Kote-Jarai, Z.
Muir, K.
Doherty, J.A.
Schildkraut, J.M.
(2016). A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer. Cancer epidemiol biomarkers prev,
Vol.25
(1),
pp. 193-200.
show abstract
full text
BACKGROUND: DNA damage is an established mediator of carcinogenesis, although genome-wide association studies (GWAS) have identified few significant loci. This cross-cancer site, pooled analysis was performed to increase the power to detect common variants of DNA repair genes associated with cancer susceptibility. METHODS: We conducted a cross-cancer analysis of 60,297 single nucleotide polymorphisms, at 229 DNA repair gene regions, using data from the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Our analysis included data from 32 GWAS and 48,734 controls and 51,537 cases across five cancer sites (breast, colon, lung, ovary, and prostate). Because of the unavailability of individual data, data were analyzed at the aggregate level. Meta-analysis was performed using the Association analysis for SubSETs (ASSET) software. To test for genetic associations that might escape individual variant testing due to small effect sizes, pathway analysis of eight DNA repair pathways was performed using hierarchical modeling. RESULTS: We identified three susceptibility DNA repair genes, RAD51B (P < 5.09 × 10(-6)), MSH5 (P < 5.09 × 10(-6)), and BRCA2 (P = 5.70 × 10(-6)). Hierarchical modeling identified several pleiotropic associations with cancer risk in the base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination pathways. CONCLUSIONS: Only three susceptibility loci were identified, which had all been previously reported. In contrast, hierarchical modeling identified several pleiotropic cancer risk associations in key DNA repair pathways. IMPACT: Results suggest that many common variants in DNA repair genes are likely associated with cancer susceptibility through small effect sizes that do not meet stringent significance testing criteria..
Mancuso, N.
Rohland, N.
Rand, K.A.
Tandon, A.
Allen, A.
Quinque, D.
Mallick, S.
Li, H.
Stram, A.
Sheng, X.
Kote-Jarai, Z.
Easton, D.F.
Eeles, R.A.
PRACTICAL consortium,
Le Marchand, L.
Lubwama, A.
Stram, D.
Watya, S.
Conti, D.V.
Henderson, B.
Haiman, C.A.
Pasaniuc, B.
Reich, D.
(2016). The contribution of rare variation to prostate cancer heritability. Nat genet,
Vol.48
(1),
pp. 30-35.
show abstract
full text
We report targeted sequencing of 63 known prostate cancer risk regions in a multi-ancestry study of 9,237 men and use the data to explore the contribution of low-frequency variation to disease risk. We show that SNPs with minor allele frequencies (MAFs) of 0.1-1% explain a substantial fraction of prostate cancer risk in men of African ancestry. We estimate that these SNPs account for 0.12 (standard error (s.e.) = 0.05) of variance in risk (∼42% of the variance contributed by SNPs with MAF of 0.1-50%). This contribution is much larger than the fraction of neutral variation due to SNPs in this class, implying that natural selection has driven down the frequency of many prostate cancer risk alleles; we estimate the coupling between selection and allelic effects at 0.48 (95% confidence interval [0.19, 0.78]) under the Eyre-Walker model. Our results indicate that rare variants make a disproportionate contribution to genetic risk for prostate cancer and suggest the possibility that rare variants may also have an outsize effect on other common traits..
Bonilla, C.
Lewis, S.J.
Rowlands, M.-.
Gaunt, T.R.
Davey Smith, G.
Gunnell, D.
Palmer, T.
Donovan, J.L.
Hamdy, F.C.
Neal, D.E.
Eeles, R.
Easton, D.
Kote-Jarai, Z.
Al Olama, A.A.
Benlloch, S.
Muir, K.
Giles, G.G.
Wiklund, F.
Grönberg, H.
Haiman, C.A.
Schleutker, J.
Nordestgaard, B.G.
Travis, R.C.
Pashayan, N.
Khaw, K.-.
Stanford, J.L.
Blot, W.J.
Thibodeau, S.
Maier, C.
Kibel, A.S.
Cybulski, C.
Cannon-Albright, L.
Brenner, H.
Park, J.
Kaneva, R.
Batra, J.
Teixeira, M.R.
Pandha, H.
PRACTICAL consortium,
Lathrop, M.
Martin, R.M.
Holly, J.M.
(2016). Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels. Int j cancer,
Vol.139
(7),
pp. 1520-1533.
show abstract
full text
Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker..
Scott, R.A.
Freitag, D.F.
Li, L.
Chu, A.Y.
Surendran, P.
Young, R.
Grarup, N.
Stancáková, A.
Chen, Y.
Varga, T.V.
Yaghootkar, H.
Luan, J.
Zhao, J.H.
Willems, S.M.
Wessel, J.
Wang, S.
Maruthur, N.
Michailidou, K.
Pirie, A.
van der Lee, S.J.
Gillson, C.
Al Olama, A.A.
Amouyel, P.
Arriola, L.
Arveiler, D.
Aviles-Olmos, I.
Balkau, B.
Barricarte, A.
Barroso, I.
Garcia, S.B.
Bis, J.C.
Blankenberg, S.
Boehnke, M.
Boeing, H.
Boerwinkle, E.
Borecki, I.B.
Bork-Jensen, J.
Bowden, S.
Caldas, C.
Caslake, M.
CVD50 consortium,
Cupples, L.A.
Cruchaga, C.
Czajkowski, J.
den Hoed, M.
Dunn, J.A.
Earl, H.M.
Ehret, G.B.
Ferrannini, E.
Ferrieres, J.
Foltynie, T.
Ford, I.
Forouhi, N.G.
Gianfagna, F.
Gonzalez, C.
Grioni, S.
Hiller, L.
Jansson, J.-.
Jørgensen, M.E.
Jukema, J.W.
Kaaks, R.
Kee, F.
Kerrison, N.D.
Key, T.J.
Kontto, J.
Kote-Jarai, Z.
Kraja, A.T.
Kuulasmaa, K.
Kuusisto, J.
Linneberg, A.
Liu, C.
Marenne, G.
Mohlke, K.L.
Morris, A.P.
Muir, K.
Müller-Nurasyid, M.
Munroe, P.B.
Navarro, C.
Nielsen, S.F.
Nilsson, P.M.
Nordestgaard, B.G.
Packard, C.J.
Palli, D.
Panico, S.
Peloso, G.M.
Perola, M.
Peters, A.
Poole, C.J.
Quirós, J.R.
Rolandsson, O.
Sacerdote, C.
Salomaa, V.
Sánchez, M.-.
Sattar, N.
Sharp, S.J.
Sims, R.
Slimani, N.
Smith, J.A.
Thompson, D.J.
Trompet, S.
Tumino, R.
van der A, D.L.
van der Schouw, Y.T.
Virtamo, J.
Walker, M.
Walter, K.
GERAD_EC Consortium,
Neurology Working Group of the Cohorts for Heart,
Aging Research in Genomic Epidemiology (CHARGE),
Alzheimer’s Disease Genetics Consortium,
Pancreatic Cancer Cohort Consortium,
European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD),
EPIC-InterAct,
Abraham, J.E.
Amundadottir, L.T.
Aponte, J.L.
Butterworth, A.S.
Dupuis, J.
Easton, D.F.
Eeles, R.A.
Erdmann, J.
Franks, P.W.
Frayling, T.M.
Hansen, T.
Howson, J.M.
Jørgensen, T.
Kooner, J.
Laakso, M.
Langenberg, C.
McCarthy, M.I.
Pankow, J.S.
Pedersen, O.
Riboli, E.
Rotter, J.I.
Saleheen, D.
Samani, N.J.
Schunkert, H.
Vollenweider, P.
O'Rahilly, S.
CHARGE consortium,
CHD Exome+ Consortium,
CARDIOGRAM Exome Consortium,
Deloukas, P.
Danesh, J.
Goodarzi, M.O.
Kathiresan, S.
Meigs, J.B.
Ehm, M.G.
Wareham, N.J.
Waterworth, D.M.
(2016). A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease. Sci transl med,
Vol.8
(341),
p. 341ra76.
show abstract
full text
Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process..
Ahmed, M.
Eeles, R.
(2016). Germline genetic profiling in prostate cancer: latest developments and potential clinical applications. Future sci oa,
Vol.2
(1),
p. FSO87.
show abstract
Familial and twin studies have demonstrated a significant inherited component to prostate cancer predisposition. Genome wide association studies have shown that there are 100 single nucleotide polymorphisms which have been associated with the development of prostate cancer. This review aims to discuss the scientific methods used to identify these susceptibility loci. It will also examine the current clinical utility of these loci, which include the development of risk models as well as predicting treatment efficacy and toxicity. In order to refine the clinical utility of the susceptibility loci, international consortia have been developed to combine statistical power as well as skills and knowledge to further develop models that could be used to predict risk and treatment outcomes..
Pritchard, C.C.
Mateo, J.
Walsh, M.F.
De Sarkar, N.
Abida, W.
Beltran, H.
Garofalo, A.
Gulati, R.
Carreira, S.
Eeles, R.
Elemento, O.
Rubin, M.A.
Robinson, D.
Lonigro, R.
Hussain, M.
Chinnaiyan, A.
Vinson, J.
Filipenko, J.
Garraway, L.
Taplin, M.-.
AlDubayan, S.
Han, G.C.
Beightol, M.
Morrissey, C.
Nghiem, B.
Cheng, H.H.
Montgomery, B.
Walsh, T.
Casadei, S.
Berger, M.
Zhang, L.
Zehir, A.
Vijai, J.
Scher, H.I.
Sawyers, C.
Schultz, N.
Kantoff, P.W.
Solit, D.
Robson, M.
Van Allen, E.M.
Offit, K.
de Bono, J.
Nelson, P.S.
(2016). Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N engl j med,
Vol.375
(5),
pp. 443-453.
show abstract
full text
BACKGROUND: Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established. METHODS: We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes. RESULTS: A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001). CONCLUSIONS: In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate cancer. The frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to age at diagnosis or family history of prostate cancer. (Funded by Stand Up To Cancer and others.)..
Bonilla, C.
Lewis, S.J.
Martin, R.M.
Donovan, J.L.
Hamdy, F.C.
Neal, D.E.
Eeles, R.
Easton, D.
Kote-Jarai, Z.
Al Olama, A.A.
Benlloch, S.
Muir, K.
Giles, G.G.
Wiklund, F.
Gronberg, H.
Haiman, C.A.
Schleutker, J.
Nordestgaard, B.G.
Travis, R.C.
Pashayan, N.
Khaw, K.-.
Stanford, J.L.
Blot, W.J.
Thibodeau, S.
Maier, C.
Kibel, A.S.
Cybulski, C.
Cannon-Albright, L.
Brenner, H.
Park, J.
Kaneva, R.
Batra, J.
Teixeira, M.R.
Pandha, H.
Lathrop, M.
Davey Smith, G.
PRACTICAL consortium,
(2016). Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort. Bmc med,
Vol.14,
p. 66.
show abstract
full text
BACKGROUND: Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach. METHODS: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the PRACTICAL consortium (n = 43,737) as a replication sample. RESULTS: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64-0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43-91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91-1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90-0.98), but not with disease grade. CONCLUSIONS: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease..
Bull, C.J.
Bonilla, C.
Holly, J.M.
Perks, C.M.
Davies, N.
Haycock, P.
Yu, O.H.
Richards, J.B.
Eeles, R.
Easton, D.
Kote-Jarai, Z.
Amin Al Olama, A.
Benlloch, S.
Muir, K.
Giles, G.G.
MacInnis, R.J.
Wiklund, F.
Gronberg, H.
Haiman, C.A.
Schleutker, J.
Nordestgaard, B.G.
Travis, R.C.
Neal, D.
Pashayan, N.
Khaw, K.-.
Stanford, J.L.
Blot, W.J.
Thibodeau, S.
Maier, C.
Kibel, A.S.
Cybulski, C.
Cannon-Albright, L.
Brenner, H.
Park, J.
Kaneva, R.
Batra, J.
Teixeira, M.R.
Micheal, A.
Pandha, H.
Smith, G.D.
Lewis, S.J.
Martin, R.M.
PRACTICAL consortium,
(2016). Blood lipids and prostate cancer: a Mendelian randomization analysis. Cancer med,
Vol.5
(6),
pp. 1125-1136.
show abstract
full text
Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high- (≥7 Gleason score) versus low-grade (<7 Gleason score) cancers was 1.50 (95% CI: 0.92, 2.46; P = 0.11). A genetically instrumented SD increase in TGs was weakly associated with stage: the OR for advanced versus localized cancer per unit increase in genetic risk score was 1.68 (95% CI: 0.95, 3.00; P = 0.08). The rs12916-T variant in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was inversely associated with prostate cancer (OR: 0.97; 95% CI: 0.94, 1.00; P = 0.03). In conclusion, circulating lipids, instrumented by our genetic risk scores, did not appear to alter prostate cancer risk. We found weak evidence that higher LDL and TG levels increase aggressive prostate cancer risk, and that a variant in HMGCR (that mimics the LDL lowering effect of statin drugs) reduces risk. However, inferences are limited by sample size and evidence of pleiotropy..
Castro, E.
Mikropoulos, C.
Bancroft, E.K.
Dadaev, T.
Goh, C.
Taylor, N.
Saunders, E.
Borley, N.
Keating, D.
Page, E.C.
Saya, S.
Hazell, S.
Livni, N.
deSouza, N.
Neal, D.
Hamdy, F.C.
Kumar, P.
Antoniou, A.C.
Kote-Jarai, Z.
PROFILE Study Steering Committee,
Eeles, R.A.
(2016). The PROFILE Feasibility Study: Targeted Screening of Men With a Family History of Prostate Cancer. Oncologist,
Vol.21
(6),
pp. 716-722.
show abstract
full text
BACKGROUND: A better assessment of individualized prostate cancer (PrCa) risk is needed to improve screening. The use of the prostate-specific antigen (PSA) level for screening in the general population has limitations and is not currently advocated. Approximately 100 common single nucleotide polymorphisms (SNPs) have been identified that are associated with the risk of developing PrCa. The PROFILE pilot study explored the feasibility of using SNP profiling in men with a family history (FH) of PrCa to investigate the probability of detecting PrCa at prostate biopsy (PB). The primary aim of this pilot study was to determine the safety and feasibility of PrCa screening using transrectal ultrasound-guided PB with or without diffusion-weighted magnetic resonance imaging (DW-MRI) in men with a FH. A secondary aim was to evaluate the potential use of SNP profiling as a screening tool in this population. PATIENTS AND METHODS: A total of 100 men aged 40-69 years with a FH of PrCa underwent PB, regardless of their baseline PSA level. Polygenic risk scores (PRSs) were calculated for each participant using 71 common PrCa susceptibility alleles. We treated the disease outcome at PB as the outcome variable and evaluated its associations with the PRS, PSA level, and DW-MRI findings using univariate logistic regression. RESULTS: Of the 100 men, 25 were diagnosed with PrCa, of whom 12 (48%) had clinically significant disease. Four adverse events occurred and no deaths. The PSA level and age at study entry were associated with PrCa at PB (p = .00037 and p = .00004, respectively). CONCLUSION: The results of the present pilot study have demonstrated that PB is a feasible and safe method of PrCa screening in men with a FH, with a high proportion of PrCa identified requiring radical treatment. It is feasible to collect data on PrCa-risk SNPs to evaluate their combined effect as a potential screening tool. A larger prospective study powered to detect statistical associations is in progress. IMPLICATIONS FOR PRACTICE: Prostate biopsy is a feasible and safe approach to prostate cancer screening in men with a family history and detects a high proportion of prostate cancer that needs radical treatment. Calculating a polygenic risk score using prostate cancer risk single nucleotide polymorphisms could be a potential future screening tool for prostate cancer..
Ioannidis, N.M.
Rothstein, J.H.
Pejaver, V.
Middha, S.
McDonnell, S.K.
Baheti, S.
Musolf, A.
Li, Q.
Holzinger, E.
Karyadi, D.
Cannon-Albright, L.A.
Teerlink, C.C.
Stanford, J.L.
Isaacs, W.B.
Xu, J.
Cooney, K.A.
Lange, E.M.
Schleutker, J.
Carpten, J.D.
Powell, I.J.
Cussenot, O.
Cancel-Tassin, G.
Giles, G.G.
MacInnis, R.J.
Maier, C.
Hsieh, C.-.
Wiklund, F.
Catalona, W.J.
Foulkes, W.D.
Mandal, D.
Eeles, R.A.
Kote-Jarai, Z.
Bustamante, C.D.
Schaid, D.J.
Hastie, T.
Ostrander, E.A.
Bailey-Wilson, J.E.
Radivojac, P.
Thibodeau, S.N.
Whittemore, A.S.
Sieh, W.
(2016). REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. Am j hum genet,
Vol.99
(4),
pp. 877-885.
show abstract
full text
The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10-12) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046-0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027-0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale..
Gusev, A.
Shi, H.
Kichaev, G.
Pomerantz, M.
Li, F.
Long, H.W.
Ingles, S.A.
Kittles, R.A.
Strom, S.S.
Rybicki, B.A.
Nemesure, B.
Isaacs, W.B.
Zheng, W.
Pettaway, C.A.
Yeboah, E.D.
Tettey, Y.
Biritwum, R.B.
Adjei, A.A.
Tay, E.
Truelove, A.
Niwa, S.
Chokkalingam, A.P.
John, E.M.
Murphy, A.B.
Signorello, L.B.
Carpten, J.
Leske, M.C.
Wu, S.-.
Hennis, A.J.
Neslund-Dudas, C.
Hsing, A.W.
Chu, L.
Goodman, P.J.
Klein, E.A.
Witte, J.S.
Casey, G.
Kaggwa, S.
Cook, M.B.
Stram, D.O.
Blot, W.J.
Eeles, R.A.
Easton, D.
Kote-Jarai, Z.
Al Olama, A.A.
Benlloch, S.
Muir, K.
Giles, G.G.
Southey, M.C.
Fitzgerald, L.M.
Gronberg, H.
Wiklund, F.
Aly, M.
Henderson, B.E.
Schleutker, J.
Wahlfors, T.
Tammela, T.L.
Nordestgaard, B.G.
Key, T.J.
Travis, R.C.
Neal, D.E.
Donovan, J.L.
Hamdy, F.C.
Pharoah, P.
Pashayan, N.
Khaw, K.-.
Stanford, J.L.
Thibodeau, S.N.
McDonnell, S.K.
Schaid, D.J.
Maier, C.
Vogel, W.
Luedeke, M.
Herkommer, K.
Kibel, A.S.
Cybulski, C.
Wokolorczyk, D.
Kluzniak, W.
Cannon-Albright, L.
Teerlink, C.
Brenner, H.
Dieffenbach, A.K.
Arndt, V.
Park, J.Y.
Sellers, T.A.
Lin, H.-.
Slavov, C.
Kaneva, R.
Mitev, V.
Batra, J.
Spurdle, A.
Clements, J.A.
Teixeira, M.R.
Pandha, H.
Michael, A.
Paulo, P.
Maia, S.
Kierzek, A.
PRACTICAL consortium,
Conti, D.V.
Albanes, D.
Berg, C.
Berndt, S.I.
Campa, D.
Crawford, E.D.
Diver, W.R.
Gapstur, S.M.
Gaziano, J.M.
Giovannucci, E.
Hoover, R.
Hunter, D.J.
Johansson, M.
Kraft, P.
Le Marchand, L.
Lindström, S.
Navarro, C.
Overvad, K.
Riboli, E.
Siddiq, A.
Stevens, V.L.
Trichopoulos, D.
Vineis, P.
Yeager, M.
Trynka, G.
Raychaudhuri, S.
Schumacher, F.R.
Price, A.L.
Freedman, M.L.
Haiman, C.A.
Pasaniuc, B.
(2016). Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation. Nat commun,
Vol.7,
p. 10979.
show abstract
full text
Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa..
Teerlink, C.C.
Leongamornlert, D.
Dadaev, T.
Thomas, A.
Farnham, J.
Stephenson, R.A.
Riska, S.
McDonnell, S.K.
Schaid, D.J.
Catalona, W.J.
Zheng, S.L.
Cooney, K.A.
Ray, A.M.
Zuhlke, K.A.
Lange, E.M.
Giles, G.G.
Southey, M.C.
Fitzgerald, L.M.
Rinckleb, A.
Luedeke, M.
Maier, C.
Stanford, J.L.
Ostrander, E.A.
Kaikkonen, E.M.
Sipeky, C.
Tammela, T.
Schleutker, J.
Wiley, K.E.
Isaacs, S.D.
Walsh, P.C.
Isaacs, W.B.
Xu, J.
Cancel-Tassin, G.
Cussenot, O.
Mandal, D.
Laurie, C.
Laurie, C.
PRACTICAL consortium,
International Consortium for Prostate Cancer Genetics,
Thibodeau, S.N.
Eeles, R.A.
Kote-Jarai, Z.
Cannon-Albright, L.
(2016). Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24 21. Hum genet,
Vol.135
(8),
pp. 923-938.
show abstract
full text
Previous genome-wide association studies (GWAS) of prostate cancer risk focused on cases unselected for family history and have reported over 100 significant associations. The International Consortium for Prostate Cancer Genetics (ICPCG) has now performed a GWAS of 2511 (unrelated) familial prostate cancer cases and 1382 unaffected controls from 12 member sites. All samples were genotyped on the Illumina 5M+exome single nucleotide polymorphism (SNP) platform. The GWAS identified a significant evidence for association for SNPs in six regions previously associated with prostate cancer in population-based cohorts, including 3q26.2, 6q25.3, 8q24.21, 10q11.23, 11q13.3, and 17q12. Of note, SNP rs138042437 (p = 1.7e(-8)) at 8q24.21 achieved a large estimated effect size in this cohort (odds ratio = 13.3). 116 previously sampled affected relatives of 62 risk-allele carriers from the GWAS cohort were genotyped for this SNP, identifying 78 additional affected carriers in 62 pedigrees. A test for an excess number of affected carriers among relatives exhibited strong evidence for co-segregation of the variant with disease (p = 8.5e(-11)). The majority (92 %) of risk-allele carriers at rs138042437 had a consistent estimated haplotype spanning approximately 100 kb of 8q24.21 that contained the minor alleles of three rare SNPs (dosage minor allele frequencies <1.7 %), rs183373024 (PRNCR1), previously associated SNP rs188140481, and rs138042437 (CASC19). Strong evidence for co-segregation of a SNP on the haplotype further characterizes the haplotype as a prostate cancer predisposition locus..
Larson, N.B.
McDonnell, S.
Albright, L.C.
Teerlink, C.
Stanford, J.
Ostrander, E.A.
Isaacs, W.B.
Xu, J.
Cooney, K.A.
Lange, E.
Schleutker, J.
Carpten, J.D.
Powell, I.
Bailey-Wilson, J.
Cussenot, O.
Cancel-Tassin, G.
Giles, G.
MacInnis, R.
Maier, C.
Whittemore, A.S.
Hsieh, C.-.
Wiklund, F.
Catalona, W.J.
Foulkes, W.
Mandal, D.
Eeles, R.
Kote-Jarai, Z.
Ackerman, M.J.
Olson, T.M.
Klein, C.J.
Thibodeau, S.N.
Schaid, D.J.
(2016). Post hoc Analysis for Detecting Individual Rare Variant Risk Associations Using Probit Regression Bayesian Variable Selection Methods in Case-Control Sequencing Studies. Genet epidemiol,
Vol.40
(6),
pp. 461-469.
show abstract
full text
Rare variants (RVs) have been shown to be significant contributors to complex disease risk. By definition, these variants have very low minor allele frequencies and traditional single-marker methods for statistical analysis are underpowered for typical sequencing study sample sizes. Multimarker burden-type approaches attempt to identify aggregation of RVs across case-control status by analyzing relatively small partitions of the genome, such as genes. However, it is generally the case that the aggregative measure would be a mixture of causal and neutral variants, and these omnibus tests do not directly provide any indication of which RVs may be driving a given association. Recently, Bayesian variable selection approaches have been proposed to identify RV associations from a large set of RVs under consideration. Although these approaches have been shown to be powerful at detecting associations at the RV level, there are often computational limitations on the total quantity of RVs under consideration and compromises are necessary for large-scale application. Here, we propose a computationally efficient alternative formulation of this method using a probit regression approach specifically capable of simultaneously analyzing hundreds to thousands of RVs. We evaluate our approach to detect causal variation on simulated data and examine sensitivity and specificity in instances of high RV dimensionality as well as apply it to pathway-level RV analysis results from a prostate cancer (PC) risk case-control sequencing study. Finally, we discuss potential extensions and future directions of this work..
Khankari, N.K.
Shu, X.-.
Wen, W.
Kraft, P.
Lindström, S.
Peters, U.
Schildkraut, J.
Schumacher, F.
Bofetta, P.
Risch, A.
Bickeböller, H.
Amos, C.I.
Easton, D.
Eeles, R.A.
Gruber, S.B.
Haiman, C.A.
Hunter, D.J.
Chanock, S.J.
Pierce, B.L.
Zheng, W.
Colorectal Transdisciplinary Study (CORECT),
Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE),
Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE),
Transdisciplinary Research in Cancer of the Lung (TRICL),
(2016). Association between Adult Height and Risk of Colorectal, Lung, and Prostate Cancer: Results from Meta-analyses of Prospective Studies and Mendelian Randomization Analyses. Plos med,
Vol.13
(9),
p. e1002118.
show abstract
full text
BACKGROUND: Observational studies examining associations between adult height and risk of colorectal, prostate, and lung cancers have generated mixed results. We conducted meta-analyses using data from prospective cohort studies and further carried out Mendelian randomization analyses, using height-associated genetic variants identified in a genome-wide association study (GWAS), to evaluate the association of adult height with these cancers. METHODS AND FINDINGS: A systematic review of prospective studies was conducted using the PubMed, Embase, and Web of Science databases. Using meta-analyses, results obtained from 62 studies were summarized for the association of a 10-cm increase in height with cancer risk. Mendelian randomization analyses were conducted using summary statistics obtained for 423 genetic variants identified from a recent GWAS of adult height and from a cancer genetics consortium study of multiple cancers that included 47,800 cases and 81,353 controls. For a 10-cm increase in height, the summary relative risks derived from the meta-analyses of prospective studies were 1.12 (95% CI 1.10, 1.15), 1.07 (95% CI 1.05, 1.10), and 1.06 (95% CI 1.02, 1.11) for colorectal, prostate, and lung cancers, respectively. Mendelian randomization analyses showed increased risks of colorectal (odds ratio [OR] = 1.58, 95% CI 1.14, 2.18) and lung cancer (OR = 1.10, 95% CI 1.00, 1.22) associated with each 10-cm increase in genetically predicted height. No association was observed for prostate cancer (OR = 1.03, 95% CI 0.92, 1.15). Our meta-analysis was limited to published studies. The sample size for the Mendelian randomization analysis of colorectal cancer was relatively small, thus affecting the precision of the point estimate. CONCLUSIONS: Our study provides evidence for a potential causal association of adult height with the risk of colorectal and lung cancers and suggests that certain genetic factors and biological pathways affecting adult height may also affect the risk of these cancers..
Silvestri, V.
Barrowdale, D.
Mulligan, A.M.
Neuhausen, S.L.
Fox, S.
Karlan, B.Y.
Mitchell, G.
James, P.
Thull, D.L.
Zorn, K.K.
Carter, N.J.
Nathanson, K.L.
Domchek, S.M.
Rebbeck, T.R.
Ramus, S.J.
Nussbaum, R.L.
Olopade, O.I.
Rantala, J.
Yoon, S.-.
Caligo, M.A.
Spugnesi, L.
Bojesen, A.
Pedersen, I.S.
Thomassen, M.
Jensen, U.B.
Toland, A.E.
Senter, L.
Andrulis, I.L.
Glendon, G.
Hulick, P.J.
Imyanitov, E.N.
Greene, M.H.
Mai, P.L.
Singer, C.F.
Rappaport-Fuerhauser, C.
Kramer, G.
Vijai, J.
Offit, K.
Robson, M.
Lincoln, A.
Jacobs, L.
Machackova, E.
Foretova, L.
Navratilova, M.
Vasickova, P.
Couch, F.J.
Hallberg, E.
Ruddy, K.J.
Sharma, P.
Kim, S.-.
kConFab Investigators,
Teixeira, M.R.
Pinto, P.
Montagna, M.
Matricardi, L.
Arason, A.
Johannsson, O.T.
Barkardottir, R.B.
Jakubowska, A.
Lubinski, J.
Izquierdo, A.
Pujana, M.A.
Balmaña, J.
Diez, O.
Ivady, G.
Papp, J.
Olah, E.
Kwong, A.
Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON),
Nevanlinna, H.
Aittomäki, K.
Perez Segura, P.
Caldes, T.
Van Maerken, T.
Poppe, B.
Claes, K.B.
Isaacs, C.
Elan, C.
Lasset, C.
Stoppa-Lyonnet, D.
Barjhoux, L.
Belotti, M.
Meindl, A.
Gehrig, A.
Sutter, C.
Engel, C.
Niederacher, D.
Steinemann, D.
Hahnen, E.
Kast, K.
Arnold, N.
Varon-Mateeva, R.
Wand, D.
Godwin, A.K.
Evans, D.G.
Frost, D.
Perkins, J.
Adlard, J.
Izatt, L.
Platte, R.
Eeles, R.
Ellis, S.
EMBRACE,
Hamann, U.
Garber, J.
Fostira, F.
Fountzilas, G.
Pasini, B.
Giannini, G.
Rizzolo, P.
Russo, A.
Cortesi, L.
Papi, L.
Varesco, L.
Palli, D.
Zanna, I.
Savarese, A.
Radice, P.
Manoukian, S.
Peissel, B.
Barile, M.
Bonanni, B.
Viel, A.
Pensotti, V.
Tommasi, S.
Peterlongo, P.
Weitzel, J.N.
Osorio, A.
Benitez, J.
McGuffog, L.
Healey, S.
Gerdes, A.-.
Ejlertsen, B.
Hansen, T.V.
Steele, L.
Ding, Y.C.
Tung, N.
Janavicius, R.
Goldgar, D.E.
Buys, S.S.
Daly, M.B.
Bane, A.
Terry, M.B.
John, E.M.
Southey, M.
Easton, D.F.
Chenevix-Trench, G.
Antoniou, A.C.
Ottini, L.
(2016). Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2. Breast cancer res,
Vol.18
(1),
p. 15.
show abstract
full text
BACKGROUND: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). METHODS: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)). CONCLUSIONS: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management..
Kar, S.P.
Beesley, J.
Amin Al Olama, A.
Michailidou, K.
Tyrer, J.
Kote-Jarai, Z.
Lawrenson, K.
Lindstrom, S.
Ramus, S.J.
Thompson, D.J.
ABCTB Investigators,
Kibel, A.S.
Dansonka-Mieszkowska, A.
Michael, A.
Dieffenbach, A.K.
Gentry-Maharaj, A.
Whittemore, A.S.
Wolk, A.
Monteiro, A.
Peixoto, A.
Kierzek, A.
Cox, A.
Rudolph, A.
Gonzalez-Neira, A.
Wu, A.H.
Lindblom, A.
Swerdlow, A.
AOCS Study Group & Australian Cancer Study (Ovarian Cancer),
APCB BioResource,
Ziogas, A.
Ekici, A.B.
Burwinkel, B.
Karlan, B.Y.
Nordestgaard, B.G.
Blomqvist, C.
Phelan, C.
McLean, C.
Pearce, C.L.
Vachon, C.
Cybulski, C.
Slavov, C.
Stegmaier, C.
Maier, C.
Ambrosone, C.B.
Høgdall, C.K.
Teerlink, C.C.
Kang, D.
Tessier, D.C.
Schaid, D.J.
Stram, D.O.
Cramer, D.W.
Neal, D.E.
Eccles, D.
Flesch-Janys, D.
Edwards, D.R.
Wokozorczyk, D.
Levine, D.A.
Yannoukakos, D.
Sawyer, E.J.
Bandera, E.V.
Poole, E.M.
Goode, E.L.
Khusnutdinova, E.
Høgdall, E.
Song, F.
Bruinsma, F.
Heitz, F.
Modugno, F.
Hamdy, F.C.
Wiklund, F.
Giles, G.G.
Olsson, H.
Wildiers, H.
Ulmer, H.-.
Pandha, H.
Risch, H.A.
Darabi, H.
Salvesen, H.B.
Nevanlinna, H.
Gronberg, H.
Brenner, H.
Brauch, H.
Anton-Culver, H.
Song, H.
Lim, H.-.
McNeish, I.
Campbell, I.
Vergote, I.
Gronwald, J.
Lubiński, J.
Stanford, J.L.
Benítez, J.
Doherty, J.A.
Permuth, J.B.
Chang-Claude, J.
Donovan, J.L.
Dennis, J.
Schildkraut, J.M.
Schleutker, J.
Hopper, J.L.
Kupryjanczyk, J.
Park, J.Y.
Figueroa, J.
Clements, J.A.
Knight, J.A.
Peto, J.
Cunningham, J.M.
Pow-Sang, J.
Batra, J.
Czene, K.
Lu, K.H.
Herkommer, K.
Khaw, K.-.
kConFab Investigators,
Matsuo, K.
Muir, K.
Offitt, K.
Chen, K.
Moysich, K.B.
Aittomäki, K.
Odunsi, K.
Kiemeney, L.A.
Massuger, L.F.
Fitzgerald, L.M.
Cook, L.S.
Cannon-Albright, L.
Hooning, M.J.
Pike, M.C.
Bolla, M.K.
Luedeke, M.
Teixeira, M.R.
Goodman, M.T.
Schmidt, M.K.
Riggan, M.
Aly, M.
Rossing, M.A.
Beckmann, M.W.
Moisse, M.
Sanderson, M.
Southey, M.C.
Jones, M.
Lush, M.
Hildebrandt, M.A.
Hou, M.-.
Schoemaker, M.J.
Garcia-Closas, M.
Bogdanova, N.
Rahman, N.
NBCS Investigators,
Le, N.D.
Orr, N.
Wentzensen, N.
Pashayan, N.
Peterlongo, P.
Guénel, P.
Brennan, P.
Paulo, P.
Webb, P.M.
Broberg, P.
Fasching, P.A.
Devilee, P.
Wang, Q.
Cai, Q.
Li, Q.
Kaneva, R.
Butzow, R.
Kopperud, R.K.
Schmutzler, R.K.
Stephenson, R.A.
MacInnis, R.J.
Hoover, R.N.
Winqvist, R.
Ness, R.
Milne, R.L.
Travis, R.C.
Benlloch, S.
Olson, S.H.
McDonnell, S.K.
Tworoger, S.S.
Maia, S.
Berndt, S.
Lee, S.C.
Teo, S.-.
Thibodeau, S.N.
Bojesen, S.E.
Gapstur, S.M.
Kjær, S.K.
Pejovic, T.
Tammela, T.L.
GENICA Network,
PRACTICAL consortium,
Dörk, T.
Brüning, T.
Wahlfors, T.
Key, T.J.
Edwards, T.L.
Menon, U.
Hamann, U.
Mitev, V.
Kosma, V.-.
Setiawan, V.W.
Kristensen, V.
Arndt, V.
Vogel, W.
Zheng, W.
Sieh, W.
Blot, W.J.
Kluzniak, W.
Shu, X.-.
Gao, Y.-.
Schumacher, F.
Freedman, M.L.
Berchuck, A.
Dunning, A.M.
Simard, J.
Haiman, C.A.
Spurdle, A.
Sellers, T.A.
Hunter, D.J.
Henderson, B.E.
Kraft, P.
Chanock, S.J.
Couch, F.J.
Hall, P.
Gayther, S.A.
Easton, D.F.
Chenevix-Trench, G.
Eeles, R.
Pharoah, P.D.
Lambrechts, D.
(2016). Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types. Cancer discov,
Vol.6
(9),
pp. 1052-1067.
show abstract
full text
UNLABELLED: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932..
Ahmed, M.
Dorling, L.
Kerns, S.
Fachal, L.
Elliott, R.
Partliament, M.
Rosenstein, B.S.
Vega, A.
Gómez-Caamaño, A.
Barnett, G.
Dearnaley, D.P.
Hall, E.
Sydes, M.
Burnet, N.
Pharoah, P.D.
Eeles, R.
West, C.M.
(2016). Common genetic variation associated with increased susceptibility to prostate cancer does not increase risk of radiotherapy toxicity. Br j cancer,
Vol.114
(10),
pp. 1165-1174.
show abstract
full text
BACKGROUND: Numerous germline single-nucleotide polymorphisms increase susceptibility to prostate cancer, some lying near genes involved in cellular radiation response. This study investigated whether prostate cancer patients with a high genetic risk have increased toxicity following radiotherapy. METHODS: The study included 1560 prostate cancer patients from four radiotherapy cohorts: RAPPER (n=533), RADIOGEN (n=597), GenePARE (n=290) and CCI (n=150). Data from genome-wide association studies were imputed with the 1000 Genomes reference panel. Individuals were genetically similar with a European ancestry based on principal component analysis. Genetic risks were quantified using polygenic risk scores. Regression models tested associations between risk scores and 2-year toxicity (overall, urinary frequency, decreased stream, rectal bleeding). Results were combined across studies using standard inverse-variance fixed effects meta-analysis methods. RESULTS: A total of 75 variants were genotyped/imputed successfully. Neither non-weighted nor weighted polygenic risk scores were associated with late radiation toxicity in individual studies (P>0.11) or after meta-analysis (P>0.24). No individual variant was associated with 2-year toxicity. CONCLUSION: Patients with a high polygenic susceptibility for prostate cancer have no increased risk for developing late radiotherapy toxicity. These findings suggest that patients with a genetic predisposition for prostate cancer, inferred by common variants, can be safely treated using current standard radiotherapy regimens..
Southey, M.C.
Goldgar, D.E.
Winqvist, R.
Pylkäs, K.
Couch, F.
Tischkowitz, M.
Foulkes, W.D.
Dennis, J.
Michailidou, K.
van Rensburg, E.J.
Heikkinen, T.
Nevanlinna, H.
Hopper, J.L.
Dörk, T.
Claes, K.B.
Reis-Filho, J.
Teo, Z.L.
Radice, P.
Catucci, I.
Peterlongo, P.
Tsimiklis, H.
Odefrey, F.A.
Dowty, J.G.
Schmidt, M.K.
Broeks, A.
Hogervorst, F.B.
Verhoef, S.
Carpenter, J.
Clarke, C.
Scott, R.J.
Fasching, P.A.
Haeberle, L.
Ekici, A.B.
Beckmann, M.W.
Peto, J.
Dos-Santos-Silva, I.
Fletcher, O.
Johnson, N.
Bolla, M.K.
Sawyer, E.J.
Tomlinson, I.
Kerin, M.J.
Miller, N.
Marme, F.
Burwinkel, B.
Yang, R.
Guénel, P.
Truong, T.
Menegaux, F.
Sanchez, M.
Bojesen, S.
Nielsen, S.F.
Flyger, H.
Benitez, J.
Zamora, M.P.
Perez, J.I.
Menéndez, P.
Anton-Culver, H.
Neuhausen, S.
Ziogas, A.
Clarke, C.A.
Brenner, H.
Arndt, V.
Stegmaier, C.
Brauch, H.
Brüning, T.
Ko, Y.-.
Muranen, T.A.
Aittomäki, K.
Blomqvist, C.
Bogdanova, N.V.
Antonenkova, N.N.
Lindblom, A.
Margolin, S.
Mannermaa, A.
Kataja, V.
Kosma, V.-.
Hartikainen, J.M.
Spurdle, A.B.
Investigators, K.
Australian Ovarian Cancer Study Group,
Wauters, E.
Smeets, D.
Beuselinck, B.
Floris, G.
Chang-Claude, J.
Rudolph, A.
Seibold, P.
Flesch-Janys, D.
Olson, J.E.
Vachon, C.
Pankratz, V.S.
McLean, C.
Haiman, C.A.
Henderson, B.E.
Schumacher, F.
Le Marchand, L.
Kristensen, V.
Alnæs, G.G.
Zheng, W.
Hunter, D.J.
Lindstrom, S.
Hankinson, S.E.
Kraft, P.
Andrulis, I.
Knight, J.A.
Glendon, G.
Mulligan, A.M.
Jukkola-Vuorinen, A.
Grip, M.
Kauppila, S.
Devilee, P.
Tollenaar, R.A.
Seynaeve, C.
Hollestelle, A.
Garcia-Closas, M.
Figueroa, J.
Chanock, S.J.
Lissowska, J.
Czene, K.
Darabi, H.
Eriksson, M.
Eccles, D.M.
Rafiq, S.
Tapper, W.J.
Gerty, S.M.
Hooning, M.J.
Martens, J.W.
Collée, J.M.
Tilanus-Linthorst, M.
Hall, P.
Li, J.
Brand, J.S.
Humphreys, K.
Cox, A.
Reed, M.W.
Luccarini, C.
Baynes, C.
Dunning, A.M.
Hamann, U.
Torres, D.
Ulmer, H.U.
Rüdiger, T.
Jakubowska, A.
Lubinski, J.
Jaworska, K.
Durda, K.
Slager, S.
Toland, A.E.
Ambrosone, C.B.
Yannoukakos, D.
Swerdlow, A.
Ashworth, A.
Orr, N.
Jones, M.
González-Neira, A.
Pita, G.
Alonso, M.R.
Álvarez, N.
Herrero, D.
Tessier, D.C.
Vincent, D.
Bacot, F.
Simard, J.
Dumont, M.
Soucy, P.
Eeles, R.
Muir, K.
Wiklund, F.
Gronberg, H.
Schleutker, J.
Nordestgaard, B.G.
Weischer, M.
Travis, R.C.
Neal, D.
Donovan, J.L.
Hamdy, F.C.
Khaw, K.-.
Stanford, J.L.
Blot, W.J.
Thibodeau, S.
Schaid, D.J.
Kelley, J.L.
Maier, C.
Kibel, A.S.
Cybulski, C.
Cannon-Albright, L.
Butterbach, K.
Park, J.
Kaneva, R.
Batra, J.
Teixeira, M.R.
Kote-Jarai, Z.
Olama, A.A.
Benlloch, S.
Renner, S.P.
Hartmann, A.
Hein, A.
Ruebner, M.
Lambrechts, D.
Van Nieuwenhuysen, E.
Vergote, I.
Lambretchs, S.
Doherty, J.A.
Rossing, M.A.
Nickels, S.
Eilber, U.
Wang-Gohrke, S.
Odunsi, K.
Sucheston-Campbell, L.E.
Friel, G.
Lurie, G.
Killeen, J.L.
Wilkens, L.R.
Goodman, M.T.
Runnebaum, I.
Hillemanns, P.A.
Pelttari, L.M.
Butzow, R.
Modugno, F.
Edwards, R.P.
Ness, R.B.
Moysich, K.B.
du Bois, A.
Heitz, F.
Harter, P.
Kommoss, S.
Karlan, B.Y.
Walsh, C.
Lester, J.
Jensen, A.
Kjaer, S.K.
Høgdall, E.
Peissel, B.
Bonanni, B.
Bernard, L.
Goode, E.L.
Fridley, B.L.
Vierkant, R.A.
Cunningham, J.M.
Larson, M.C.
Fogarty, Z.C.
Kalli, K.R.
Liang, D.
Lu, K.H.
Hildebrandt, M.A.
Wu, X.
Levine, D.A.
Dao, F.
Bisogna, M.
Berchuck, A.
Iversen, E.S.
Marks, J.R.
Akushevich, L.
Cramer, D.W.
Schildkraut, J.
Terry, K.L.
Poole, E.M.
Stampfer, M.
Tworoger, S.S.
Bandera, E.V.
Orlow, I.
Olson, S.H.
Bjorge, L.
Salvesen, H.B.
van Altena, A.M.
Aben, K.K.
Kiemeney, L.A.
Massuger, L.F.
Pejovic, T.
Bean, Y.
Brooks-Wilson, A.
Kelemen, L.E.
Cook, L.S.
Le, N.D.
Górski, B.
Gronwald, J.
Menkiszak, J.
Høgdall, C.K.
Lundvall, L.
Nedergaard, L.
Engelholm, S.A.
Dicks, E.
Tyrer, J.
Campbell, I.
McNeish, I.
Paul, J.
Siddiqui, N.
Glasspool, R.
Whittemore, A.S.
Rothstein, J.H.
McGuire, V.
Sieh, W.
Cai, H.
Shu, X.-.
Teten, R.T.
Sutphen, R.
McLaughlin, J.R.
Narod, S.A.
Phelan, C.M.
Monteiro, A.N.
Fenstermacher, D.
Lin, H.-.
Permuth, J.B.
Sellers, T.A.
Chen, Y.A.
Tsai, Y.-.
Chen, Z.
Gentry-Maharaj, A.
Gayther, S.A.
Ramus, S.J.
Menon, U.
Wu, A.H.
Pearce, C.L.
Van Den Berg, D.
Pike, M.C.
Dansonka-Mieszkowska, A.
Plisiecka-Halasa, J.
Moes-Sosnowska, J.
Kupryjanczyk, J.
Pharoah, P.D.
Song, H.
Winship, I.
Chenevix-Trench, G.
Giles, G.G.
Tavtigian, S.V.
Easton, D.F.
Milne, R.L.
(2016). PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J med genet,
Vol.53
(12),
pp. 800-811.
show abstract
full text
BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. METHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. RESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. CONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important..
Behjati, S.
Gundem, G.
Wedge, D.C.
Roberts, N.D.
Tarpey, P.S.
Cooke, S.L.
Van Loo, P.
Alexandrov, L.B.
Ramakrishna, M.
Davies, H.
Nik-Zainal, S.
Hardy, C.
Latimer, C.
Raine, K.M.
Stebbings, L.
Menzies, A.
Jones, D.
Shepherd, R.
Butler, A.P.
Teague, J.W.
Jorgensen, M.
Khatri, B.
Pillay, N.
Shlien, A.
Futreal, P.A.
Badie, C.
ICGC Prostate Group,
McDermott, U.
Bova, G.S.
Richardson, A.L.
Flanagan, A.M.
Stratton, M.R.
Campbell, P.J.
(2016). Mutational signatures of ionizing radiation in second malignancies. Nat commun,
Vol.7,
p. 12605.
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Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1-100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential..
Benafif, S.
Eeles, R.
(2016). Genetic predisposition to prostate cancer. Br med bull,
Vol.120
(1),
pp. 75-89.
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INTRODUCTION: Prostate cancer (PrCa) is the commonest non-cutaneous cancer in men in the UK. Epidemiological evidence as well as twin studies points towards a genetic component contributing to aetiology. SOURCES OF DATA: Key recently published literature. AREAS OF AGREEMENT: A family history of PrCa doubles the risk of disease development in first-degree relatives. Linkage and genetic sequencing studies identified rare moderate-high-risk gene loci, which predispose to PrCa development when altered by mutation. Genome-wide association studies have identified common single-nucleotide polypmorphisms (SNPs), which confer a cumulative risk of PrCa development with increasing number of risk alleles. There are emerging data that castrate-resistant disease is associated with mutations in DNA repair genes. AREAS OF CONTROVERSY: Linkage studies investigating possible high-risk loci leading to PrCa development identified possible loci on several chromosomes, but most have not been consistently replicated by subsequent studies. Germline SNPs related to prostate specific antigen (PSA) levels and to normal tissue radiosensitivity have also been identified though not all have been validated in subsequent studies. GROWING POINTS: Utilizing germline SNP profiles as well as identifying high-risk genetic variants could target screening to high-risk groups, avoiding the drawbacks of PSA screening. AREAS TIMELY FOR DEVELOPING RESEARCH: Incorporating genetics into PrCa screening is being investigated currently using both common SNP profiles and higher risk rare variants. Knowledge of germline genetic defects will allow the development of targeted screening programs, preventive strategies and the personalized treatment of PrCa..
MacInnis, R.J.
Schmidt, D.F.
Makalic, E.
Severi, G.
FitzGerald, L.M.
Reumann, M.
Kapuscinski, M.K.
Kowalczyk, A.
Zhou, Z.
Goudey, B.
Qian, G.
Bui, Q.M.
Park, D.J.
Freeman, A.
Southey, M.C.
Al Olama, A.A.
Kote-Jarai, Z.
Eeles, R.A.
Hopper, J.L.
Giles, G.G.
UK Genetic Prostate Cancer Study Collaborators,
(2016). Use of a Novel Nonparametric Version of DEPTH to Identify Genomic Regions Associated with Prostate Cancer Risk. Cancer epidemiol biomarkers prev,
Vol.25
(12),
pp. 1619-1624.
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full text
BACKGROUND: We have developed a genome-wide association study analysis method called DEPTH (DEPendency of association on the number of Top Hits) to identify genomic regions potentially associated with disease by considering overlapping groups of contiguous markers (e.g., SNPs) across the genome. DEPTH is a machine learning algorithm for feature ranking of ultra-high dimensional datasets, built from well-established statistical tools such as bootstrapping, penalized regression, and decision trees. Unlike marginal regression, which considers each SNP individually, the key idea behind DEPTH is to rank groups of SNPs in terms of their joint strength of association with the outcome. Our aim was to compare the performance of DEPTH with that of standard logistic regression analysis. METHODS: We selected 1,854 prostate cancer cases and 1,894 controls from the UK for whom 541,129 SNPs were measured using the Illumina Infinium HumanHap550 array. Confirmation was sought using 4,152 cases and 2,874 controls, ascertained from the UK and Australia, for whom 211,155 SNPs were measured using the iCOGS Illumina Infinium array. RESULTS: From the DEPTH analysis, we identified 14 regions associated with prostate cancer risk that had been reported previously, five of which would not have been identified by conventional logistic regression. We also identified 112 novel putative susceptibility regions. CONCLUSIONS: DEPTH can reveal new risk-associated regions that would not have been identified using a conventional logistic regression analysis of individual SNPs. IMPACT: This study demonstrates that the DEPTH algorithm could identify additional genetic susceptibility regions that merit further investigation. Cancer Epidemiol Biomarkers Prev; 25(12); 1619-24. ©2016 AACR..
Saunders, E.J.
Dadaev, T.
Leongamornlert, D.A.
Al Olama, A.A.
Benlloch, S.
Giles, G.G.
Wiklund, F.
Gronberg, H.
Haiman, C.A.
Schleutker, J.
Nordestgaard, B.G.
Travis, R.C.
Neal, D.
Pasayan, N.
Khaw, K.-.
Stanford, J.L.
Blot, W.J.
Thibodeau, S.N.
Maier, C.
Kibel, A.S.
Cybulski, C.
Cannon-Albright, L.
Brenner, H.
Park, J.Y.
Kaneva, R.
Batra, J.
Teixeira, M.R.
Pandha, H.
Govindasami, K.
Muir, K.
UK Genetic Prostate Cancer Study Collaborators,
UK ProtecT Study Collaborators,
PRACTICAL Consortium,
Easton, D.F.
Eeles, R.A.
Kote-Jarai, Z.
(2016). Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array. Br j cancer,
Vol.114
(8),
pp. 945-952.
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full text
BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. RESULTS: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. CONCLUSIONS: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers..
Karami, S.
Han, Y.
Pande, M.
Cheng, I.
Rudd, J.
Pierce, B.L.
Nutter, E.L.
Schumacher, F.R.
Kote-Jarai, Z.
Lindstrom, S.
Witte, J.S.
Fang, S.
Han, J.
Kraft, P.
Hunter, D.J.
Song, F.
Hung, R.J.
McKay, J.
Gruber, S.B.
Chanock, S.J.
Risch, A.
Shen, H.
Haiman, C.A.
Boardman, L.
Ulrich, C.M.
Casey, G.
Peters, U.
Amin Al Olama, A.
Berchuck, A.
Berndt, S.I.
Bezieau, S.
Brennan, P.
Brenner, H.
Brinton, L.
Caporaso, N.
Chan, A.T.
Chang-Claude, J.
Christiani, D.C.
Cunningham, J.M.
Easton, D.
Eeles, R.A.
Eisen, T.
Gala, M.
Gallinger, S.J.
Gayther, S.A.
Goode, E.L.
Grönberg, H.
Henderson, B.E.
Houlston, R.
Joshi, A.D.
Küry, S.
Landi, M.T.
Le Marchand, L.
Muir, K.
Newcomb, P.A.
Permuth-Wey, J.
Pharoah, P.
Phelan, C.
Potter, J.D.
Ramus, S.J.
Risch, H.
Schildkraut, J.
Slattery, M.L.
Song, H.
Wentzensen, N.
White, E.
Wiklund, F.
Zanke, B.W.
Sellers, T.A.
Zheng, W.
Chatterjee, N.
Amos, C.I.
Doherty, J.A.
GECCO and the GAME-ON Network: CORECT, DRIVE, ELLIPSE, FOCI, and TRICL,
(2016). Telomere structure and maintenance gene variants and risk of five cancer types. Int j cancer,
Vol.139
(12),
pp. 2655-2670.
show abstract
full text
Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ≤3.08 × 10-5 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk..
Luedeke, M.
Rinckleb, A.E.
FitzGerald, L.M.
Geybels, M.S.
Schleutker, J.
Eeles, R.A.
Teixeira, M.R.
Cannon-Albright, L.
Ostrander, E.A.
Weikert, S.
Herkommer, K.
Wahlfors, T.
Visakorpi, T.
Leinonen, K.A.
Tammela, T.L.
Cooper, C.S.
Kote-Jarai, Z.
Edwards, S.
Goh, C.L.
McCarthy, F.
Parker, C.
Flohr, P.
Paulo, P.
Jerónimo, C.
Henrique, R.
Krause, H.
Wach, S.
Lieb, V.
Rau, T.T.
Vogel, W.
Kuefer, R.
Hofer, M.D.
Perner, S.
Rubin, M.A.
Agarwal, A.M.
Easton, D.F.
Al Olama, A.A.
Benlloch, S.
PRACTICAL consortium,
Hoegel, J.
Stanford, J.L.
Maier, C.
(2016). Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status. Hum mol genet,
Vol.25
(24),
pp. 5490-5499.
show abstract
full text
Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (P < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR = 0.53, P = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, P = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa..
Dadaev, T.
Leongamornlert, D.A.
Saunders, E.J.
Eeles, R.
Kote-Jarai, Z.
(2016). LocusExplorer: a user-friendly tool for integrated visualization of human genetic association data and biological annotations. Bioinformatics,
Vol.32
(6),
pp. 949-951.
show abstract
full text
UNLABELLED: : In this article, we present LocusExplorer, a data visualization and exploration tool for genetic association data. LocusExplorer is written in R using the Shiny library, providing access to powerful R-based functions through a simple user interface. LocusExplorer allows users to simultaneously display genetic, statistical and biological data for humans in a single image and allows dynamic zooming and customization of the plot features. Publication quality plots may then be produced in a variety of file formats. AVAILABILITY AND IMPLEMENTATION: LocusExplorer is open source and runs through R and a web browser. It is available at www.oncogenetics.icr.ac.uk/LocusExplorer/ or can be installed locally and the source code accessed from https://github.com/oncogenetics/LocusExplorer CONTACT: [email protected]..
Rand, K.A.
Rohland, N.
Tandon, A.
Stram, A.
Sheng, X.
Do, R.
Pasaniuc, B.
Allen, A.
Quinque, D.
Mallick, S.
Le Marchand, L.
Kaggwa, S.
Lubwama, A.
African Ancestry Prostate Cancer GWAS Consortium,
ELLIPSE/GAME-ON Consortium,
Stram, D.O.
Watya, S.
Henderson, B.E.
Conti, D.V.
Reich, D.
Haiman, C.A.
(2016). Whole-exome sequencing of over 4100 men of African ancestry and prostate cancer risk. Hum mol genet,
Vol.25
(2),
pp. 371-381.
show abstract
Prostate cancer is the most common non-skin cancer in males, with a ∼1.5-2-fold higher incidence in African American men when compared with whites. Epidemiologic evidence supports a large heritable contribution to prostate cancer, with over 100 susceptibility loci identified to date that can explain ∼33% of the familial risk. To explore the contribution of both rare and common variation in coding regions to prostate cancer risk, we sequenced the exomes of 2165 prostate cancer cases and 2034 controls of African ancestry at a mean coverage of 10.1×. We identified 395 220 coding variants down to 0.05% frequency [57% non-synonymous (NS), 42% synonymous and 1% gain or loss of stop codon or splice site variant] in 16 751 genes with the strongest associations observed in SPARCL1 on 4q22.1 (rs13051, Ala49Asp, OR = 0.78, P = 1.8 × 10(-6)) and PTPRR on 12q15 (rs73341069, Val239Ile, OR = 1.62, P = 2.5 × 10(-5)). In gene-level testing, the two most significant genes were C1orf100 (P = 2.2 × 10(-4)) and GORAB (P = 2.3 × 10(-4)). We did not observe exome-wide significant associations (after correcting for multiple hypothesis testing) in single variant or gene-level testing in the overall case-control or case-case analyses of disease aggressiveness. In this first whole-exome sequencing study of prostate cancer, our findings do not provide strong support for the hypothesis that NS coding variants down to 0.5-1.0% frequency have large effects on prostate cancer risk in men of African ancestry. Higher-coverage sequencing efforts in larger samples will be needed to study rarer variants with smaller effect sizes associated with prostate cancer risk..
Marzec, J.
Mao, X.
Li, M.
Wang, M.
Feng, N.
Gou, X.
Wang, G.
Sun, Z.
Xu, J.
Xu, H.
Zhang, X.
Zhao, S.-.
Ren, G.
Yu, Y.
Wu, Y.
Wu, J.
Xue, Y.
Zhou, B.
Zhang, Y.
Xu, X.
Li, J.
He, W.
Benlloch, S.
Ross-Adams, H.
Chen, L.
Li, J.
Hong, Y.
Kote-Jarai, Z.
Cui, X.
Hou, J.
Guo, J.
Xu, L.
Yin, C.
Zhou, Y.
Neal, D.E.
Oliver, T.
Cao, G.
Zhang, Z.
Easton, D.F.
Chelala, C.
PRACTICAL Consortium,
CHIPGECS Group,
Al Olama, A.A.
Eeles, R.A.
Zhang, H.
Lu, Y.-.
(2016). A genetic study and meta-analysis of the genetic predisposition of prostate cancer in a Chinese population. Oncotarget,
Vol.7
(16),
pp. 21393-21403.
show abstract
full text
Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotide polymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotide polymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer..
Khankari, N.K.
Murff, H.J.
Zeng, C.
Wen, W.
Eeles, R.A.
Easton, D.F.
Kote-Jarai, Z.
Al Olama, A.A.
Benlloch, S.
Muir, K.
Giles, G.G.
Wiklund, F.
Gronberg, H.
Haiman, C.A.
Schleutker, J.
Nordestgaard, B.G.
Travis, R.C.
Donovan, J.L.
Pashayan, N.
Khaw, K.-.
Stanford, J.L.
Blot, W.J.
Thibodeau, S.N.
Maier, C.
Kibel, A.S.
Cybulski, C.
Cannon-Albright, L.
Brenner, H.
Park, J.
Kaneva, R.
Batra, J.
Teixeira, M.R.
Pandha, H.
Zheng, W.
PRACTICAL consortium,
(2016). Polyunsaturated fatty acids and prostate cancer risk: a Mendelian randomisation analysis from the PRACTICAL consortium. Br j cancer,
Vol.115
(5),
pp. 624-631.
show abstract
full text
BACKGROUND: Prostate cancer is a common cancer worldwide with no established modifiable lifestyle factors to guide prevention. The associations between polyunsaturated fatty acids (PUFAs) and prostate cancer risk have been inconsistent. Using Mendelian randomisation, we evaluated associations between PUFAs and prostate cancer risk. METHODS: We used individual-level data from a consortium of 22 721 cases and 23 034 controls of European ancestry. Externally-weighted PUFA-specific polygenic risk scores (wPRSs), with explanatory variation ranging from 0.65 to 33.07%, were constructed and used to evaluate associations with prostate cancer risk per one standard deviation (s.d.) increase in genetically-predicted plasma PUFA levels using multivariable-adjusted unconditional logistic regression. RESULTS: No overall association was observed between the genetically-predicted PUFAs evaluated in this study and prostate cancer risk. However, risk reductions were observed for short-chain PUFAs, linoleic (ORLA=0.95, 95%CI=0.92, 0.98) and α-linolenic acids (ORALA=0.96, 95%CI=0.93, 0.98), among men <62 years; whereas increased risk was found among men ⩾62 years for LA (ORLA=1.04, 95%CI=1.01, 1.07). For long-chain PUFAs (i.e., arachidonic, eicosapentaenoic, and docosapentaenoic acids), increased risks were observed among men <62 years (ORAA=1.05, 95%CI=1.02, 1.08; OREPA=1.04, 95%CI=1.01, 1.06; ORDPA=1.05, 95%CI=1.02, 1.08). CONCLUSION: Results from this study suggest that circulating ω-3 and ω-6 PUFAs may have a different role in the aetiology of early- and late-onset prostate cancer..
Benafif, S.
Eeles, R.
(2016). Diagnosis and Management of Hereditary Carcinoids. Recent results cancer res,
Vol.205,
pp. 149-168.
show abstract
Carcinoid tumours arise in cells of the diffuse neuroendocrine system and can develop in a number of anatomical sites including the lungs and the gastrointestinal tract. There has been a move away from the use of the term carcinoid tumour to the more appropriate use of neuroendocrine tumour (NET) to highlight the potential for invasion and metastasis associated with some NETs. Although most cases are sporadic, 15-20% of cases are related to a hereditary syndrome, the most common of these being multiple endocrine neoplasia 1 (MEN1). Other hereditary syndromes include the following: von Hippel-Lindau (VHL), neurofibromatosis 1 and tuberous sclerosis complex (TSC), which are all associated with a germline mutation of the associated tumour suppressor gene and an autosomal dominant inheritance pattern. Familial small intestinal NET (SI NET) is a recently described condition which is also inherited in an autosomal dominant manner. There appears to be more than one causative gene; thus far, only the IPMK gene has been identified as a causative germline mutation. This was identified by carrying out whole-exome sequencing of germline and tumour DNA in a family with multiple members diagnosed with SI NET. Identification of NET predisposition genes in other families via these methods will allow the development of dedicated NET gene panels which can be used to screen NET patients and at-risk relatives for hereditary mutations. Close surveillance of at-risk individuals is important to detect NETs early when curative surgery can be offered and the morbidity and mortality of metastatic NETs can be avoided..
Vigorito, E.
Kuchenbaecker, K.B.
Beesley, J.
Adlard, J.
Agnarsson, B.A.
Andrulis, I.L.
Arun, B.K.
Barjhoux, L.
Belotti, M.
Benitez, J.
Berger, A.
Bojesen, A.
Bonanni, B.
Brewer, C.
Caldes, T.
Caligo, M.A.
Campbell, I.
Chan, S.B.
Claes, K.B.
Cohn, D.E.
Cook, J.
Daly, M.B.
Damiola, F.
Davidson, R.
Pauw, A.D.
Delnatte, C.
Diez, O.
Domchek, S.M.
Dumont, M.
Durda, K.
Dworniczak, B.
Easton, D.F.
Eccles, D.
Edwinsdotter Ardnor, C.
Eeles, R.
Ejlertsen, B.
Ellis, S.
Evans, D.G.
Feliubadalo, L.
Fostira, F.
Foulkes, W.D.
Friedman, E.
Frost, D.
Gaddam, P.
Ganz, P.A.
Garber, J.
Garcia-Barberan, V.
Gauthier-Villars, M.
Gehrig, A.
Gerdes, A.-.
Giraud, S.
Godwin, A.K.
Goldgar, D.E.
Hake, C.R.
Hansen, T.V.
Healey, S.
Hodgson, S.
Hogervorst, F.B.
Houdayer, C.
Hulick, P.J.
Imyanitov, E.N.
Isaacs, C.
Izatt, L.
Izquierdo, A.
Jacobs, L.
Jakubowska, A.
Janavicius, R.
Jaworska-Bieniek, K.
Jensen, U.B.
John, E.M.
Vijai, J.
Karlan, B.Y.
Kast, K.
KConFab Investigators,
Khan, S.
Kwong, A.
Laitman, Y.
Lester, J.
Lesueur, F.
Liljegren, A.
Lubinski, J.
Mai, P.L.
Manoukian, S.
Mazoyer, S.
Meindl, A.
Mensenkamp, A.R.
Montagna, M.
Nathanson, K.L.
Neuhausen, S.L.
Nevanlinna, H.
Niederacher, D.
Olah, E.
Olopade, O.I.
Ong, K.-.
Osorio, A.
Park, S.K.
Paulsson-Karlsson, Y.
Pedersen, I.S.
Peissel, B.
Peterlongo, P.
Pfeiler, G.
Phelan, C.M.
Piedmonte, M.
Poppe, B.
Pujana, M.A.
Radice, P.
Rennert, G.
Rodriguez, G.C.
Rookus, M.A.
Ross, E.A.
Schmutzler, R.K.
Simard, J.
Singer, C.F.
Slavin, T.P.
Soucy, P.
Southey, M.
Steinemann, D.
Stoppa-Lyonnet, D.
Sukiennicki, G.
Sutter, C.
Szabo, C.I.
Tea, M.-.
Teixeira, M.R.
Teo, S.-.
Terry, M.B.
Thomassen, M.
Tibiletti, M.G.
Tihomirova, L.
Tognazzo, S.
van Rensburg, E.J.
Varesco, L.
Varon-Mateeva, R.
Vratimos, A.
Weitzel, J.N.
McGuffog, L.
Kirk, J.
Toland, A.E.
Hamann, U.
Lindor, N.
Ramus, S.J.
Greene, M.H.
Couch, F.J.
Offit, K.
Pharoah, P.D.
Chenevix-Trench, G.
Antoniou, A.C.
(2016). Fine-Scale Mapping at 9p22 2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. Plos one,
Vol.11
(7),
p. e0158801.
show abstract
full text
Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population..
Copson, E.R.
Cutress, R.I.
Maishman, T.
Eccles, B.K.
Gerty, S.
Stanton, L.
Altman, D.G.
Durcan, L.
Wong, C.
Simmonds, P.D.
Jones, L.
Eccles, D.M.
POSH Study Steering Group,
(2015). Obesity and the outcome of young breast cancer patients in the UK: the POSH study. Ann oncol,
Vol.26
(1),
pp. 101-112.
show abstract
BACKGROUND: Obese breast cancer patients have a poorer prognosis than non-obese patients. We examined data from a large prospective cohort study to explore the associations of obesity with tumour pathology, treatment and outcome in young British breast cancer patients receiving modern oncological treatments. PATIENTS AND METHODS: A total of 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 126 UK hospitals from 2001 to 2007. Height and weight were measured at registration. Tumour pathology and treatment details were collected. Follow-up data were collected at 6, 12 months, and annually. RESULTS: A total of 2843 eligible patients (96.2%) had a body mass index (BMI) recorded: 1526 (53.7%) were under/healthy-weight (U/H, BMI <25 kg/m(2)), 784 (27.6%) were overweight (ov, BMI ≥25 to <30), and 533 (18.7%) were obese (ob, BMI ≥30). The median tumour size was significantly higher in obese and overweight patients than U/H patients (Ob 26 mm versus U/H 20 mm, P < 0.001; Ov 24 mm versus U/H 20 mm, P < 0.001). Obese and overweight patients had significantly more grade 3 tumours (63.9% versus 59.0%, P = 0.048; Ov 63.6% versus U/H 59.0% P = 0.034) and node-positive tumours (Ob 54.6% versus U/H 49.0%, P = 0.027; Ov 54.2% versus U/H 49%, P = 0.019) than U/H patients. Obese patients had more ER/PR/HER2-negative tumours than healthy-weight patients (25.0% versus 18.3%, P = 0.001). Eight-year overall survival (OS) and distant disease-free interval (DDFI) were significantly lower in obese patients than healthy-weight patients [OS: hazard ratio (HR) 1.65, P < 0.001; DDFI: HR 1.44, P < 0.001]. Multivariable analyses adjusting for tumour grade, size, nodal, and HER2 status indicated that obesity was a significant independent predictor of OS and DDFI in patients with ER-positive disease. CONCLUSIONS: Young obese breast cancer patients present with adverse tumour characteristics. Despite adjustment for this, obesity still independently predicts DDFI and OS..
Han, Y.
Signorello, L.B.
Strom, S.S.
Kittles, R.A.
Rybicki, B.A.
Stanford, J.L.
Goodman, P.J.
Berndt, S.I.
Carpten, J.
Casey, G.
Chu, L.
Conti, D.V.
Rand, K.A.
Diver, W.R.
Hennis, A.J.
John, E.M.
Kibel, A.S.
Klein, E.A.
Kolb, S.
Le Marchand, L.
Leske, M.C.
Murphy, A.B.
Neslund-Dudas, C.
Park, J.Y.
Pettaway, C.
Rebbeck, T.R.
Gapstur, S.M.
Zheng, S.L.
Wu, S.-.
Witte, J.S.
Xu, J.
Isaacs, W.
Ingles, S.A.
Hsing, A.
PRACTICAL Consortium,
ELLIPSE GAME-ON Consortium,
Easton, D.F.
Eeles, R.A.
Schumacher, F.R.
Chanock, S.
Nemesure, B.
Blot, W.J.
Stram, D.O.
Henderson, B.E.
Haiman, C.A.
(2015). Generalizability of established prostate cancer risk variants in men of African ancestry. Int j cancer,
Vol.136
(5),
pp. 1210-1217.
show abstract
Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry..
Han, Y.
Hazelett, D.J.
Wiklund, F.
Schumacher, F.R.
Stram, D.O.
Berndt, S.I.
Wang, Z.
Rand, K.A.
Hoover, R.N.
Machiela, M.J.
Yeager, M.
Burdette, L.
Chung, C.C.
Hutchinson, A.
Yu, K.
Xu, J.
Travis, R.C.
Key, T.J.
Siddiq, A.
Canzian, F.
Takahashi, A.
Kubo, M.
Stanford, J.L.
Kolb, S.
Gapstur, S.M.
Diver, W.R.
Stevens, V.L.
Strom, S.S.
Pettaway, C.A.
Al Olama, A.A.
Kote-Jarai, Z.
Eeles, R.A.
Yeboah, E.D.
Tettey, Y.
Biritwum, R.B.
Adjei, A.A.
Tay, E.
Truelove, A.
Niwa, S.
Chokkalingam, A.P.
Isaacs, W.B.
Chen, C.
Lindstrom, S.
Le Marchand, L.
Giovannucci, E.L.
Pomerantz, M.
Long, H.
Li, F.
Ma, J.
Stampfer, M.
John, E.M.
Ingles, S.A.
Kittles, R.A.
Murphy, A.B.
Blot, W.J.
Signorello, L.B.
Zheng, W.
Albanes, D.
Virtamo, J.
Weinstein, S.
Nemesure, B.
Carpten, J.
Leske, M.C.
Wu, S.-.
Hennis, A.J.
Rybicki, B.A.
Neslund-Dudas, C.
Hsing, A.W.
Chu, L.
Goodman, P.J.
Klein, E.A.
Zheng, S.L.
Witte, J.S.
Casey, G.
Riboli, E.
Li, Q.
Freedman, M.L.
Hunter, D.J.
Gronberg, H.
Cook, M.B.
Nakagawa, H.
Kraft, P.
Chanock, S.J.
Easton, D.F.
Henderson, B.E.
Coetzee, G.A.
Conti, D.V.
Haiman, C.A.
(2015). Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions. Hum mol genet,
Vol.24
(19),
pp. 5603-5618.
show abstract
Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation..
Amin Al Olama, A.
Dadaev, T.
Hazelett, D.J.
Li, Q.
Leongamornlert, D.
Saunders, E.J.
Stephens, S.
Cieza-Borrella, C.
Whitmore, I.
Benlloch Garcia, S.
Giles, G.G.
Southey, M.C.
Fitzgerald, L.
Gronberg, H.
Wiklund, F.
Aly, M.
Henderson, B.E.
Schumacher, F.
Haiman, C.A.
Schleutker, J.
Wahlfors, T.
Tammela, T.L.
Nordestgaard, B.G.
Key, T.J.
Travis, R.C.
Neal, D.E.
Donovan, J.L.
Hamdy, F.C.
Pharoah, P.
Pashayan, N.
Khaw, K.-.
Stanford, J.L.
Thibodeau, S.N.
Mcdonnell, S.K.
Schaid, D.J.
Maier, C.
Vogel, W.
Luedeke, M.
Herkommer, K.
Kibel, A.S.
Cybulski, C.
Wokołorczyk, D.
Kluzniak, W.
Cannon-Albright, L.
Brenner, H.
Butterbach, K.
Arndt, V.
Park, J.Y.
Sellers, T.
Lin, H.-.
Slavov, C.
Kaneva, R.
Mitev, V.
Batra, J.
Clements, J.A.
Spurdle, A.
Teixeira, M.R.
Paulo, P.
Maia, S.
Pandha, H.
Michael, A.
Kierzek, A.
Govindasami, K.
Guy, M.
Lophatonanon, A.
Muir, K.
Viñuela, A.
Brown, A.A.
PRACTICAL Consortium,
COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative,
Australian Prostate Cancer BioResource,
UK Genetic Prostate Cancer Study Collaborators,
UK ProtecT Study Collaborators,
Freedman, M.
Conti, D.V.
Easton, D.
Coetzee, G.A.
Eeles, R.A.
Kote-Jarai, Z.
(2015). Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans. Hum mol genet,
Vol.24
(19),
pp. 5589-5602.
show abstract
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region..
Peterlongo, P.
Chang-Claude, J.
Moysich, K.B.
Rudolph, A.
Schmutzler, R.K.
Simard, J.
Soucy, P.
Eeles, R.A.
Easton, D.F.
Hamann, U.
Wilkening, S.
Chen, B.
Rookus, M.A.
Schmidt, M.K.
van der Baan, F.H.
Spurdle, A.B.
Walker, L.C.
Lose, F.
Maia, A.-.
Montagna, M.
Matricardi, L.
Lubinski, J.
Jakubowska, A.
Gómez Garcia, E.B.
Olopade, O.I.
Nussbaum, R.L.
Nathanson, K.L.
Domchek, S.M.
Rebbeck, T.R.
Arun, B.K.
Karlan, B.Y.
Orsulic, S.
Lester, J.
Chung, W.K.
Miron, A.
Southey, M.C.
Goldgar, D.E.
Buys, S.S.
Janavicius, R.
Dorfling, C.M.
van Rensburg, E.J.
Ding, Y.C.
Neuhausen, S.L.
Hansen, T.V.
Gerdes, A.-.
Ejlertsen, B.
Jønson, L.
Osorio, A.
Martínez-Bouzas, C.
Benitez, J.
Conway, E.E.
Blazer, K.R.
Weitzel, J.N.
Manoukian, S.
Peissel, B.
Zaffaroni, D.
Scuvera, G.
Barile, M.
Ficarazzi, F.
Mariette, F.
Fortuzzi, S.
Viel, A.
Giannini, G.
Papi, L.
Martayan, A.
Tibiletti, M.G.
Radice, P.
Vratimos, A.
Fostira, F.
Garber, J.E.
Donaldson, A.
Brewer, C.
Foo, C.
Evans, D.G.
Frost, D.
Eccles, D.
Brady, A.
Cook, J.
Tischkowitz, M.
Adlard, J.
Barwell, J.
Walker, L.
Izatt, L.
Side, L.E.
Kennedy, M.J.
Rogers, M.T.
Porteous, M.E.
Morrison, P.J.
Platte, R.
Davidson, R.
Hodgson, S.V.
Ellis, S.
Cole, T.
EMBRACE,
Godwin, A.K.
Claes, K.
Van Maerken, T.
Meindl, A.
Gehrig, A.
Sutter, C.
Engel, C.
Niederacher, D.
Steinemann, D.
Plendl, H.
Kast, K.
Rhiem, K.
Ditsch, N.
Arnold, N.
Varon-Mateeva, R.
Wappenschmidt, B.
Wang-Gohrke, S.
Bressac-de Paillerets, B.
Buecher, B.
Delnatte, C.
Houdayer, C.
Stoppa-Lyonnet, D.
Damiola, F.
Coupier, I.
Barjhoux, L.
Venat-Bouvet, L.
Golmard, L.
Boutry-Kryza, N.
Sinilnikova, O.M.
Caron, O.
Pujol, P.
Mazoyer, S.
Belotti, M.
GEMO Study Collaborators,
Piedmonte, M.
Friedlander, M.L.
Rodriguez, G.C.
Copeland, L.J.
de la Hoya, M.
Segura, P.P.
Nevanlinna, H.
Aittomäki, K.
van Os, T.A.
Meijers-Heijboer, H.E.
van der Hout, A.H.
Vreeswijk, M.P.
Hoogerbrugge, N.
Ausems, M.G.
van Doorn, H.C.
Collée, J.M.
HEBON,
Olah, E.
Diez, O.
Blanco, I.
Lazaro, C.
Brunet, J.
Feliubadalo, L.
Cybulski, C.
Gronwald, J.
Durda, K.
Jaworska-Bieniek, K.
Sukiennicki, G.
Arason, A.
Chiquette, J.
Teixeira, M.R.
Olswold, C.
Couch, F.J.
Lindor, N.M.
Wang, X.
Szabo, C.I.
Offit, K.
Corines, M.
Jacobs, L.
Robson, M.E.
Zhang, L.
Joseph, V.
Berger, A.
Singer, C.F.
Rappaport, C.
Kaulich, D.G.
Pfeiler, G.
Tea, M.-.
Phelan, C.M.
Greene, M.H.
Mai, P.L.
Rennert, G.
Mulligan, A.M.
Glendon, G.
Tchatchou, S.
Andrulis, I.L.
Toland, A.E.
Bojesen, A.
Pedersen, I.S.
Thomassen, M.
Jensen, U.B.
Laitman, Y.
Rantala, J.
von Wachenfeldt, A.
Ehrencrona, H.
Askmalm, M.S.
Borg, Å.
Kuchenbaecker, K.B.
McGuffog, L.
Barrowdale, D.
Healey, S.
Lee, A.
Pharoah, P.D.
Chenevix-Trench, G.
KConFab Investigators,
Antoniou, A.C.
Friedman, E.
(2015). Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer epidemiol biomarkers prev,
Vol.24
(1),
pp. 308-316.
show abstract
full text
BACKGROUND: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. METHODS: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. RESULTS: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. CONCLUSION: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. IMPACT: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies..
Kuchenbaecker, K.B.
Ramus, S.J.
Tyrer, J.
Lee, A.
Shen, H.C.
Beesley, J.
Lawrenson, K.
McGuffog, L.
Healey, S.
Lee, J.M.
Spindler, T.J.
Lin, Y.G.
Pejovic, T.
Bean, Y.
Li, Q.
Coetzee, S.
Hazelett, D.
Miron, A.
Southey, M.
Terry, M.B.
Goldgar, D.E.
Buys, S.S.
Janavicius, R.
Dorfling, C.M.
van Rensburg, E.J.
Neuhausen, S.L.
Ding, Y.C.
Hansen, T.V.
Jønson, L.
Gerdes, A.-.
Ejlertsen, B.
Barrowdale, D.
Dennis, J.
Benitez, J.
Osorio, A.
Garcia, M.J.
Komenaka, I.
Weitzel, J.N.
Ganschow, P.
Peterlongo, P.
Bernard, L.
Viel, A.
Bonanni, B.
Peissel, B.
Manoukian, S.
Radice, P.
Papi, L.
Ottini, L.
Fostira, F.
Konstantopoulou, I.
Garber, J.
Frost, D.
Perkins, J.
Platte, R.
Ellis, S.
EMBRACE,
Godwin, A.K.
Schmutzler, R.K.
Meindl, A.
Engel, C.
Sutter, C.
Sinilnikova, O.M.
GEMO Study Collaborators,
Damiola, F.
Mazoyer, S.
Stoppa-Lyonnet, D.
Claes, K.
De Leeneer, K.
Kirk, J.
Rodriguez, G.C.
Piedmonte, M.
O'Malley, D.M.
de la Hoya, M.
Caldes, T.
Aittomäki, K.
Nevanlinna, H.
Collée, J.M.
Rookus, M.A.
Oosterwijk, J.C.
Breast Cancer Family Registry,
Tihomirova, L.
Tung, N.
Hamann, U.
Isaccs, C.
Tischkowitz, M.
Imyanitov, E.N.
Caligo, M.A.
Campbell, I.G.
Hogervorst, F.B.
HEBON,
Olah, E.
Diez, O.
Blanco, I.
Brunet, J.
Lazaro, C.
Pujana, M.A.
Jakubowska, A.
Gronwald, J.
Lubinski, J.
Sukiennicki, G.
Barkardottir, R.B.
Plante, M.
Simard, J.
Soucy, P.
Montagna, M.
Tognazzo, S.
Teixeira, M.R.
KConFab Investigators,
Pankratz, V.S.
Wang, X.
Lindor, N.
Szabo, C.I.
Kauff, N.
Vijai, J.
Aghajanian, C.A.
Pfeiler, G.
Berger, A.
Singer, C.F.
Tea, M.-.
Phelan, C.M.
Greene, M.H.
Mai, P.L.
Rennert, G.
Mulligan, A.M.
Tchatchou, S.
Andrulis, I.L.
Glendon, G.
Toland, A.E.
Jensen, U.B.
Kruse, T.A.
Thomassen, M.
Bojesen, A.
Zidan, J.
Friedman, E.
Laitman, Y.
Soller, M.
Liljegren, A.
Arver, B.
Einbeigi, Z.
Stenmark-Askmalm, M.
Olopade, O.I.
Nussbaum, R.L.
Rebbeck, T.R.
Nathanson, K.L.
Domchek, S.M.
Lu, K.H.
Karlan, B.Y.
Walsh, C.
Lester, J.
Australian Cancer Study (Ovarian Cancer Investigators),
Australian Ovarian Cancer Study Group,
Hein, A.
Ekici, A.B.
Beckmann, M.W.
Fasching, P.A.
Lambrechts, D.
Van Nieuwenhuysen, E.
Vergote, I.
Lambrechts, S.
Dicks, E.
Doherty, J.A.
Wicklund, K.G.
Rossing, M.A.
Rudolph, A.
Chang-Claude, J.
Wang-Gohrke, S.
Eilber, U.
Moysich, K.B.
Odunsi, K.
Sucheston, L.
Lele, S.
Wilkens, L.R.
Goodman, M.T.
Thompson, P.J.
Shvetsov, Y.B.
Runnebaum, I.B.
Dürst, M.
Hillemanns, P.
Dörk, T.
Antonenkova, N.
Bogdanova, N.
Leminen, A.
Pelttari, L.M.
Butzow, R.
Modugno, F.
Kelley, J.L.
Edwards, R.P.
Ness, R.B.
du Bois, A.
Heitz, F.
Schwaab, I.
Harter, P.
Matsuo, K.
Hosono, S.
Orsulic, S.
Jensen, A.
Kjaer, S.K.
Hogdall, E.
Hasmad, H.N.
Azmi, M.A.
Teo, S.-.
Woo, Y.-.
Fridley, B.L.
Goode, E.L.
Cunningham, J.M.
Vierkant, R.A.
Bruinsma, F.
Giles, G.G.
Liang, D.
Hildebrandt, M.A.
Wu, X.
Levine, D.A.
Bisogna, M.
Berchuck, A.
Iversen, E.S.
Schildkraut, J.M.
Concannon, P.
Weber, R.P.
Cramer, D.W.
Terry, K.L.
Poole, E.M.
Tworoger, S.S.
Bandera, E.V.
Orlow, I.
Olson, S.H.
Krakstad, C.
Salvesen, H.B.
Tangen, I.L.
Bjorge, L.
van Altena, A.M.
Aben, K.K.
Kiemeney, L.A.
Massuger, L.F.
Kellar, M.
Brooks-Wilson, A.
Kelemen, L.E.
Cook, L.S.
Le, N.D.
Cybulski, C.
Yang, H.
Lissowska, J.
Brinton, L.A.
Wentzensen, N.
Hogdall, C.
Lundvall, L.
Nedergaard, L.
Baker, H.
Song, H.
Eccles, D.
McNeish, I.
Paul, J.
Carty, K.
Siddiqui, N.
Glasspool, R.
Whittemore, A.S.
Rothstein, J.H.
McGuire, V.
Sieh, W.
Ji, B.-.
Zheng, W.
Shu, X.-.
Gao, Y.-.
Rosen, B.
Risch, H.A.
McLaughlin, J.R.
Narod, S.A.
Monteiro, A.N.
Chen, A.
Lin, H.-.
Permuth-Wey, J.
Sellers, T.A.
Tsai, Y.-.
Chen, Z.
Ziogas, A.
Anton-Culver, H.
Gentry-Maharaj, A.
Menon, U.
Harrington, P.
Lee, A.W.
Wu, A.H.
Pearce, C.L.
Coetzee, G.
Pike, M.C.
Dansonka-Mieszkowska, A.
Timorek, A.
Rzepecka, I.K.
Kupryjanczyk, J.
Freedman, M.
Noushmehr, H.
Easton, D.F.
Offit, K.
Couch, F.J.
Gayther, S.
Pharoah, P.P.
Antoniou, A.C.
Chenevix-Trench, G.
Consortium of Investigators of Modifiers of BRCA1 and BRCA2,
(2015). Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nat genet,
Vol.47
(2),
pp. 164-171.
show abstract
full text
Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers..
Dénes, J.
Swords, F.
Rattenberry, E.
Stals, K.
Owens, M.
Cranston, T.
Xekouki, P.
Moran, L.
Kumar, A.
Wassif, C.
Fersht, N.
Baldeweg, S.E.
Morris, D.
Lightman, S.
Agha, A.
Rees, A.
Grieve, J.
Powell, M.
Boguszewski, C.L.
Dutta, P.
Thakker, R.V.
Srirangalingam, U.
Thompson, C.J.
Druce, M.
Higham, C.
Davis, J.
Eeles, R.
Stevenson, M.
O'Sullivan, B.
Taniere, P.
Skordilis, K.
Gabrovska, P.
Barlier, A.
Webb, S.M.
Aulinas, A.
Drake, W.M.
Bevan, J.S.
Preda, C.
Dalantaeva, N.
Ribeiro-Oliveira, A.
Garcia, I.T.
Yordanova, G.
Iotova, V.
Evanson, J.
Grossman, A.B.
Trouillas, J.
Ellard, S.
Stratakis, C.A.
Maher, E.R.
Roncaroli, F.
Korbonits, M.
(2015). Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. J clin endocrinol metab,
Vol.100
(3),
pp. E531-E541.
show abstract
CONTEXT: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence. OBJECTIVE: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL. DESIGN: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. SETTING: The study was conducted at university hospitals. PATIENTS: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study. OUTCOME: Outcomes included genetic screening and clinical characteristics. RESULTS: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context. CONCLUSIONS: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma..
Kote-Jarai, Z.
Mikropoulos, C.
Leongamornlert, D.A.
Dadaev, T.
Tymrakiewicz, M.
Saunders, E.J.
Jones, M.
Jugurnauth-Little, S.
Govindasami, K.
Guy, M.
Hamdy, F.C.
Donovan, J.L.
Neal, D.E.
Lane, J.A.
Dearnaley, D.
Wilkinson, R.A.
Sawyer, E.J.
Morgan, A.
Antoniou, A.C.
Eeles, R.A.
UK Genetic Prostate Cancer Study Collaborators, and the ProtecT Study Group,
(2015). Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes. Ann oncol,
Vol.26
(4),
pp. 756-761.
show abstract
BACKGROUND: A rare recurrent missense variant in HOXB13 (rs138213197/G84E) was recently reported to be associated with hereditary prostate cancer. Population-based studies have established that, since the frequency of this single-nucleotide polymorphism (SNP) varies between geographic regions, the associated proportion of prostate cancer (PrCa) risk contribution is also highly variable by country. PATIENTS AND METHODS: This is the largest comprehensive case-control study assessing the prevalence of the HOXB13 G84E variant to date and is the first in the UK population. We genotyped 8652 men diagnosed with PrCa within the UK Genetic Prostate Cancer Study (UKGPCS) and 5252 healthy men from the UK ProtecT study. RESULTS: HOXB13 G84E was identified in 0.5% of the healthy controls and 1.5% of the PrCa cases, and it was associated with a 2.93-fold increased risk of PrCa [95% confidence interval (CI) 1.94-4.59; P = 6.27 × 10(-8)]. The risk was even higher among men with family history of PrCa [odds ratio (OR) = 4.53, 95% CI 2.86-7.34; P = 3.1 × 10(-8)] and in young-onset PrCa (diagnosed up to the age of 55 years; OR = 3.11, 95% CI 1.98-5.00; P = 6.1 × 10(-7)). There was no significant association between Gleason Score, presenting prostate specific antigen, tumour-node-metastasis (TNM) stage or NCCN risk group and carrier status. HOXB13 G84E was not associated with overall or cancer-specific survival. We found that the polygenic PrCa risk score (PR score), calculated using the 71 known single-nucleotide polymorphisms (SNPs) associated with PrCa and the HOXB13 G84E variant act multiplicatively on PrCa risk. Based on the estimated prevalence and risk, this rare variant explains ∼1% of the familial risk of PrCa in the UK population. CONCLUSIONS: The clinical importance of HOXB13 G84E in PrCa management has not been established. This variant was found to have no effect on prognostic implications but could be used for stratifying screening, by identifying men at high risk. CLINICAL TRIALS NUMBERS: Prostate Testing for Cancer and Treatment (ProtecT): NCT02044172. UK GENETIC PROSTATE CANCER STUDY: Epidemiology and Molecular Genetics Studies (UKGPCS): NCT01737242..
Cooper, C.S.
Eeles, R.
Wedge, D.C.
Van Loo, P.
Gundem, G.
Alexandrov, L.B.
Kremeyer, B.
Butler, A.
Lynch, A.G.
Camacho, N.
Massie, C.E.
Kay, J.
Luxton, H.J.
Edwards, S.
Kote-Jarai, Z.
Dennis, N.
Merson, S.
Leongamornlert, D.
Zamora, J.
Corbishley, C.
Thomas, S.
Nik-Zainal, S.
O'Meara, S.
Matthews, L.
Clark, J.
Hurst, R.
Mithen, R.
Bristow, R.G.
Boutros, P.C.
Fraser, M.
Cooke, S.
Raine, K.
Jones, D.
Menzies, A.
Stebbings, L.
Hinton, J.
Teague, J.
McLaren, S.
Mudie, L.
Hardy, C.
Anderson, E.
Joseph, O.
Goody, V.
Robinson, B.
Maddison, M.
Gamble, S.
Greenman, C.
Berney, D.
Hazell, S.
Livni, N.
ICGC Prostate Group,
Fisher, C.
Ogden, C.
Kumar, P.
Thompson, A.
Woodhouse, C.
Nicol, D.
Mayer, E.
Dudderidge, T.
Shah, N.C.
Gnanapragasam, V.
Voet, T.
Campbell, P.
Futreal, A.
Easton, D.
Warren, A.Y.
Foster, C.S.
Stratton, M.R.
Whitaker, H.C.
McDermott, U.
Brewer, D.S.
Neal, D.E.
(2015). Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Nat genet,
Vol.47
(4),
pp. 367-372.
show abstract
full text
Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases..
Massie, C.E.
Spiteri, I.
Ross-Adams, H.
Luxton, H.
Kay, J.
Whitaker, H.C.
Dunning, M.J.
Lamb, A.D.
Ramos-Montoya, A.
Brewer, D.S.
Cooper, C.S.
Eeles, R.
UK Prostate ICGC Group,
Warren, A.Y.
Tavaré, S.
Neal, D.E.
Lynch, A.G.
(2015). HES5 silencing is an early and recurrent change in prostate tumourigenesis. Endocr relat cancer,
Vol.22
(2),
pp. 131-144.
show abstract
Prostate cancer is the most common cancer in men, resulting in over 10 000 deaths/year in the UK. Sequencing and copy number analysis of primary tumours has revealed heterogeneity within tumours and an absence of recurrent founder mutations, consistent with non-genetic disease initiating events. Using methylation profiling in a series of multi-focal prostate tumours, we identify promoter methylation of the transcription factor HES5 as an early event in prostate tumourigenesis. We confirm that this epigenetic alteration occurs in 86-97% of cases in two independent prostate cancer cohorts (n=49 and n=39 tumour-normal pairs). Treatment of prostate cancer cells with the demethylating agent 5-aza-2'-deoxycytidine increased HES5 expression and downregulated its transcriptional target HES6, consistent with functional silencing of the HES5 gene in prostate cancer. Finally, we identify and test a transcriptional module involving the AR, ERG, HES1 and HES6 and propose a model for the impact of HES5 silencing on tumourigenesis as a starting point for future functional studies..
Panagiotou, O.A.
Travis, R.C.
Campa, D.
Berndt, S.I.
Lindstrom, S.
Kraft, P.
Schumacher, F.R.
Siddiq, A.
Papatheodorou, S.I.
Stanford, J.L.
Albanes, D.
Virtamo, J.
Weinstein, S.J.
Diver, W.R.
Gapstur, S.M.
Stevens, V.L.
Boeing, H.
Bueno-de-Mesquita, H.B.
Barricarte Gurrea, A.
Kaaks, R.
Khaw, K.-.
Krogh, V.
Overvad, K.
Riboli, E.
Trichopoulos, D.
Giovannucci, E.
Stampfer, M.
Haiman, C.
Henderson, B.
Le Marchand, L.
Gaziano, J.M.
Hunter, D.J.
Koutros, S.
Yeager, M.
Hoover, R.N.
PRACTICAL Consortium,
Chanock, S.J.
Wacholder, S.
Key, T.J.
Tsilidis, K.K.
(2015). A genome-wide pleiotropy scan for prostate cancer risk. Eur urol,
Vol.67
(4),
pp. 649-657.
show abstract
full text
BACKGROUND: No single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS). OBJECTIVE: To test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: SNPs implicated in any phenotype other than prostate cancer (p≤10(-7)) were identified through the catalog of published GWAS and tested in 2891 aggressive prostate cancer cases and 4592 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). The 40 most significant SNPs were followed up in 4872 aggressive prostate cancer cases and 24,534 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) and 95% confidence intervals (CIs) for aggressive prostate cancer were estimated. RESULTS AND LIMITATIONS: A total of 4666 SNPs were evaluated by the BPC3. Two signals were seen in regions already reported for prostate cancer risk. rs7014346 at 8q24.21 was marginally associated with aggressive prostate cancer in the BPC3 trial (p=1.6×10(-6)), whereas after meta-analysis by PRACTICAL the summary OR was 1.21 (95% CI 1.16-1.27; p=3.22×10(-18)). rs9900242 at 17q24.3 was also marginally associated with aggressive disease in the meta-analysis (OR 0.90, 95% CI 0.86-0.94; p=2.5×10(-6)). Neither of these SNPs remained statistically significant when conditioning on correlated known prostate cancer SNPs. The meta-analysis by BPC3 and PRACTICAL identified a third promising signal, marked by rs16844874 at 2q34, independent of known prostate cancer loci (OR 1.12, 95% CI 1.06-1.19; p=4.67×10(-5)); it has been shown that SNPs correlated with this signal affect glycine concentrations. The main limitation is the heterogeneity in the definition of aggressive prostate cancer between BPC3 and PRACTICAL. CONCLUSIONS: We did not identify new SNPs for aggressive prostate cancer. However, rs16844874 may provide preliminary genetic evidence on the role of the glycine pathway in prostate cancer etiology. PATIENT SUMMARY: We evaluated whether genetic variants associated with several traits are linked to the risk of aggressive prostate cancer. No new such variants were identified..
Stegeman, S.
Amankwah, E.
Klein, K.
O'Mara, T.A.
Kim, D.
Lin, H.-.
Permuth-Wey, J.
Sellers, T.A.
Srinivasan, S.
Eeles, R.
Easton, D.
Kote-Jarai, Z.
Amin Al Olama, A.
Benlloch, S.
Muir, K.
Giles, G.G.
Wiklund, F.
Gronberg, H.
Haiman, C.A.
Schleutker, J.
Nordestgaard, B.G.
Travis, R.C.
Neal, D.
Pharoah, P.
Khaw, K.-.
Stanford, J.L.
Blot, W.J.
Thibodeau, S.
Maier, C.
Kibel, A.S.
Cybulski, C.
Cannon-Albright, L.
Brenner, H.
Kaneva, R.
Teixeira, M.R.
PRACTICAL Consortium,
Australian Prostate Cancer BioResource,
Spurdle, A.B.
Clements, J.A.
Park, J.Y.
Batra, J.
(2015). A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer. Cancer discov,
Vol.5
(4),
pp. 368-379.
show abstract
UNLABELLED: Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies have identified 100 risk variants for prostate cancer, which can explain approximately 33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3' untranslated region of genes predicted to affect miRNA binding (miRSNP) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (P<2.3×10(-5)) with risk of prostate cancer, 10 of which were within 7 genes previously not mapped by GWAS studies. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele, whereas miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role. SIGNIFICANCE: Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk..
Cremers, R.G.
Eeles, R.A.
Bancroft, E.K.
Ringelberg-Borsboom, J.
Vasen, H.F.
Van Asperen, C.J.
IMPACT Steering Committee,
Schalken, J.A.
Verhaegh, G.W.
Kiemeney, L.A.
(2015). The role of the prostate cancer gene 3 urine test in addition to serum prostate-specific antigen level in prostate cancer screening among breast cancer, early-onset gene mutation carriers. Urol oncol,
Vol.33
(5),
pp. 202.e19-202.e28.
show abstract
OBJECTIVE: To evaluate the additive value of the prostate cancer gene 3 (PCA3) urine test to serum prostate-specific antigen (PSA) in prostate cancer (PC) screening among breast cancer, early-onset gene (BRCA) mutation carriers. This study was performed among the Dutch participants of IMPACT, a large international study on the effectiveness of PSA screening among BRCA mutation carriers. MATERIALS AND METHODS: Urinary PCA3 was measured in 191 BRCA1 mutation carriers, 75 BRCA2 mutation carriers, and 308 noncarriers. The physicians and participants were blinded for the results. Serum PSA level ≥ 3.0 ng/ml was used to indicate prostate biopsies. PCA3 was evaluated (1) as an independent indicator for prostate b iopsies and (2) as an indicator for prostate biopsies among men with an elevated PSA level. PC detected up to the 2-year screening was used as gold standard as end-of-study biopsies were not performed. RESULTS: Overall, 23 PCs were diagnosed, 20 of which were in men who had an elevated PSA level in the initial screening round. (1) PCA3, successfully determined in 552 participants, was elevated in 188 (cutoff ≥ 25; 34%) or 134 (cutoff ≥ 35; 24%) participants, including 2 of the 3 PCs missed by PSA. PCA3 would have added 157 (≥ 25; 28%) or 109 (≥ 35; 20%) biopsy sessions to screening with PSA only. (2) Elevated PCA3 as a requirement for biopsies in addition to PSA would have saved 37 (cutoff ≥ 25) or 43 (cutoff ≥ 35) of the 68 biopsy sessions, and 7 or 11 PCs would have been missed, respectively, including multiple high-risk PCs. So far, PCA3 performed best among BRCA2 mutation carriers, but the numbers are still small. Because PCA3 was not used to indicate prostate biopsies, its true diagnostic value cannot be calculated. CONCLUSIONS: The results do not provide evidence for PCA3 as a useful additional indicator of prostate biopsies in BRCA mutation carriers, as many participants had an elevated PCA3 in the absence of PC. This must be interpreted with caution because PCA3 was not used to indicate biopsies. Many participants diagnosed with PC had low PCA3, making it invalid as a restrictive marker for prostate biopsies in men with elevated PSA levels..
Huddart, R.
Dearnaley, D.
Eeles, R.
Khoo, V.
Horwich, A.
(2015). Selective organ preservation with neo-adjuvant chemotherapy for the treatment of muscle invasive transitional cell carcinoma of the bladder. British journal of cancer,
Vol.112
(10),
pp. 1626-1635.
show abstract
Background: Radiotherapy for muscle invasive bladder cancer (MIBC) aims to offer organ preservation without oncological compromise. Neo-adjuvant chemotherapy provides survival advantage; response may guide patient selection for bladder preservation and identify those most likely to have favourable result with radiotherapy. Methods: Ninety-four successive patients with T2-T4aN0M0 bladder cancer treated between January 2000 and June 2011 were analysed at the Royal Marsden Hospital. Patients received platinum-based chemotherapy following transurethral resection of bladder tumour; repeat cystoscopy (+/- biopsy) was performed to guide subsequent management. Responders were treated with radiotherapy. Poor responders were recommended radical cystectomy. Progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OS) were estimated using Kaplan-Meier method; univariate and multivariate analyses were performed using the Cox proportional hazard regression model. Results: Response assessment was performed in 89 patients. Seventy-eight (88%) demonstrated response; 53 (60%) achieved complete response (CR); 74 responders had radiotherapy; 4 opted for cystectomy. Eleven (12%) demonstrated poor response, 10 received cystectomy. Median survival for CR was 90 months (95% CI 64.7, 115.9) compared with 16 months (95% CI 5.4, 27.4; P<0.001) poor responders. On multivariate analysis, only response was associated with significantly improved PFS, OS and DSS. After a median follow-up of 39 months (range 4-127 months), 14 patients (16%) required salvage cystectomy (8 for non-muscle invasive disease, 5 for invasive recurrence, 1 for radiotherapy related toxicity). In all, 82% had an intact bladder at last follow-up after radiotherapy; 67% had an intact bladder at last follow-up or death. Our study is limited by its retrospective nature. Conclusions: Response to neo-adjuvant chemotherapy is a favourable prognostic indicator and can be used to select patients for radiotherapy allowing bladder preservation in 480% of the selected patients..
Ju, Y.S.
Tubio, J.M.
Mifsud, W.
Fu, B.
Davies, H.R.
Ramakrishna, M.
Li, Y.
Yates, L.
Gundem, G.
Tarpey, P.S.
Behjati, S.
Papaemmanuil, E.
Martin, S.
Fullam, A.
Gerstung, M.
ICGC Prostate Cancer Working Group,
ICGC Bone Cancer Working Group,
ICGC Breast Cancer Working Group,
Nangalia, J.
Green, A.R.
Caldas, C.
Borg, Å.
Tutt, A.
Lee, M.T.
van't Veer, L.J.
Tan, B.K.
Aparicio, S.
Span, P.N.
Martens, J.W.
Knappskog, S.
Vincent-Salomon, A.
Børresen-Dale, A.-.
Eyfjörd, J.E.
Myklebost, O.
Flanagan, A.M.
Foster, C.
Neal, D.E.
Cooper, C.
Eeles, R.
Bova, S.G.
Lakhani, S.R.
Desmedt, C.
Thomas, G.
Richardson, A.L.
Purdie, C.A.
Thompson, A.M.
McDermott, U.
Yang, F.
Nik-Zainal, S.
Campbell, P.J.
Stratton, M.R.
(2015). Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells. Genome res,
Vol.25
(6),
pp. 814-824.
show abstract
Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent DNA double-strand break repair are the dominant mechanisms involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells..
Eccles, B.K.
Copson, E.R.
Cutress, R.I.
Maishman, T.
Altman, D.G.
Simmonds, P.
Gerty, S.M.
Durcan, L.
Stanton, L.
Eccles, D.M.
POSH Study Steering Group,
(2015). Family history and outcome of young patients with breast cancer in the UK (POSH study). Br j surg,
Vol.102
(8),
pp. 924-935.
show abstract
BACKGROUND: Young patients presenting to surgical clinics with breast cancer are usually aware of their family history and frequently believe that a positive family history may adversely affect their prognosis. Tumour pathology and outcomes were compared in young British patients with breast cancer with and without a family history of breast cancer. METHODS: Prospective Outcomes in Sporadic versus Hereditary breast cancer (POSH) is a large prospective cohort study of women aged less than 41 years with breast cancer diagnosed and treated in the UK using modern oncological management. Personal characteristics, tumour pathology, treatment and family history of breast/ovarian cancer were recorded. Follow-up data were collected annually. RESULTS: Family history data were available for 2850 patients. No family history was reported by 65·9 per cent, and 34·1 per cent reported breast/ovarian cancer in at least one first- or second-degree relative. Patients with a family history were more likely to have grade 3 tumours (63·3 versus 58·9 per cent) and less likely to have human epidermal growth factor receptor 2-positive tumours (24·7 versus 28·8 per cent) than those with no family history. In multivariable analyses, there were no significant differences in distant disease-free intervals for patients with versus those without a family history, either for the whole cohort (hazard ratio (HR) 0·89, 95 per cent c.i. 0·76 to 1·03; P = 0·120) or when stratified by oestrogen receptor (ER) status (ER-negative: HR 0·80, 0·62 to 1·04, P = 0·101; ER-positive: HR 0·95, 0·78 to 1·15, P = 0·589). CONCLUSION: Young British patients presenting to breast surgical clinics with a positive family history can be reassured that this is not a significant independent risk factor for breast cancer outcome..
Boutros, P.C.
Fraser, M.
Harding, N.J.
de Borja, R.
Trudel, D.
Lalonde, E.
Meng, A.
Hennings-Yeomans, P.H.
McPherson, A.
Sabelnykova, V.Y.
Zia, A.
Fox, N.S.
Livingstone, J.
Shiah, Y.-.
Wang, J.
Beck, T.A.
Have, C.L.
Chong, T.
Sam, M.
Johns, J.
Timms, L.
Buchner, N.
Wong, A.
Watson, J.D.
Simmons, T.T.
P'ng, C.
Zafarana, G.
Nguyen, F.
Luo, X.
Chu, K.C.
Prokopec, S.D.
Sykes, J.
Dal Pra, A.
Berlin, A.
Brown, A.
Chan-Seng-Yue, M.A.
Yousif, F.
Denroche, R.E.
Chong, L.C.
Chen, G.M.
Jung, E.
Fung, C.
Starmans, M.H.
Chen, H.
Govind, S.K.
Hawley, J.
D'Costa, A.
Pintilie, M.
Waggott, D.
Hach, F.
Lambin, P.
Muthuswamy, L.B.
Cooper, C.
Eeles, R.
Neal, D.
Tetu, B.
Sahinalp, C.
Stein, L.D.
Fleshner, N.
Shah, S.P.
Collins, C.C.
Hudson, T.J.
McPherson, J.D.
van der Kwast, T.
Bristow, R.G.
(2015). Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nat genet,
Vol.47
(7),
pp. 736-745.
show abstract
Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis..
Amin Al Olama, A.
Benlloch, S.
Antoniou, A.C.
Giles, G.G.
Severi, G.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Muir, K.
Schleutker, J.
Henderson, B.E.
Haiman, C.A.
Schumacher, F.R.
Pashayan, N.
Pharoah, P.D.
Ostrander, E.A.
Stanford, J.L.
Batra, J.
Clements, J.A.
Chambers, S.K.
Weischer, M.
Nordestgaard, B.G.
Ingles, S.A.
Sorensen, K.D.
Orntoft, T.F.
Park, J.Y.
Cybulski, C.
Maier, C.
Doerk, T.
Dickinson, J.L.
Cannon-Albright, L.
Brenner, H.
Rebbeck, T.R.
Zeigler-Johnson, C.
Habuchi, T.
Thibodeau, S.N.
Cooney, K.A.
Chappuis, P.O.
Hutter, P.
Kaneva, R.P.
Foulkes, W.D.
Zeegers, M.P.
Lu, Y.-.
Zhang, H.-.
Stephenson, R.
Cox, A.
Southey, M.C.
Spurdle, A.B.
FitzGerald, L.
Leongamornlert, D.
Saunders, E.
Tymrakiewicz, M.
Guy, M.
Dadaev, T.
Little, S.J.
Govindasami, K.
Sawyer, E.
Wilkinson, R.
Herkommer, K.
Hopper, J.L.
Lophatonanon, A.
Rinckleb, A.E.
Kote-Jarai, Z.
Eeles, R.A.
Easton, D.F.
UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology,
UK ProtecT Study Collaborators,
PRACTICAL Consortium,
(2015). Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci. Cancer epidemiol biomarkers prev,
Vol.24
(7),
pp. 1121-1129.
show abstract
BACKGROUND: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. METHODS: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. RESULTS: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). CONCLUSIONS: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. IMPACT: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs..
Rebbeck, T.R.
Mitra, N.
Wan, F.
Sinilnikova, O.M.
Healey, S.
McGuffog, L.
Mazoyer, S.
Chenevix-Trench, G.
Easton, D.F.
Antoniou, A.C.
Nathanson, K.L.
CIMBA Consortium,
Laitman, Y.
Kushnir, A.
Paluch-Shimon, S.
Berger, R.
Zidan, J.
Friedman, E.
Ehrencrona, H.
Stenmark-Askmalm, M.
Einbeigi, Z.
Loman, N.
Harbst, K.
Rantala, J.
Melin, B.
Huo, D.
Olopade, O.I.
Seldon, J.
Ganz, P.A.
Nussbaum, R.L.
Chan, S.B.
Odunsi, K.
Gayther, S.A.
Domchek, S.M.
Arun, B.K.
Lu, K.H.
Mitchell, G.
Karlan, B.Y.
Walsh, C.
Lester, J.
Godwin, A.K.
Pathak, H.
Ross, E.
Daly, M.B.
Whittemore, A.S.
John, E.M.
Miron, A.
Terry, M.B.
Chung, W.K.
Goldgar, D.E.
Buys, S.S.
Janavicius, R.
Tihomirova, L.
Tung, N.
Dorfling, C.M.
van Rensburg, E.J.
Steele, L.
Neuhausen, S.L.
Ding, Y.C.
Ejlertsen, B.
Gerdes, A.-.
Hansen, T.V.
Ramón y Cajal, T.
Osorio, A.
Benitez, J.
Godino, J.
Tejada, M.-.
Duran, M.
Weitzel, J.N.
Bobolis, K.A.
Sand, S.R.
Fontaine, A.
Savarese, A.
Pasini, B.
Peissel, B.
Bonanni, B.
Zaffaroni, D.
Vignolo-Lutati, F.
Scuvera, G.
Giannini, G.
Bernard, L.
Genuardi, M.
Radice, P.
Dolcetti, R.
Manoukian, S.
Pensotti, V.
Gismondi, V.
Yannoukakos, D.
Fostira, F.
Garber, J.
Torres, D.
Rashid, M.U.
Hamann, U.
Peock, S.
Frost, D.
Platte, R.
Evans, D.G.
Eeles, R.
Davidson, R.
Eccles, D.
Cole, T.
Cook, J.
Brewer, C.
Hodgson, S.
Morrison, P.J.
Walker, L.
Porteous, M.E.
Kennedy, M.J.
Izatt, L.
Adlard, J.
Donaldson, A.
Ellis, S.
Sharma, P.
Schmutzler, R.K.
Wappenschmidt, B.
Becker, A.
Rhiem, K.
Hahnen, E.
Engel, C.
Meindl, A.
Engert, S.
Ditsch, N.
Arnold, N.
Plendl, H.J.
Mundhenke, C.
Niederacher, D.
Fleisch, M.
Sutter, C.
Bartram, C.R.
Dikow, N.
Wang-Gohrke, S.
Gadzicki, D.
Steinemann, D.
Kast, K.
Beer, M.
Varon-Mateeva, R.
Gehrig, A.
Weber, B.H.
Stoppa-Lyonnet, D.
Sinilnikova, O.M.
Mazoyer, S.
Houdayer, C.
Belotti, M.
Gauthier-Villars, M.
Damiola, F.
Boutry-Kryza, N.
Lasset, C.
Sobol, H.
Peyrat, J.-.
Muller, D.
Fricker, J.-.
Collonge-Rame, M.-.
Mortemousque, I.
Nogues, C.
Rouleau, E.
Isaacs, C.
De Paepe, A.
Poppe, B.
Claes, K.
De Leeneer, K.
Piedmonte, M.
Rodriguez, G.
Wakely, K.
Boggess, J.
Blank, S.V.
Basil, J.
Azodi, M.
Phillips, K.-.
Caldes, T.
de la Hoya, M.
Romero, A.
Nevanlinna, H.
Aittomäki, K.
van der Hout, A.H.
Hogervorst, F.B.
Verhoef, S.
Collée, J.M.
Seynaeve, C.
Oosterwijk, J.C.
Gille, J.J.
Wijnen, J.T.
Gómez Garcia, E.B.
Kets, C.M.
Ausems, M.G.
Aalfs, C.M.
Devilee, P.
Mensenkamp, A.R.
Kwong, A.
Olah, E.
Papp, J.
Diez, O.
Lazaro, C.
Darder, E.
Blanco, I.
Salinas, M.
Jakubowska, A.
Lubinski, J.
Gronwald, J.
Jaworska-Bieniek, K.
Durda, K.
Sukiennicki, G.
Huzarski, T.
Byrski, T.
Cybulski, C.
Toloczko-Grabarek, A.
Złowocka-Perłowska, E.
Menkiszak, J.
Arason, A.
Barkardottir, R.B.
Simard, J.
Laframboise, R.
Montagna, M.
Agata, S.
Alducci, E.
Peixoto, A.
Teixeira, M.R.
Spurdle, A.B.
Lee, M.H.
Park, S.K.
Kim, S.-.
Friebel, T.M.
Couch, F.J.
Lindor, N.M.
Pankratz, V.S.
Guidugli, L.
Wang, X.
Tischkowitz, M.
Foretova, L.
Vijai, J.
Offit, K.
Robson, M.
Rau-Murthy, R.
Kauff, N.
Fink-Retter, A.
Singer, C.F.
Rappaport, C.
Gschwantler-Kaulich, D.
Pfeiler, G.
Tea, M.-.
Berger, A.
Greene, M.H.
Mai, P.L.
Imyanitov, E.N.
Toland, A.E.
Senter, L.
Bojesen, A.
Pedersen, I.S.
Skytte, A.-.
Sunde, L.
Thomassen, M.
Moeller, S.T.
Kruse, T.A.
Jensen, U.B.
Caligo, M.A.
Aretini, P.
Teo, S.-.
Selkirk, C.G.
Hulick, P.J.
Andrulis, I.
(2015). Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. Jama,
Vol.313
(13),
pp. 1347-1361.
show abstract
IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES: Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks. RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations..
Castro, E.
Goh, C.
Leongamornlert, D.
Saunders, E.
Tymrakiewicz, M.
Dadaev, T.
Govindasami, K.
Guy, M.
Ellis, S.
Frost, D.
Bancroft, E.
Cole, T.
Tischkowitz, M.
Kennedy, M.J.
Eason, J.
Brewer, C.
Evans, D.G.
Davidson, R.
Eccles, D.
Porteous, M.E.
Douglas, F.
Adlard, J.
Donaldson, A.
Antoniou, A.C.
Kote-Jarai, Z.
Easton, D.F.
Olmos, D.
Eeles, R.
(2015). Effect of BRCA Mutations on Metastatic Relapse and Cause-specific Survival After Radical Treatment for Localised Prostate Cancer. Eur urol,
Vol.68
(2),
pp. 186-193.
show abstract
BACKGROUND: Germline BRCA mutations are associated with worse prostate cancer (PCa) outcomes; however, the most appropriate management for mutation carriers has not yet been investigated. OBJECTIVE: To evaluate the response of BRCA carriers to conventional treatments for localised PCa by analysing metastasis-free survival (MFS) and cause-specific survival (CSS) following radical prostatectomy (RP) or external-beam radiation therapy (RT). DESIGN, SETTING, AND PARTICIPANTS: Tumour features and outcomes of 1302 patients with local/locally advanced PCa (including 67 BRCA mutation carriers) were analysed. RP was undergone by 535 patients (35 BRCA); 767 received RT (32 BRCA). Median follow-up was 64 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Median survival and 3-, 5-, and 10-yr survival rates were estimated using the Kaplan-Meier method. Generated survival curves were compared using the log-rank test. Cox regression analyses were used to assess the prognostic value of BRCA mutations. RESULTS AND LIMITATIONS: A total of 67 BRCA carriers and 1235 noncarriers were included. At 3, 5, and 10 yr after treatment, 97%, 94%, and 84% of noncarriers and 90%, 72%, and 50% of carriers were free from metastasis (p<0.001). The 3-, 5- and 10-yr CSS rates were significantly better in the noncarrier cohort (99%, 97%, and 85%, respectively) than in carriers (96%, 76%, and 61%, respectively; p<0.001). Multivariate analysis confirmed BRCA mutations as an independent prognostic factor for MFS (hazard ratio [HR]: 2.36; 95% confidence interval [CI], 1.38-4.03; p=0.002) and CSS (HR: 2.17; 95% CI, 1.16-4.07; p=0.016). CONCLUSIONS: BRCA carriers had worse outcomes than noncarriers when conventionally treated for local/locally advanced PCa. PATIENT SUMMARY: Prostate cancer patients with germline BRCA mutations had worse outcomes than noncarriers when conventionally treated with surgery or radiation therapy..
Hernández-Ramírez, L.C.
Gabrovska, P.
Dénes, J.
Stals, K.
Trivellin, G.
Tilley, D.
Ferrau, F.
Evanson, J.
Ellard, S.
Grossman, A.B.
Roncaroli, F.
Gadelha, M.R.
Korbonits, M.
International FIPA Consortium,
(2015). Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIP Mutation Carriers. J clin endocrinol metab,
Vol.100
(9),
pp. E1242-E1254.
show abstract
CONTEXT: Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIP mutation (AIPmut) carriers could identify previously unrecognized disease. OBJECTIVE: To determine the AIP mutational status of FIPA and young pituitary adenoma patients, analyzing their clinical characteristics, and to perform clinical screening of apparently unaffected AIPmut carrier family members. DESIGN: This was an observational, longitudinal study conducted over 7 years. SETTING: International collaborative study conducted at referral centers for pituitary diseases. PARTICIPANTS: FIPA families (n 216) and sporadic young-onset (30 y) pituitary adenoma patients (n 404) participated in the study. INTERVENTIONS: We performed genetic screening of patients for AIPmuts, clinical assessment of their family members, and genetic screening for somatic GNAS1 mutations and the germline FGFR4 p.G388R variant. MAIN OUTCOME MEASURE(S): We assessed clinical disease in mutation carriers, comparison of characteristics of AIPmut positive and negative patients, results of GNAS1, and FGFR4 analysis. RESULTS: Thirty-seven FIPA families and 34 sporadic patients had AIPmuts. Patients with truncating AIPmuts had a younger age at disease onset and diagnosis, compared with patients with nontruncating AIPmuts. Somatic GNAS1 mutations were absent in tumors from AIPmut-positive patients, and the studied FGFR4 variant did not modify the disease behavior or penetrance in AIPmut-positive individuals. A total of 164 AIPmut-positive unaffected family members were identified; pituitary disease was detected in 18 of those who underwent clinical screening. CONCLUSIONS: A quarter of the AIPmut carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for AIPmut-positive pituitary adenomas..
Szulkin, R.
Whitington, T.
Eklund, M.
Aly, M.
Eeles, R.A.
Easton, D.
Kote-Jarai, Z.S.
Amin Al Olama, A.
Benlloch, S.
Muir, K.
Giles, G.G.
Southey, M.C.
Fitzgerald, L.M.
Henderson, B.E.
Schumacher, F.
Haiman, C.A.
Schleutker, J.
Wahlfors, T.
Tammela, T.L.
Nordestgaard, B.G.
Key, T.J.
Travis, R.C.
Neal, D.E.
Donovan, J.L.
Hamdy, F.C.
Pharoah, P.
Pashayan, N.
Khaw, K.-.
Stanford, J.L.
Thibodeau, S.N.
McDonnell, S.K.
Schaid, D.J.
Maier, C.
Vogel, W.
Luedeke, M.
Herkommer, K.
Kibel, A.S.
Cybulski, C.
Lubiński, J.
Kluźniak, W.
Cannon-Albright, L.
Brenner, H.
Butterbach, K.
Stegmaier, C.
Park, J.Y.
Sellers, T.
Lin, H.-.
Slavov, C.
Kaneva, R.
Mitev, V.
Batra, J.
Clements, J.A.
Australian Prostate Cancer BioResource,
Spurdle, A.
Teixeira, M.R.
Paulo, P.
Maia, S.
Pandha, H.
Michael, A.
Kierzek, A.
Practical Consortium,
Gronberg, H.
Wiklund, F.
(2015). Prediction of individual genetic risk to prostate cancer using a polygenic score. Prostate,
Vol.75
(13),
pp. 1467-1474.
show abstract
full text
BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. METHODS: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction..
Eeles, R.A.
Morden, J.P.
Gore, M.
Mansi, J.
Glees, J.
Wenczl, M.
Williams, C.
Kitchener, H.
Osborne, R.
Guthrie, D.
Harper, P.
Bliss, J.M.
(2015). Adjuvant Hormone Therapy May Improve Survival in Epithelial Ovarian Cancer: Results of the AHT Randomized Trial. J clin oncol,
Vol.33
(35),
pp. 4138-4144.
show abstract
PURPOSE: To assess the effects of adjuvant hormone therapy (AHT) on survival and disease outcome in women with epithelial ovarian cancer. PATIENTS AND METHODS: Participants were premenopausal and postmenopausal women who had been diagnosed with epithelial ovarian cancer (any International Federation of Gynecology and Obstetrics stage) 9 or fewer months previously. Ineligible patients included those with deliberately preserved ovarian function, with a history of a hormone-dependent malignancy, or with any contraindications to hormone-replacement therapy. Patients were centrally randomly assigned in a 1:1 ratio to either AHT for 5 years after random assignment or no AHT (control). Main outcome measures were overall survival (OS), defined as time from random assignment to death (any cause), and relapse-free survival, defined as time from random assignment to relapse or death (any cause). Patients who continued, alive and relapse free, were censored at their last known follow-up. RESULTS: A total of 150 patients (n = 75, AHT; n = 75, control) were randomly assigned from 1990 to 1995 from 19 centers in the United Kingdom, Spain, and Hungary; all patients were included in intention-to-treat analyses. The median follow-up in alive patients is currently 19.1 years. Of the 75 patients with AHT, 53 (71%) have died compared with 68 (91%) of 75 patients in the control group. OS was significantly improved in patients who were receiving AHT (hazard ratio, 0.63; 95% CI, 0.44 to 0.90; P = .011). A similar effect was seen for relapse-free survival (hazard ratio, 0.67; 95% CI, 0.47 to 0.97; P = .032). Effects remained after adjustment for known prognostic factors. CONCLUSION: These results show that women who have severe menopausal symptoms after ovarian cancer treatment can safely take hormone-replacement therapy, and this may, in fact, infer benefits in terms of OS in addition to known advantages in terms of quality of life..
Pashayan, N.
Duffy, S.W.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Martin, R.M.
Harrington, P.
Benlloch, S.
Amin Al Olama, A.
Shah, M.
Kote-Jarai, Z.
Easton, D.F.
Eeles, R.
Pharoah, P.D.
(2015). Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis. Genet med,
Vol.17
(10),
pp. 789-795.
show abstract
PURPOSE: This study aimed to quantify the probability of overdiagnosis of prostate cancer by polygenic risk. METHODS: We calculated the polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,012 men aged 50-69 years (9,404 men identified with prostate cancer and 7,608 with no cancer) derived from three UK-based ongoing studies. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence of screen-detected prostate cancer is a combination of underlying incidence, mean sojourn time (MST), test sensitivity, and overdiagnosis. RESULTS: Polygenic risk quartiles 1 to 4 comprised 9, 18, 25, and 48% of the cases, respectively. For a prostate-specific antigen test sensitivity of 80% and MST of 9 years, 43, 30, 25, and 19% of the prevalent screen-detected cancers in quartiles 1 to 4, respectively, were likely to be overdiagnosed cancers. Overdiagnosis decreased with increasing polygenic risk, with 56% decrease between the lowest and the highest polygenic risk quartiles. CONCLUSION: Targeting screening to men at higher polygenic risk could reduce the problem of overdiagnosis and lead to a better benefit-to-harm balance in screening for prostate cancer..
Day, F.R.
Ruth, K.S.
Thompson, D.J.
Lunetta, K.L.
Pervjakova, N.
Chasman, D.I.
Stolk, L.
Finucane, H.K.
Sulem, P.
Bulik-Sullivan, B.
Esko, T.
Johnson, A.D.
Elks, C.E.
Franceschini, N.
He, C.
Altmaier, E.
Brody, J.A.
Franke, L.L.
Huffman, J.E.
Keller, M.F.
McArdle, P.F.
Nutile, T.
Porcu, E.
Robino, A.
Rose, L.M.
Schick, U.M.
Smith, J.A.
Teumer, A.
Traglia, M.
Vuckovic, D.
Yao, J.
Zhao, W.
Albrecht, E.
Amin, N.
Corre, T.
Hottenga, J.-.
Mangino, M.
Smith, A.V.
Tanaka, T.
Abecasis, G.
Andrulis, I.L.
Anton-Culver, H.
Antoniou, A.C.
Arndt, V.
Arnold, A.M.
Barbieri, C.
Beckmann, M.W.
Beeghly-Fadiel, A.
Benitez, J.
Bernstein, L.
Bielinski, S.J.
Blomqvist, C.
Boerwinkle, E.
Bogdanova, N.V.
Bojesen, S.E.
Bolla, M.K.
Borresen-Dale, A.-.
Boutin, T.S.
Brauch, H.
Brenner, H.
Brüning, T.
Burwinkel, B.
Campbell, A.
Campbell, H.
Chanock, S.J.
Chapman, J.R.
Chen, Y.-.
Chenevix-Trench, G.
Couch, F.J.
Coviello, A.D.
Cox, A.
Czene, K.
Darabi, H.
De Vivo, I.
Demerath, E.W.
Dennis, J.
Devilee, P.
Dörk, T.
Dos-Santos-Silva, I.
Dunning, A.M.
Eicher, J.D.
Fasching, P.A.
Faul, J.D.
Figueroa, J.
Flesch-Janys, D.
Gandin, I.
Garcia, M.E.
García-Closas, M.
Giles, G.G.
Girotto, G.G.
Goldberg, M.S.
González-Neira, A.
Goodarzi, M.O.
Grove, M.L.
Gudbjartsson, D.F.
Guénel, P.
Guo, X.
Haiman, C.A.
Hall, P.
Hamann, U.
Henderson, B.E.
Hocking, L.J.
Hofman, A.
Homuth, G.
Hooning, M.J.
Hopper, J.L.
Hu, F.B.
Huang, J.
Humphreys, K.
Hunter, D.J.
Jakubowska, A.
Jones, S.E.
Kabisch, M.
Karasik, D.
Knight, J.A.
Kolcic, I.
Kooperberg, C.
Kosma, V.-.
Kriebel, J.
Kristensen, V.
Lambrechts, D.
Langenberg, C.
Li, J.
Li, X.
Lindström, S.
Liu, Y.
Luan, J.
Lubinski, J.
Mägi, R.
Mannermaa, A.
Manz, J.
Margolin, S.
Marten, J.
Martin, N.G.
Masciullo, C.
Meindl, A.
Michailidou, K.
Mihailov, E.
Milani, L.
Milne, R.L.
Müller-Nurasyid, M.
Nalls, M.
Neale, B.M.
Nevanlinna, H.
Neven, P.
Newman, A.B.
Nordestgaard, B.G.
Olson, J.E.
Padmanabhan, S.
Peterlongo, P.
Peters, U.
Petersmann, A.
Peto, J.
Pharoah, P.D.
Pirastu, N.N.
Pirie, A.
Pistis, G.
Polasek, O.
Porteous, D.
Psaty, B.M.
Pylkäs, K.
Radice, P.
Raffel, L.J.
Rivadeneira, F.
Rudan, I.
Rudolph, A.
Ruggiero, D.
Sala, C.F.
Sanna, S.
Sawyer, E.J.
Schlessinger, D.
Schmidt, M.K.
Schmidt, F.
Schmutzler, R.K.
Schoemaker, M.J.
Scott, R.A.
Seynaeve, C.M.
Simard, J.
Sorice, R.
Southey, M.C.
Stöckl, D.
Strauch, K.
Swerdlow, A.
Taylor, K.D.
Thorsteinsdottir, U.
Toland, A.E.
Tomlinson, I.
Truong, T.
Tryggvadottir, L.
Turner, S.T.
Vozzi, D.
Wang, Q.
Wellons, M.
Willemsen, G.
Wilson, J.F.
Winqvist, R.
Wolffenbuttel, B.B.
Wright, A.F.
Yannoukakos, D.
Zemunik, T.
Zheng, W.
Zygmunt, M.
Bergmann, S.
Boomsma, D.I.
Buring, J.E.
Ferrucci, L.
Montgomery, G.W.
Gudnason, V.
Spector, T.D.
van Duijn, C.M.
Alizadeh, B.Z.
Ciullo, M.
Crisponi, L.
Easton, D.F.
Gasparini, P.P.
Gieger, C.
Harris, T.B.
Hayward, C.
Kardia, S.L.
Kraft, P.
McKnight, B.
Metspalu, A.
Morrison, A.C.
Reiner, A.P.
Ridker, P.M.
Rotter, J.I.
Toniolo, D.
Uitterlinden, A.G.
Ulivi, S.
Völzke, H.
Wareham, N.J.
Weir, D.R.
Yerges-Armstrong, L.M.
PRACTICAL consortium,
kConFab Investigators,
AOCS Investigators,
Generation Scotland,
EPIC-InterAct Consortium,
LifeLines Cohort Study,
Price, A.L.
Stefansson, K.
Visser, J.A.
Ong, K.K.
Chang-Claude, J.
Murabito, J.M.
Perry, J.R.
Murray, A.
(2015). Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat genet,
Vol.47
(11),
pp. 1294-1303.
show abstract
full text
Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms..
Hung, R.J.
Ulrich, C.M.
Goode, E.L.
Brhane, Y.
Muir, K.
Chan, A.T.
Marchand, L.L.
Schildkraut, J.
Witte, J.S.
Eeles, R.
Boffetta, P.
Spitz, M.R.
Poirier, J.G.
Rider, D.N.
Fridley, B.L.
Chen, Z.
Haiman, C.
Schumacher, F.
Easton, D.F.
Landi, M.T.
Brennan, P.
Houlston, R.
Christiani, D.C.
Field, J.K.
Bickeböller, H.
Risch, A.
Kote-Jarai, Z.
Wiklund, F.
Grönberg, H.
Chanock, S.
Berndt, S.I.
Kraft, P.
Lindström, S.
Al Olama, A.A.
Song, H.
Phelan, C.
Wentzensen, N.
Peters, U.
Slattery, M.L.
GECCO,
Sellers, T.A.
FOCI,
Casey, G.
Gruber, S.B.
CORECT,
Hunter, D.J.
DRIVE,
Amos, C.I.
Henderson, B.
GAME-ON Network,
(2015). Cross Cancer Genomic Investigation of Inflammation Pathway for Five Common Cancers: Lung, Ovary, Prostate, Breast, and Colorectal Cancer. J natl cancer inst,
Vol.107
(11).
show abstract
BACKGROUND: Inflammation has been hypothesized to increase the risk of cancer development as an initiator or promoter, yet no large-scale study of inherited variation across cancer sites has been conducted. METHODS: We conducted a cross-cancer genomic analysis for the inflammation pathway based on 48 genome-wide association studies within the National Cancer Institute GAME-ON Network across five common cancer sites, with a total of 64 591 cancer patients and 74 467 control patients. Subset-based meta-analysis was used to account for possible disease heterogeneity, and hierarchical modeling was employed to estimate the effect of the subcomponents within the inflammation pathway. The network was visualized by enrichment map. All statistical tests were two-sided. RESULTS: We identified three pleiotropic loci within the inflammation pathway, including one novel locus in Ch12q24 encoding SH2B3 (rs3184504), which reached GWAS significance with a P value of 1.78 x 10(-8), and it showed an association with lung cancer (P = 2.01 x 10(-6)), colorectal cancer (GECCO P = 6.72x10(-6); CORECT P = 3.32x10(-5)), and breast cancer (P = .009). We also identified five key subpathway components with genetic variants that are relevant for the risk of these five cancer sites: inflammatory response for colorectal cancer (P = .006), inflammation related cell cycle gene for lung cancer (P = 1.35x10(-6)), and activation of immune response for ovarian cancer (P = .009). In addition, sequence variations in immune system development played a role in breast cancer etiology (P = .001) and innate immune response was involved in the risk of both colorectal (P = .022) and ovarian cancer (P = .003). CONCLUSIONS: Genetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer..
Bancroft, E.K.
Castro, E.
Bancroft, G.A.
Ardern-Jones, A.
Moynihan, C.
Page, E.
Taylor, N.
Eeles, R.A.
Rowley, E.
Cox, K.
(2015). The psychological impact of undergoing genetic-risk profiling in men with a family history of prostate cancer. Psychooncology,
Vol.24
(11),
pp. 1492-1499.
show abstract
BACKGROUND: The ability to identify men at genetically high-risk of prostate cancer (PrCa) would enable screening to be targeted at those most in need. This study explored the psychological impact (in terms of general and PrCa-specific worry and risk perceptions) on men with a family history of PrCa, undergoing prostate screening and genetic-risk profiling, within a research study. METHODS: A prospective exploratory approach was adopted, incorporating a sequential mixed-method design. Questionnaires were completed at two time points to measure the impact of undergoing screening and genetic-risk profiling. In-depth interviews were completed in a subgroup after all study procedures were completed and analysed using a framework approach. RESULTS: Ninety-five men completed both questionnaires, and 26 were interviewed. No measurable psychological distress was detectable in the group as a whole. The interview findings fell into two categories: 'feeling at risk' and 'living with risk'. The feeling of being at risk of PrCa is a part of men's lives, shaped by assumptions and information gathered over many years. Men used this information to communicate about PrCa risk to their peers. Men overestimate their risk of PrCa and have an innate assumption that they will develop PrCa. The interviews revealed that men experienced acute anxiety when waiting for screening results. CONCLUSIONS: Personalised genetic-risk assessments do not prevent men from overestimating their risk of PrCa. Screening anxiety is common, and timeframes for receiving results should be kept to a minimum. Methods of risk communication in men at risk of PrCa should be the subject of future research..
Castro, E.
Jugurnauth-Little, S.
Karlsson, Q.
Al-Shahrour, F.
Piñeiro-Yañez, E.
Van de Poll, F.
Leongamornlert, D.
Dadaev, T.
Govindasami, K.
Guy, M.
Eeles, R.
Kote-Jarai, Z.
UKGPCS, EMBRACE and IMPACT studies,
(2015). High burden of copy number alterations and c-MYC amplification in prostate cancer from BRCA2 germline mutation carriers. Ann oncol,
Vol.26
(11),
pp. 2293-2300.
show abstract
BACKGROUND: Germline BRCA2 mutations are associated with poorer outcome prostate cancer (PCa) compared with sporadic tumours but this association remains to be characterised. In this study, we aim to assess if there is a signature set of copy number alterations (CNA) that could aid to the identification of BRCA2-mutated tumours and would assist us to understand their aggressive clinical behaviour. METHODS: High-resolution array comparative genomic hybridisation profiling of DNA from PCa and matched morphologically normal prostate samples from 9 BRCA2 germline mutation carriers and 16 non-carriers in combination with unsupervised analysis was used to define copy number features. RESULTS: PCa from BRCA2 germline mutation carriers (B2T) harbour significantly more CNA than non-carrier tumours (NCTs) (P = 14 × 10(-6)). A hundred and sixteen regions had a significantly different distribution with both false discovery rate (FDR) and P value <0.01, including CNA in the genomic region containing c-MYC that was present in 89% B2T versus 12.5% NCT (P = 3 × 10(-4)). Loss of heterozygosity (LOH) at the BRCA2 locus was observed in 67% of B2T. Elevated CNA are already present in 50% of the morphologically normal prostate tissue from BRCA2 carriers. CONCLUSION: The relative high amount of CNAs in morphologically normal prostate tissue of BRCA2 carriers implies a field effect and together with the observed LOH could be used as a marker of PCa risk in these men. Several features previously associated with poor PCa outcome have been found to be significantly more common in BRCA2-mutated PCa than in sporadic tumours and may help to explain their adverse prognosis and be of relevance for targeted therapies..
Szulkin, R.
Karlsson, R.
Whitington, T.
Aly, M.
Gronberg, H.
Eeles, R.A.
Easton, D.F.
Kote-Jarai, Z.
Al Olama, A.A.
Benlloch, S.
Muir, K.
Giles, G.G.
Southey, M.C.
FitzGerald, L.M.
Henderson, B.E.
Schumacher, F.R.
Haiman, C.A.
Sipeky, C.
Tammela, T.L.
Nordestgaard, B.G.
Key, T.J.
Travis, R.C.
Neal, D.E.
Donovan, J.L.
Hamdy, F.C.
Pharoah, P.D.
Pashayan, N.
Khaw, K.-.
Stanford, J.L.
Thibodeau, S.N.
McDonnell, S.K.
Schaid, D.J.
Maier, C.
Vogel, W.
Luedeke, M.
Herkommer, K.
Kibel, A.S.
Cybulski, C.
Lubiński, J.
Kluźniak, W.
Cannon-Albright, L.
Brenner, H.
Herrmann, V.
Holleczek, B.
Park, J.Y.
Sellers, T.A.
Lim, H.-.
Slavov, C.
Kaneva, R.P.
Mitev, V.I.
Spurdle, A.
Teixeira, M.R.
Paulo, P.
Maia, S.
Pandha, H.
Michael, A.
Kierzek, A.
PRACTICAL consortium,
Batra, J.
Clements, J.A.
Australian Prostate Cancer BioResource,
Albanes, D.
Andriole, G.L.
Berndt, S.I.
Chanock, S.
Gapstur, S.M.
Giovannucci, E.L.
Hunter, D.J.
Kraft, P.
Le Marchand, L.
Ma, J.
Mondul, A.M.
Penney, K.L.
Stampfer, M.J.
Stevens, V.L.
Weinstein, S.J.
Trichopoulou, A.
Bueno-de-Mesquita, B.H.
Tjønneland, A.
Cox, D.G.
BPC3 consortium,
Maehle, L.
Schleutker, J.
Lindström, S.
Wiklund, F.
(2015). Genome-wide association study of prostate cancer-specific survival. Cancer epidemiol biomarkers prev,
Vol.24
(11),
pp. 1796-1800.
show abstract
BACKGROUND: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical. METHODS: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR). RESULTS: We observed no significant association between genetic variants and prostate cancer survival. CONCLUSIONS: Common genetic variants with large impact on prostate cancer survival were not observed in this study. IMPACT: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes..
Davies, N.M.
Gaunt, T.R.
Lewis, S.J.
Holly, J.
Donovan, J.L.
Hamdy, F.C.
Kemp, J.P.
Eeles, R.
Easton, D.
Kote-Jarai, Z.
Al Olama, A.A.
Benlloch, S.
Muir, K.
Giles, G.G.
Wiklund, F.
Gronberg, H.
Haiman, C.A.
Schleutker, J.
Nordestgaard, B.G.
Travis, R.C.
Neal, D.
Pashayan, N.
Khaw, K.-.
Stanford, J.L.
Blot, W.J.
Thibodeau, S.
Maier, C.
Kibel, A.S.
Cybulski, C.
Cannon-Albright, L.
Brenner, H.
Park, J.
Kaneva, R.
Batra, J.
Teixeira, M.R.
Pandha, H.
PRACTICAL consortium,
Lathrop, M.
Smith, G.D.
Martin, R.M.
(2015). The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium. Cancer causes control,
Vol.26
(11),
pp. 1603-1616.
show abstract
BACKGROUND: Epidemiological studies suggest a potential role for obesity and determinants of adult stature in prostate cancer risk and mortality, but the relationships described in the literature are complex. To address uncertainty over the causal nature of previous observational findings, we investigated associations of height- and adiposity-related genetic variants with prostate cancer risk and mortality. METHODS: We conducted a case-control study based on 20,848 prostate cancers and 20,214 controls of European ancestry from 22 studies in the PRACTICAL consortium. We constructed genetic risk scores that summed each man's number of height and BMI increasing alleles across multiple single nucleotide polymorphisms robustly associated with each phenotype from published genome-wide association studies. RESULTS: The genetic risk scores explained 6.31 and 1.46% of the variability in height and BMI, respectively. There was only weak evidence that genetic variants previously associated with increased BMI were associated with a lower prostate cancer risk (odds ratio per standard deviation increase in BMI genetic score 0.98; 95% CI 0.96, 1.00; p = 0.07). Genetic variants associated with increased height were not associated with prostate cancer incidence (OR 0.99; 95% CI 0.97, 1.01; p = 0.23), but were associated with an increase (OR 1.13; 95 % CI 1.08, 1.20) in prostate cancer mortality among low-grade disease (p heterogeneity, low vs. high grade <0.001). Genetic variants associated with increased BMI were associated with an increase (OR 1.08; 95 % CI 1.03, 1.14) in all-cause mortality among men with low-grade disease (p heterogeneity = 0.03). CONCLUSIONS: We found little evidence of a substantial effect of genetically elevated height or BMI on prostate cancer risk, suggesting that previously reported observational associations may reflect common environmental determinants of height or BMI and prostate cancer risk. Genetically elevated height and BMI were associated with increased mortality (prostate cancer-specific and all-cause, respectively) in men with low-grade disease, a potentially informative but novel finding that requires replication..
Murtola, T.J.
Wahlfors, T.
Haring, A.
Taari, K.
Stenman, U.-.
Tammela, T.L.
PRACTICAL Consortium,
Schleutker, J.
Auvinen, A.
(2015). Polymorphisms of Genes Involved in Glucose and Energy Metabolic Pathways and Prostate Cancer: Interplay with Metformin. Eur urol,
Vol.68
(6),
pp. 1089-1097.
show abstract
BACKGROUND: Energy metabolism is important in cancer proliferation and progression, but its role in prostate cancer (PCa) remains unclear. OBJECTIVE: We explored whether single-nucleotide polymorphisms (SNPs) of genes involved in energy metabolic pathways are associated with PCa risk and prognosis, and whether antidiabetic treatment modifies any such association. DESIGN, SETTING, AND PARTICIPANTS: The PRACTICAL Consortium genotyped 397 SNPs among 3241 screened participants (including 801 PCa cases) in the Finnish Prostate Cancer Screening Trial and 1983 hospital-based PCa cases. Information on medication use was obtained from a national prescription database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Genetic risk scores were calculated in terms of SNPs associated with PCa incidence or survival at a significance level of p < 5×10(-3). Hazard ratios for PCa and disease-specific death were calculated via Cox regression modelling. The predictive value of the genetic risk score was evaluated using receiver operating characteristic and Harrell's c-index analyses. RESULTS AND LIMITATIONS: A total of 30 SNPs were associated with PCa risk and ten SNPs with survival. The genetic risk score was consistently associated with PCa survival. The risk association was non-significantly weaker in metformin users. The genetic risk score did not improve prediction of PCa risk, but slightly improved the ability to predict PCa survival when added to conventional predictors (c-index improved from 87.4 to 87.9; p<0.001). A limitation is that information on diabetes apart from medication use was unavailable for the study population. CONCLUSIONS: SNPs of genes involved in energy metabolic pathways are associated with PCa survival. This suggests an important role of glucose metabolism in PCa progression, which could point to new avenues for prevention of PCa death. PATIENT SUMMARY: Genetic changes in glucose and energy metabolic pathways are associated with a higher risk of high-risk prostate cancer and adverse outcomes..
Binder, M.
Shui, I.M.
Wilson, K.M.
Penney, K.L.
PRACTICAL/ELLIPSE Consortium,
Mucci, L.A.
Kibel, A.S.
(2015). Calcium intake, polymorphisms of the calcium-sensing receptor, and recurrent/aggressive prostate cancer. Cancer causes control,
Vol.26
(12),
pp. 1751-1759.
show abstract
full text
PURPOSE: To assess whether calcium intake and common genetic variants of the calcium-sensing receptor (CASR) are associated with either aggressive prostate cancer (PCa) or disease recurrence after prostatectomy. METHODS: Calcium intake at diagnosis was assessed, and 65 common single-nucleotide polymorphisms (SNPs) in CASR were genotyped in 886 prostatectomy patients. We investigated the association between calcium intake and CASR variants with both PCa recurrence and aggressiveness (defined as Gleason score ≥4 + 3, stage ≥pT3, or nodal-positive disease). RESULTS: A total of 285 men had aggressive disease and 91 experienced recurrence. A U-shaped relationship between calcium intake and both disease recurrence and aggressiveness was observed. Compared to the middle quintile, the HR for disease recurrence was 3.07 (95% CI 1.41-6.69) for the lowest quintile and 3.21 (95% CI 1.47-7.00) and 2.97 (95% CI 1.37-6.45) for the two upper quintiles, respectively. Compared to the middle quintile, the OR for aggressive disease was 1.80 (95% CI 1.11-2.91) for the lowest quintile and 1.75 (95% CI 1.08-2.85) for the highest quintile of calcium intake. The main effects of CASR variants were not associated with PCa recurrence or aggressiveness. In the subgroup of patients with moderate calcium intake, 31 SNPs in four distinct blocks of high linkage disequilibrium were associated with PCa recurrence. CONCLUSIONS: We observed a protective effect of moderate calcium intake for PCa aggressiveness and recurrence. While CASR variants were not associated with these outcomes in the entire cohort, they may be associated with disease recurrence in men with moderate calcium intakes..
Litchfield, K.
Sultana, R.
Renwick, A.
Dudakia, D.
Seal, S.
Ramsay, E.
Powell, S.
Elliott, A.
Warren-Perry, M.
Eeles, R.
Peto, J.
Kote-Jarai, Z.
Muir, K.
Nsengimana, J.
UKTCC,
Stratton, M.R.
Easton, D.F.
Bishop, D.T.
Huddart, R.A.
Rahman, N.
Turnbull, C.
UKTCC,
(2015). Multi-stage genome-wide association study identifies new susceptibility locus for testicular germ cell tumour on chromosome 3q25. Hum mol genet,
Vol.24
(4),
pp. 1169-1176.
show abstract
Recent genome-wide association studies (GWAS) and subsequent meta-analyses have identified over 25 SNPs at 18 loci, together accounting for >15% of the genetic susceptibility to testicular germ cell tumour (TGCT). To identify further common SNPs associated with TGCT, here we report a three-stage experiment, involving 4098 cases and 18 972 controls. Stage 1 comprised previously published GWAS analysis of 307 291 SNPs in 986 cases and 4946 controls. In Stage 2, we used previously published customised Illumina iSelect genotyping array (iCOGs) data across 694 SNPs in 1064 cases and 10 082 controls. Here, we report new genotyping of eight SNPs showing some evidence of association in combined analysis of Stage 1 and Stage 2 in an additional 2048 cases of TGCT and 3944 controls (Stage 3). Through fixed-effects meta-analysis across three stages, we identified a novel locus at 3q25.31 (rs1510272) demonstrating association with TGCT [per-allele odds ratio (OR) = 1.16, 95% confidence interval (CI) = 1.06-1.27; P = 1.2 × 10(-9)]..
Zhang, C.
Doherty, J.A.
Burgess, S.
Hung, R.J.
Lindström, S.
Kraft, P.
Gong, J.
Amos, C.I.
Sellers, T.A.
Monteiro, A.N.
Chenevix-Trench, G.
Bickeböller, H.
Risch, A.
Brennan, P.
Mckay, J.D.
Houlston, R.S.
Landi, M.T.
Timofeeva, M.N.
Wang, Y.
Heinrich, J.
Kote-Jarai, Z.
Eeles, R.A.
Muir, K.
Wiklund, F.
Grönberg, H.
Berndt, S.I.
Chanock, S.J.
Schumacher, F.
Haiman, C.A.
Henderson, B.E.
Amin Al Olama, A.
Andrulis, I.L.
Hopper, J.L.
Chang-Claude, J.
John, E.M.
Malone, K.E.
Gammon, M.D.
Ursin, G.
Whittemore, A.S.
Hunter, D.J.
Gruber, S.B.
Knight, J.A.
Hou, L.
Le Marchand, L.
Newcomb, P.A.
Hudson, T.J.
Chan, A.T.
Li, L.
Woods, M.O.
Ahsan, H.
Pierce, B.L.
GECCO and GAME-ON Network: CORECT, DRIVE, ELLIPSE, FOCI, and TRICL,
(2015). Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study. Hum mol genet,
Vol.24
(18),
pp. 5356-5366.
show abstract
full text
Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk..
Laitinen, V.H.
Rantapero, T.
Fischer, D.
Vuorinen, E.M.
Tammela, T.L.
PRACTICAL Consortium,
Wahlfors, T.
Schleutker, J.
(2015). Fine-mapping the 2q37 and 17q11 2-q22 loci for novel genes and sequence variants associated with a genetic predisposition to prostate cancer. Int j cancer,
Vol.136
(10),
pp. 2316-2327.
show abstract
The 2q37 and 17q12-q22 loci are linked to an increased prostate cancer (PrCa) risk. No candidate gene has been localized at 2q37 and the HOXB13 variant G84E only partially explains the linkage to 17q21-q22 observed in Finland. We screened these regions by targeted DNA sequencing to search for cancer-associated variants. Altogether, four novel susceptibility alleles were identified. Two ZNF652 (17q21.3) variants, rs116890317 and rs79670217, increased the risk of both sporadic and hereditary PrCa (rs116890317: OR = 3.3-7.8, p = 0.003-3.3 × 10(-5) ; rs79670217: OR = 1.6-1.9, p = 0.002-0.009). The HDAC4 (2q37.2) variant rs73000144 (OR = 14.6, p = 0.018) and the EFCAB13 (17q21.3) variant rs118004742 (OR = 1.8, p = 0.048) were overrepresented in patients with familial PrCa. To map the variants within 2q37 and 17q11.2-q22 that may regulate PrCa-associated genes, we combined DNA sequencing results with transcriptome data obtained by RNA sequencing. This expression quantitative trait locus (eQTL) analysis identified 272 single-nucleotide polymorphisms (SNPs) possibly regulating six genes that were differentially expressed between cases and controls. In a modified approach, prefiltered PrCa-associated SNPs were exploited and interestingly, a novel eQTL targeting ZNF652 was identified. The novel variants identified in this study could be utilized for PrCa risk assessment, and they further validate the suggested role of ZNF652 as a PrCa candidate gene. The regulatory regions discovered by eQTL mapping increase our understanding of the relationship between regulation of gene expression and susceptibility to PrCa and provide a valuable starting point for future functional research..
Gundem, G.
Van Loo, P.
Kremeyer, B.
Alexandrov, L.B.
Tubio, J.M.
Papaemmanuil, E.
Brewer, D.S.
Kallio, H.M.
Högnäs, G.
Annala, M.
Kivinummi, K.
Goody, V.
Latimer, C.
O'Meara, S.
Dawson, K.J.
Isaacs, W.
Emmert-Buck, M.R.
Nykter, M.
Foster, C.
Kote-Jarai, Z.
Easton, D.
Whitaker, H.C.
ICGC Prostate Group,
Neal, D.E.
Cooper, C.S.
Eeles, R.A.
Visakorpi, T.
Campbell, P.J.
McDermott, U.
Wedge, D.C.
Bova, G.S.
(2015). The evolutionary history of lethal metastatic prostate cancer. Nature,
Vol.520
(7547),
pp. 353-357.
show abstract
full text
Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer..
Goulart, L.F.
Bettella, F.
Sønderby, I.E.
Schork, A.J.
Thompson, W.K.
Mattingsdal, M.
Steen, V.M.
Zuber, V.
Wang, Y.
Dale, A.M.
PRACTICAL/ELLIPSE consortium,
Andreassen, O.A.
Djurovic, S.
(2015). MicroRNAs enrichment in GWAS of complex human phenotypes. Bmc genomics,
Vol.16
(1),
p. 304.
show abstract
BACKGROUND: The genotype information carried by Genome-wide association studies (GWAS) seems to have the potential to explain more of the 'missing heritability' of complex human phenotypes, given improved statistical approaches. Several lines of evidence support the involvement of microRNA (miRNA) and other non-coding RNA in complex human traits and diseases. We employed a novel, genetic annotation-informed enrichment method for GWAS that captures more polygenic effects than standard GWAS analysis, to investigate if miRNA-tagging Single Nucleotide Polymorphisms (SNPs) are enriched of associations with 15 complex human phenotypes. We then leveraged the enrichment using a conditional False Discovery Rate (condFDR) approach to assess any improvement in the detection of individual miRNA SNPs associated with the disorders. RESULTS: We found SNPs tagging miRNA transcription regions to be significantly enriched of associations with 10 of 15 phenotypes. The enrichment remained significant after controlling for affiliation to other genomic categories, and was confirmed by replication. Albeit only nominally significant, enrichment was found also in miRNA binding sites for 10 phenotypes out of 15. Leveraging the enrichment in the condFDR framework, we observed a 2-4-fold increase in discovery of SNPs tagging miRNA regions. CONCLUSIONS: Our results suggest that miRNAs play an important role in the polygenic architecture of complex human disorders and traits, and therefore that miRNAs are a genomic category that can and should be used to improve gene discovery..
Maishman, T.
Copson, E.
Stanton, L.
Gerty, S.
Dicks, E.
Durcan, L.
Wishart, G.C.
Pharoah, P.
POSH Steering Group,
Eccles, D.
(2015). An evaluation of the prognostic model PREDICT using the POSH cohort of women aged ⩽40 years at breast cancer diagnosis. Br j cancer,
Vol.112
(6),
pp. 983-991.
show abstract
BACKGROUND: Breast cancer is the most common cancer in younger women (aged ⩽40 years) in the United Kingdom. PREDICT (http://www.predict.nhs.uk) is an online prognostic tool developed to help determine the best available treatment and outcome for early breast cancer. This study was conducted to establish how well PREDICT performs in estimating survival in a large cohort of younger women recruited to the UK POSH study. METHODS: The POSH cohort includes data from 3000 women aged ⩽40 years at breast cancer diagnosis. Study end points were overall and breast cancer-specific survival at 5, 8, and 10 years. Evaluation of PREDICT included model discrimination and comparison of the number of predicted versus observed events. RESULTS: PREDICT provided accurate long-term (8- and 10-year) survival estimates for younger women. Five-year estimates were less accurate, with the tool overestimating survival by 25% overall, and by 56% for patients with oestrogen receptor (ER)-positive tumours. PREDICT underestimated survival at 5 years among patients with ER-negative tumours. CONCLUSIONS: PREDICT is a useful tool for providing reliable long-term (10-year) survival estimates for younger patients. However, for more accurate short-term estimates, the model requires further calibration using more data from young onset cases. Short-term prediction may be most relevant for the increasing number of women considering risk-reducing bilateral mastectomy..
Qian, D.C.
Byun, J.
Han, Y.
Greene, C.S.
Field, J.K.
Hung, R.J.
Brhane, Y.
Mclaughlin, J.R.
Fehringer, G.
Landi, M.T.
Rosenberger, A.
Bickeböller, H.
Malhotra, J.
Risch, A.
Heinrich, J.
Hunter, D.J.
Henderson, B.E.
Haiman, C.A.
Schumacher, F.R.
Eeles, R.A.
Easton, D.F.
Seminara, D.
Amos, C.I.
(2015). Identification of shared and unique susceptibility pathways among cancers of the lung, breast, and prostate from genome-wide association studies and tissue-specific protein interactions. Hum mol genet,
Vol.24
(25),
pp. 7406-7420.
show abstract
Results from genome-wide association studies (GWAS) have indicated that strong single-gene effects are the exception, not the rule, for most diseases. We assessed the joint effects of germline genetic variations through a pathway-based approach that considers the tissue-specific contexts of GWAS findings. From GWAS meta-analyses of lung cancer (12 160 cases/16 838 controls), breast cancer (15 748 cases/18 084 controls) and prostate cancer (14 160 cases/12 724 controls) in individuals of European ancestry, we determined the tissue-specific interaction networks of proteins expressed from genes that are likely to be affected by disease-associated variants. Reactome pathways exhibiting enrichment of proteins from each network were compared across the cancers. Our results show that pathways associated with all three cancers tend to be broad cellular processes required for growth and survival. Significant examples include the nerve growth factor (P = 7.86 × 10(-33)), epidermal growth factor (P = 1.18 × 10(-31)) and fibroblast growth factor (P = 2.47 × 10(-31)) signaling pathways. However, within these shared pathways, the genes that influence risk largely differ by cancer. Pathways found to be unique for a single cancer focus on more specific cellular functions, such as interleukin signaling in lung cancer (P = 1.69 × 10(-15)), apoptosis initiation by Bad in breast cancer (P = 3.14 × 10(-9)) and cellular responses to hypoxia in prostate cancer (P = 2.14 × 10(-9)). We present the largest comparative cross-cancer pathway analysis of GWAS to date. Our approach can also be applied to the study of inherited mechanisms underlying risk across multiple diseases in general..
Blein, S.
Bardel, C.
Danjean, V.
McGuffog, L.
Healey, S.
Barrowdale, D.
Lee, A.
Dennis, J.
Kuchenbaecker, K.B.
Soucy, P.
Terry, M.B.
Chung, W.K.
Goldgar, D.E.
Buys, S.S.
Breast Cancer Family Registry,
Janavicius, R.
Tihomirova, L.
Tung, N.
Dorfling, C.M.
van Rensburg, E.J.
Neuhausen, S.L.
Ding, Y.C.
Gerdes, A.-.
Ejlertsen, B.
Nielsen, F.C.
Hansen, T.V.
Osorio, A.
Benitez, J.
Conejero, R.A.
Segota, E.
Weitzel, J.N.
Thelander, M.
Peterlongo, P.
Radice, P.
Pensotti, V.
Dolcetti, R.
Bonanni, B.
Peissel, B.
Zaffaroni, D.
Scuvera, G.
Manoukian, S.
Varesco, L.
Capone, G.L.
Papi, L.
Ottini, L.
Yannoukakos, D.
Konstantopoulou, I.
Garber, J.
Hamann, U.
Donaldson, A.
Brady, A.
Brewer, C.
Foo, C.
Evans, D.G.
Frost, D.
Eccles, D.
EMBRACE,
Douglas, F.
Cook, J.
Adlard, J.
Barwell, J.
Walker, L.
Izatt, L.
Side, L.E.
Kennedy, M.J.
Tischkowitz, M.
Rogers, M.T.
Porteous, M.E.
Morrison, P.J.
Platte, R.
Eeles, R.
Davidson, R.
Hodgson, S.
Cole, T.
Godwin, A.K.
Isaacs, C.
Claes, K.
De Leeneer, K.
Meindl, A.
Gehrig, A.
Wappenschmidt, B.
Sutter, C.
Engel, C.
Niederacher, D.
Steinemann, D.
Plendl, H.
Kast, K.
Rhiem, K.
Ditsch, N.
Arnold, N.
Varon-Mateeva, R.
Schmutzler, R.K.
Preisler-Adams, S.
Markov, N.B.
Wang-Gohrke, S.
de Pauw, A.
Lefol, C.
Lasset, C.
Leroux, D.
Rouleau, E.
Damiola, F.
GEMO Study Collaborators,
Dreyfus, H.
Barjhoux, L.
Golmard, L.
Uhrhammer, N.
Bonadona, V.
Sornin, V.
Bignon, Y.-.
Carter, J.
Van Le, L.
Piedmonte, M.
DiSilvestro, P.A.
de la Hoya, M.
Caldes, T.
Nevanlinna, H.
Aittomäki, K.
Jager, A.
van den Ouweland, A.M.
Kets, C.M.
Aalfs, C.M.
van Leeuwen, F.E.
Hogervorst, F.B.
Meijers-Heijboer, H.E.
HEBON,
Oosterwijk, J.C.
van Roozendaal, K.E.
Rookus, M.A.
Devilee, P.
van der Luijt, R.B.
Olah, E.
Diez, O.
Teulé, A.
Lazaro, C.
Blanco, I.
Del Valle, J.
Jakubowska, A.
Sukiennicki, G.
Gronwald, J.
Lubinski, J.
Durda, K.
Jaworska-Bieniek, K.
Agnarsson, B.A.
Maugard, C.
Amadori, A.
Montagna, M.
Teixeira, M.R.
Spurdle, A.B.
Foulkes, W.
Olswold, C.
Lindor, N.M.
Pankratz, V.S.
Szabo, C.I.
Lincoln, A.
Jacobs, L.
Corines, M.
Robson, M.
Vijai, J.
Berger, A.
Fink-Retter, A.
Singer, C.F.
Rappaport, C.
Kaulich, D.G.
Pfeiler, G.
Tea, M.-.
Greene, M.H.
Mai, P.L.
Rennert, G.
Imyanitov, E.N.
Mulligan, A.M.
Glendon, G.
Andrulis, I.L.
Tchatchou, S.
Toland, A.E.
Pedersen, I.S.
Thomassen, M.
Kruse, T.A.
Jensen, U.B.
Caligo, M.A.
Friedman, E.
Zidan, J.
Laitman, Y.
Lindblom, A.
Melin, B.
Arver, B.
Loman, N.
Rosenquist, R.
Olopade, O.I.
Nussbaum, R.L.
Ramus, S.J.
Nathanson, K.L.
Domchek, S.M.
Rebbeck, T.R.
Arun, B.K.
Mitchell, G.
Karlan, B.Y.
Lester, J.
Orsulic, S.
Stoppa-Lyonnet, D.
Thomas, G.
Simard, J.
Couch, F.J.
Offit, K.
Easton, D.F.
Chenevix-Trench, G.
Antoniou, A.C.
Mazoyer, S.
Phelan, C.M.
Sinilnikova, O.M.
Cox, D.G.
(2015). An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers. Breast cancer res,
Vol.17
(1),
p. 61.
show abstract
INTRODUCTION: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. METHODS: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. RESULTS: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. CONCLUSIONS: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects..
Hafeez, S.
Singhera, M.
Huddart, R.
(2015). Exploration of the treatment challenges in men with intellectual difficulties and testicular cancer as seen in Down syndrome: single centre experience. Bmc med,
Vol.13,
p. 152.
show abstract
full text
Down syndrome is the most common chromosomal disorder in humans as well as the most common cause of inherited intellectual disability. A spectrum of physical and functional disability is associated with the syndrome as well as a predisposition to developing particular malignancies, including testicular cancers. These tumours ordinarily have a high cure rate even in widely disseminated disease. However, individuals with Down syndrome may have learning difficulties, behavioural problems, and multiple systemic complications that have the potential to make standard treatment more risky and necessitates individualized approach in order to avoid unacceptable harm. There is also suggestion that tumours may have a different natural history. Further, people with learning disabilities have often experienced poorer healthcare than the general population. In order to address these inequalities, legislation, professional bodies, and charities provide guidance; however, ultimately, consideration of the person in the context of their own psychosocial issues, comorbidities, and possible treatment strategies is vital in delivering optimal care. We aim to present a review of our own experience of delivering individualized care to this group of patients in order to close the existing health inequality gap..
Litchfield, K.
Holroyd, A.
Lloyd, A.
Broderick, P.
Nsengimana, J.
Eeles, R.
Easton, D.F.
Dudakia, D.
Bishop, D.T.
Reid, A.
Huddart, R.A.
Grotmol, T.
Wiklund, F.
Shipley, J.
Houlston, R.S.
Turnbull, C.
(2015). Identification of four new susceptibility loci for testicular germ cell tumour. Nat commun,
Vol.6,
p. 8690.
show abstract
Genome-wide association studies (GWAS) have identified multiple risk loci for testicular germ cell tumour (TGCT), revealing a polygenic model of disease susceptibility strongly influenced by common variation. To identify additional single-nucleotide polymorphisms (SNPs) associated with TGCT, we conducted a multistage GWAS with a combined data set of >25,000 individuals (6,059 cases and 19,094 controls). We identified new risk loci for TGCT at 3q23 (rs11705932, TFDP2, P=1.5 × 10(-9)), 11q14.1 (rs7107174, GAB2, P=9.7 × 10(-11)), 16p13.13 (rs4561483, GSPT1, P=1.6 × 10(-8)) and 16q24.2 (rs55637647, ZFPM1, P=3.4 × 10(-9)). We additionally present detailed functional analysis of these loci, identifying a statistically significant relationship between rs4561483 risk genotype and increased GSPT1 expression in TGCT patient samples. These findings provide additional support for a polygenic model of TGCT risk and further insight into the biological basis of disease development..
Mateo, J.
Carreira, S.
Sandhu, S.
Miranda, S.
Mossop, H.
Perez-Lopez, R.
Nava Rodrigues, D.
Robinson, D.
Omlin, A.
Tunariu, N.
Boysen, G.
Porta, N.
Flohr, P.
Gillman, A.
Figueiredo, I.
Paulding, C.
Seed, G.
Jain, S.
Ralph, C.
Protheroe, A.
Hussain, S.
Jones, R.
Elliott, T.
McGovern, U.
Bianchini, D.
Goodall, J.
Zafeiriou, Z.
Williamson, C.T.
Ferraldeschi, R.
Riisnaes, R.
Ebbs, B.
Fowler, G.
Roda, D.
Yuan, W.
Wu, Y.-.
Cao, X.
Brough, R.
Pemberton, H.
A'Hern, R.
Swain, A.
Kunju, L.P.
Eeles, R.
Attard, G.
Lord, C.J.
Ashworth, A.
Rubin, M.A.
Knudsen, K.E.
Feng, F.Y.
Chinnaiyan, A.M.
Hall, E.
de Bono, J.S.
(2015). DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N engl j med,
Vol.373
(18),
pp. 1697-1708.
show abstract
full text
BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib. METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies. RESULTS: Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib. CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.)..
Pashayan, N.
Pharoah, P.D.
Schleutker, J.
Talala, K.
Tammela, T.L.
Määttänen, L.
Harrington, P.
Tyrer, J.
Eeles, R.
Duffy, S.W.
Auvinen, A.
(2015). Reducing overdiagnosis by polygenic risk-stratified screening: findings from the Finnish section of the ERSPC. Br j cancer,
Vol.113
(7),
pp. 1086-1093.
show abstract
BACKGROUND: We derived estimates of overdiagnosis by polygenic risk groups and examined whether polygenic risk-stratified screening for prostate cancer reduces overdiagnosis. METHODS: We calculated the polygenic risk score based on genotypes of 66 known prostate cancer loci for 4967 men from the Finnish section of the European Randomised Study of Screening for Prostate Cancer. We stratified the 72 072 men in the trial into those with polygenic risk below and above the median. Using a maximum likelihood method based on interval cancers, we estimated the mean sojourn time (MST) and episode sensitivity. For each polygenic risk group, we estimated the proportion of screen-detected cancers that are likely to be overdiagnosed from the difference between the observed and expected number of screen-detected cancers. RESULTS: Of the prostate cancers, 74% occurred among men with polygenic risk above population median. The sensitivity was 0.55 (95% confidence interval (CI) 0.45-0.65) and MST 6.3 (95% CI 4.2-8.3) years. The overall overdiagnosis was 42% (95% CI 37-52) of the screen-detected cancers, with 58% (95% CI 54-65) in men with the lower and 37% (95% CI 31-47) in those with higher polygenic risk. CONCLUSION: Targeting screening to men at higher polygenic risk could reduce the proportion of cancers overdiagnosed..
Ju, Y.S.
Alexandrov, L.B.
Gerstung, M.
Martincorena, I.
Nik-Zainal, S.
Ramakrishna, M.
Davies, H.R.
Papaemmanuil, E.
Gundem, G.
Shlien, A.
Bolli, N.
Behjati, S.
Tarpey, P.S.
Nangalia, J.
Massie, C.E.
Butler, A.P.
Teague, J.W.
Vassiliou, G.S.
Green, A.R.
Du, M.-.
Unnikrishnan, A.
Pimanda, J.E.
Teh, B.T.
Munshi, N.
Greaves, M.
Vyas, P.
El-Naggar, A.K.
Santarius, T.
Collins, V.P.
Grundy, R.
Taylor, J.A.
Hayes, D.N.
Malkin, D.
ICGC Breast Cancer Group,
ICGC Chronic Myeloid Disorders Group,
ICGC Prostate Cancer Group,
Foster, C.S.
Warren, A.Y.
Whitaker, H.C.
Brewer, D.
Eeles, R.
Cooper, C.
Neal, D.
Visakorpi, T.
Isaacs, W.B.
Bova, G.S.
Flanagan, A.M.
Futreal, P.A.
Lynch, A.G.
Chinnery, P.F.
McDermott, U.
Stratton, M.R.
Campbell, P.J.
(2014). Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. Elife,
Vol.3.
show abstract
full text
Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication..
Mikropoulos, C.
Dadaev, T.
Tymrakiewicz, M.
Leongamornlert, D.
Saunders, E.
Little, S.J.
Govindasami, K.
Guy, M.
Wilkinson, R.
Morgan, A.
Donovan, J.
Neal, D.
Hamdy, F.
Antoniou, A.
Eeles, R.
Kote-Jarai, Z.
(2014). 751OPREVALENCE OF HOXB13G84E GERMLINE MUTATION IN UK PROSTATE CANCER CASES; CORRELATION WITH TUMOUR CHARACTERISTICS AND OUTCOMES. Ann oncol,
Vol.25
(suppl_4),
p. iv254.
Eeles, R.
Goh, C.
Castro, E.
Bancroft, E.
Guy, M.
Al Olama, A.A.
Easton, D.
Kote-Jarai, Z.
(2014). The genetic epidemiology of prostate cancer and its clinical implications. Nat rev urol,
Vol.11
(1),
pp. 18-31.
show abstract
Worldwide, familial and epidemiological studies have generated considerable evidence of an inherited component to prostate cancer. Indeed, rare highly penetrant genetic mutations have been implicated. Genome-wide association studies (GWAS) have also identified 76 susceptibility loci associated with prostate cancer risk, which occur commonly but are of low penetrance. However, these mutations interact multiplicatively, which can result in substantially increased risk. Currently, approximately 30% of the familial risk is due to such variants. Evaluating the functional aspects of these variants would contribute to our understanding of prostate cancer aetiology and would enable population risk stratification for screening. Furthermore, understanding the genetic risks of prostate cancer might inform predictions of treatment responses and toxicities, with the goal of personalized therapy. However, risk modelling and clinical translational research are needed before we can translate risk profiles generated from these variants into use in the clinical setting for targeted screening and treatment..
Hazelett, D.J.
Rhie, S.K.
Gaddis, M.
Yan, C.
Lakeland, D.L.
Coetzee, S.G.
Ellipse/GAME-ON consortium,
Practical consortium,
Henderson, B.E.
Noushmehr, H.
Cozen, W.
Kote-Jarai, Z.
Eeles, R.A.
Easton, D.F.
Haiman, C.A.
Lu, W.
Farnham, P.J.
Coetzee, G.A.
(2014). Comprehensive functional annotation of 77 prostate cancer risk loci. Plos genet,
Vol.10
(1),
p. e1004102.
show abstract
Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of the 77 known risk loci, based upon highly correlated variants in biologically relevant chromatin annotations--we identified 727 such potentially functional SNPs. We also provide a detailed account of possible protein disruption, microRNA target sequence disruption and regulatory response element disruption of all correlated SNPs at r(2) ≥ 0.88%. 88% of the 727 SNPs fall within putative enhancers, and many alter critical residues in the response elements of transcription factors known to be involved in prostate biology. We define as risk enhancers those regions with enhancer chromatin biofeatures in prostate-derived cell lines with prostate-cancer correlated SNPs. To aid the identification of these enhancers, we performed genomewide ChIP-seq for H3K27-acetylation, a mark of actively engaged enhancers, as well as the transcription factor TCF7L2. We analyzed in depth three variants in risk enhancers, two of which show significantly altered androgen sensitivity in LNCaP cells. This includes rs4907792, that is in linkage disequilibrium (r(2) = 0.91) with an eQTL for NUDT11 (on the X chromosome) in prostate tissue, and rs10486567, the index SNP in intron 3 of the JAZF1 gene on chromosome 7. Rs4907792 is within a critical residue of a strong consensus androgen response element that is interrupted in the protective allele, resulting in a 56% decrease in its androgen sensitivity, whereas rs10486567 affects both NKX3-1 and FOXA-AR motifs where the risk allele results in a 39% increase in basal activity and a 28% fold-increase in androgen stimulated enhancer activity. Identification of such enhancer variants and their potential target genes represents a preliminary step in connecting risk to disease process..
Tubio, J.M.
Li, Y.
Ju, Y.S.
Martincorena, I.
Cooke, S.L.
Tojo, M.
Gundem, G.
Pipinikas, C.P.
Zamora, J.
Raine, K.
Menzies, A.
Roman-Garcia, P.
Fullam, A.
Gerstung, M.
Shlien, A.
Tarpey, P.S.
Papaemmanuil, E.
Knappskog, S.
Van Loo, P.
Ramakrishna, M.
Davies, H.R.
Marshall, J.
Wedge, D.C.
Teague, J.W.
Butler, A.P.
Nik-Zainal, S.
Alexandrov, L.
Behjati, S.
Yates, L.R.
Bolli, N.
Mudie, L.
Hardy, C.
Martin, S.
McLaren, S.
O'Meara, S.
Anderson, E.
Maddison, M.
Gamble, S.
Foster, C.
Warren, A.Y.
Whitaker, H.
Brewer, D.
Eeles, R.
Cooper, C.
Neal, D.
Lynch, A.G.
Visakorpi, T.
Isaacs, W.B.
Veer, L.V.
Caldas, C.
Desmedt, C.
Sotiriou, C.
Aparicio, S.
Foekens, J.A.
Eyfjörd, J.E.
Lakhani, S.R.
Thomas, G.
Myklebost, O.
Span, P.N.
Børresen-Dale, A.-.
Richardson, A.L.
Van de Vijver, M.
Vincent-Salomon, A.
Van den Eynden, G.G.
Flanagan, A.M.
Futreal, P.A.
Janes, S.M.
Bova, G.S.
Stratton, M.R.
McDermott, U.
Campbell, P.J.
ICGC Breast Cancer Group,
ICGC Bone Cancer Group,
ICGC Prostate Cancer Group,
(2014). Mobile DNA in cancer Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science,
Vol.345
(6196),
p. 1251343.
show abstract
full text
Long interspersed nuclear element-1 (L1) retrotransposons are mobile repetitive elements that are abundant in the human genome. L1 elements propagate through RNA intermediates. In the germ line, neighboring, nonrepetitive sequences are occasionally mobilized by the L1 machinery, a process called 3' transduction. Because 3' transductions are potentially mutagenic, we explored the extent to which they occur somatically during tumorigenesis. Studying cancer genomes from 244 patients, we found that tumors from 53% of the patients had somatic retrotranspositions, of which 24% were 3' transductions. Fingerprinting of donor L1s revealed that a handful of source L1 elements in a tumor can spawn from tens to hundreds of 3' transductions, which can themselves seed further retrotranspositions. The activity of individual L1 elements fluctuated during tumor evolution and correlated with L1 promoter hypomethylation. The 3' transductions disseminated genes, exons, and regulatory elements to new locations, most often to heterochromatic regions of the genome..
Saunders, E.J.
Dadaev, T.
Leongamornlert, D.A.
Jugurnauth-Little, S.
Tymrakiewicz, M.
Wiklund, F.
Al Olama, A.A.
Benlloch, S.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Giles, G.G.
Severi, G.
Gronberg, H.
Aly, M.
Haiman, C.A.
Schumacher, F.
Henderson, B.E.
Lindstrom, S.
Kraft, P.
Hunter, D.J.
Gapstur, S.
Chanock, S.
Berndt, S.I.
Albanes, D.
Andriole, G.
Schleutker, J.
Weischer, M.
Nordestgaard, B.G.
Canzian, F.
Campa, D.
Riboli, E.
Key, T.J.
Travis, R.C.
Ingles, S.A.
John, E.M.
Hayes, R.B.
Pharoah, P.
Khaw, K.-.
Stanford, J.L.
Ostrander, E.A.
Signorello, L.B.
Thibodeau, S.N.
Schaid, D.
Maier, C.
Kibel, A.S.
Cybulski, C.
Cannon-Albright, L.
Brenner, H.
Park, J.Y.
Kaneva, R.
Batra, J.
Clements, J.A.
Teixeira, M.R.
Xu, J.
Mikropoulos, C.
Goh, C.
Govindasami, K.
Guy, M.
Wilkinson, R.A.
Sawyer, E.J.
Morgan, A.
COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative,
UK Genetic Prostate Cancer Study Collaborators,
UK ProtecT Study Collaborators,
PRACTICAL Consortium,
Easton, D.F.
Muir, K.
Eeles, R.A.
Kote-Jarai, Z.
(2014). Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer. Plos genet,
Vol.10
(2),
p. e1004129.
show abstract
The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility..
Teerlink, C.C.
Thibodeau, S.N.
McDonnell, S.K.
Schaid, D.J.
Rinckleb, A.
Maier, C.
Vogel, W.
Cancel-Tassin, G.
Egrot, C.
Cussenot, O.
Foulkes, W.D.
Giles, G.G.
Hopper, J.L.
Severi, G.
Eeles, R.
Easton, D.
Kote-Jarai, Z.
Guy, M.
Cooney, K.A.
Ray, A.M.
Zuhlke, K.A.
Lange, E.M.
FitzGerald, L.M.
Stanford, J.L.
Ostrander, E.A.
Wiley, K.E.
Isaacs, S.D.
Walsh, P.C.
Isaacs, W.B.
Wahlfors, T.
Tammela, T.
Schleutker, J.
Wiklund, F.
Gronberg, H.
Emanuelsson, M.
Carpten, J.
Bailey-Wilson, J.
Whittemore, A.S.
Oakley-Girvan, I.
Hsieh, C.-.
Catalona, W.J.
Zheng, S.L.
Jin, G.
Lu, L.
Xu, J.
Camp, N.J.
Cannon-Albright, L.A.
Genet, I.C.
(2014). Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease. Human genetics,
Vol.133
(3),
pp. 347-356.
full text
Jhuraney, A.
Velkova, A.
Kessing, B.
Carvalho, R.
Wiley, P.
Spurdle, A.
Vreeswijk, M.P.
Caputo, S.
Millot, G.
Vega, A.
Coquelle, N.
Galli, A.
Eccles, D.
Blok, M.J.
Pal, T.
van der Luijt, R.B.
Pena, M.S.
Neuhausen, S.L.
Donenberg, T.
Machackova, E.
Thomas, S.
Vallée, M.
Tavtigian, S.
Glover, J.N.
Carvalho, M.A.
Brody, L.
Sharan, S.
Monteiro, A.N.
Mucaki, E.
Caminsky, N.
Stuart, A.
Viner, C.
Shirley, B.
Knoll, J.
Ainsworth, P.
Rogan, P.
Mulligan, J.M.
Hill, L.A.
Deharo, S.
Irwin, G.
Boyle, D.
Keating, K.E.
Raji, O.Y.
McDyer, F.A.
O’Brien, E.
Bylesjo, M.
Salto–Tellez, M.
Johnston, P.G.
Couch, F.J.
Harkin, D.P.
Kennedy, R.D.
Witkowski, L.
Carrot–Zhang, J.
Albrecht, S.
Hamel, N.
Tomiak, E.
Grynspan, D.
Saloustros, E.
Gilpin, C.
Silva–Smith, R.
Plourde, F.
Rivera, B.
Castellsagué, E.
Wu, M.
Fahiminiya, S.
Saskin, A.
Arseneault, M.
Karabakhtsian, R.G.
Reilly, E.A.
Ueland, F.R.
Margiolaki, A.
Pavlakis, K.
Castellino, S.M.
Lamovec, J.
Roth, L.M.
Ulbright, T.M.
Bender, T.A.
Longy, M.
Berchuck, A.
Tischkowitz, M.
Nagel, I.
Siebert, R.
Georgoulias, V.
Stewart, C.J.
Arseneau, J.
McCluggage, W.G.
Clarke, B.A.
Riazalhosseini, Y.
Hasselblatt, M.
Majewski, J.
Foulkes, W.D.
Savage, K.I.
Gorski, J.J.
Barros, E.M.
Irwin, G.W.
McDade, S.S.
Manti, L.
Pellagatti, A.
Lukashchuk, N.
MCance, D.J.
McCluggage, W.G.
Schettino, G.
Salto–Tellez, M.
Boultwood, J.
Richard, D.J.
Harkin, D.P.
Pathania, S.
Bade, S.
Burke, K.
Reed, R.
Le Guillou, M.
Richardson, A.
Feunteun, J.
Garber, J.
Livingston, D.
Marques, M.
Beauchamp, M.-.
Laskov, I.
Sun, Q.
Gotlieb, W.
Witcher, M.
Metcalfe, K.
Ghadirian, P.
Lynch, H.T.
Snyder, C.
Foulkes, W.D.
Tung, N.
Kim–Sing, C.
Olopade, O.I.
Eisen, A.
Rosen, B.
Gershman, S.
Sun, P.
Narod, S.
Safra, T.
Rogowski, O.
Muggia, F.
Baltzer, H.L.
Alonzo-Proulx, O.
Mainprize, J.G.
Yaffe, M.J.
Metcalfe, K.A.
Narod, S.A.
Warner, E.
Semple, J.L.
Eeles, R.
Castro, E.
Olmos, D.
Saunders, E.
Leongamornlert, D.
Tymrakiewicz, M.
Bancroft, L.
Saya, S.
Kote–Jarai, Z.
Guy, M.
Govindasami, K.
Easton, D.F.
Ellis, S.
Antoniou, A.C.
Akbari, M.R.
Wallis, C.J.
Toi, A.
Trachtenberg, J.
Sun, P.
Narod, S.A.
Nam, R.K.
Smith, A.
Grant, R.
Hall, A.
Alirezaie, N.
Bascuñana, C.
Holter, S.
Whelan, T.
Selander, I.
McPherson, T.
Omeroglu, A.
Saloustros, E.
Majewski, J.
Foulkes, W.
Gallinger, S.
Zogopoulos, G.
Pal, T.
Cragun, D.
Bonner, D.
Akbari, M.
Narod, S.
Sawyer, S.L.
Moilanen, J.S.
Greenberg, R.A.
Schwartzentruber, J.
University of Washington Centre for Mendelian Genomics,
FORGE Canada Consortium,
Majewski, J.
Boycott, K.M.
Innes, A.M.
Dyment, D.A.
Antoniou, A.C.
Casadei, S.
Heikkinen, T.
Pylkäs, K.
De Leeneer, K.
Fostira, F.
Nevanlinna, H.
Teo, Z.L.
Turnbull, C.
Radice, P.
King, M.-.
Southey, M.C.
Winqvist, R.
Foulkes, W.D.
Tischkowitz, M.
Thompson, E.R.
Rowley, S.M.
Doyle, M.A.
Ellul, J.
Trainer, A.
James, P.
LifePool,
Wong–Brown, M.
Mitchell, G.
Scott, R.J.
Campbell, I.G.
Ford, J.M.
Kurian, A.W.
Kobayashi, Y.
Hare, E.
Mills, M.
Kingham, K.
Cargill, M.
Lincoln, S.
James, P.A.
Sawyer, S.
McInerny, S.
Beesley, J.
Harris, M.
Kathleen Cunningham Foundation,
AOCS,
Lindeman, G.J.
Chenevix–Trench, G.
Mitchell, G.
Garcia, C.
Lyon, L.
Littell, R.D.
Powell, C.B.
Ainsworth, P.J.
Rodenhiser, N.
Reith, C.
Stuart, J.A.
Rogan, P.
McCoy, H.
Moyes, K.
Arnell, C.
Landon, M.
Rosenthal, E.
Pruss, D.
Wenstrup, R.J.
Bowles, K.R.
Morris, B.
Pruss, D.
Ji, J.
Singh, N.
Roa, B.B.
Wenstrup, R.J.
Chen–Shtoyerman, R.
Ben-Baruch, N.
Allweis, T.
Ben Arie, A.
Nissani, R.
Appelman, Z.
Ancot, F.
Arcand, S.L.
Nolet, S.
Mes–Masson, A.-.
Haffaf, Z.E.
Provencher, D.M.
Tonin, P.
Llacuachaqui, M.
Abugattas, J.
Allende, Y.S.
Velásquez, A.A.
Velarde, R.
Cotrina, J.
Garcés, M.
Leon, M.
Calderon, G.
de la Cruz, M.
Royer, R.
Ragone, A.
Larson, G.
Weitzel, J.N.
Narod, S.A.
Donenberg, T.
George, S.
Akbari, M.
Alexis, C.
Wharfe, G.
Yin, S.
Dyer, H.
Turnquest, T.
Narod, S.A.
Hurley, J.
Woods, N.T.
Jhuraney, A.
Baskin, R.
Vaclova, T.
Iversen, E.S.
Monteiro, A.N.
Strom, C.
Elzinga, C.
Rivera, S.
Angeloni, T.
Rosenthal, S.H.
Siaw, M.
Platt, J.
Braastadt, C.
Ross, D.
Sun, W.
Law, F.B.
Au, C.H.
Ho, D.N.
Ip, B.K.
Wong, A.T.
Chan, T.L.
Ma, E.S.
Kwong, A.
Vyarvelska, I.
Struk, S.
Narod, S.A.
Gronwald, J.
Kotsopoulos, J.
Lubinski, J.
Lynch, H.T.
Singer, C.
Eng, C.
Neuhausen, S.L.
Karlan, B.
Kim–Sing, C.
Huzarski, T.
Gronwald, J.
McCuaig, J.
Senter, L.
Tung, N.
Ghadirian, P.
Eisen, A.
Johansen, N.
Liavaag, A.H.
Iversen, O.-.
Dørum, A.
Michelsen, T.M.
Campbell, I.
Devereux, L.
Mitchell, G.
James, P.
Pridmore, V.
Baert, A.
Depuydt, J.
Poppe, B.
Malfait, F.
Van Maerken, T.
Van Damme, T.
De Leeneer, K.
Claes, K.
Vral, A.
Buchanan, A.H.
Fine, C.
Skinner, C.S.
Schildkraut, J.M.
Horick, N.
Marcom, P.K.
Voils, C.I.
Nikitina, D.
Narod, S.A.
Kotsopoulos, J.
Bader, S.B.
Bugrein, H.
Alassam, R.
Al-Sulaiman, R.
Hirst, C.
Moss, S.
De Richter, P.
Guedaoura, S.
Pelletier, S.
Foulkes, W.D.
Hamet, P.
Chiquette, J.
Wong, N.
Haffaf, Z.E.
Simard, J.
Dorval, M.
Irwin, G.W.
Stewart, R.A.
Morton, L.A.
Hinds, G.
McFaul, L.
Savage, K.I.
Morrison, P.J.
McIntosh, S.A.
Larouche, G.
Chiquette, J.
Simard, J.
Dorval, M.
Taff, J.
Smith, J.
Hochman, T.
Alvear, M.
Marion, C.
Lin, Y.
Axelrod, D.
Muggia, F.
Androich, C.
Bell, K.
Lynch, L.
Bordeleau, L.
Zbuk, K.
Joseph, M.
Rab, F.
Panabaker, K.
Nisker, J.
St-Pierre, D.
Santerre–Theil, A.
Bouchard, K.
Gonthier, C.
Drolet, A.-.
Côté, C.
Rhéaume, J.
Chiquette, J.
Dorval, M.
Santerre–Theil, A.
St-Pierre, D.
Bouchard, K.
Drolet, A.-.
Chiquette, J.
Dorval, M.
Tamura, C.
Kaneko, K.
Masuta, H.
Nakamura, Y.
Ohsumi, S.
Dove, E.S.
Zawati, M.H.
Lévesque, E.
Simard, J.
Knoppers, B.M.
Oros, K.K.
Arcand, S.
Tonin, P.N.
Greenwood, C.M.
Trainer, A.H.
Thompson, E.
Doyle, M.
Hunter, S.
Rowley, S.
James, P.A.
Antoniou, A.
K-Confab Breast Cancer Consortium,
Pachter, N.
McGaughran, J.
Tucker, K.
Burke, J.
Campbell, I.
George, S.H.
Milea, A.
Sowamber, R.
Toccalino, D.
Shaw, P.
Pettapiece–Phillips, R.
Akbari, M.
Salmena, L.
Narod, S.
Kotsopoulos, J.
Amin, O.
Yasmeen, A.
Beauchamp, M.-.
Nader, P.R.
Iqbal, S.
Gotlieb, W.H.
Ellison, G.
Huang, S.
Carr, H.
Wallace, A.
Bashkar, S.
Mills, J.
van der Merwe, N.C.
Combrink, H.M.
Oosthuizen, J.
Moeti, P.J.
Visser, B.
Peter, N.
Buccamazza, I.
Schoeman, M.
Apffelstaedt, J.P.
Chen, W.
Foulkes, W.D.
Howitt, B.E.
Meserve, E.E.
Hanamorngruang, S.
Conner, J.R.
Lin, D.
Schulte, S.
Crum, C.P.
Anderson, K.
Djordjevic, B.
Carson, N.
Tomiak, E.
Andrei, Z.
Hall, A.
Malina, A.
Pelletier, J.
Metrakos, P.
Zogopoulos, G.
Babkina, N.
Orsulic, S.
Li, X.
Karlan, B.
Gordon, O.
Lincoln, S.
Kurian, A.
Shannon, K.
Kobayashi, Y.
Anderson, M.
Nilsen, G.
Jacobs, K.
Mills, M.
Schultz, A.
Desmond, A.
Powers, M.
Monzon, F.
Ford, J.
Ellisen, L.
Rappaport–Fuerhauser, C.
Weinhaeusel, A.
Seifert, M.
Marian, B.
Singer, C.F.
Sawyer, S.D.
McInerny, S.C.
Beesley, J.
Harris, M.
Lindeman, G.J.
Delatycki, M.B.
Trainer, A.H.
Chenevix–Trench, G.
Mitchell, G.
James, P.A.
Beebe–Dimmer, J.
Lange, E.
Zuhlke, K.
Cooney, K.
Marouf, C.
Tazzite, A.
Diakité, B.
Jouhadi, H.
Benider, A.
Nadifi, S.
Hanna, D.
Glendon, G.
Knight, J.
Lilge, L.
Bordeleau, L.
Armel, S.
Terespolsky, D.
Panchal, S.
Carroll, J.
Andrulis, I.
Fostira, F.
Apostolou, P.
Papamentzelopoulou, M.
Konstanta, I.
Vratimos, A.
Fountzilas, G.
Voutsinas, G.
Konstantopoulou, I.
Yannoukakos, D.
Klonowska, K.
Ratajska, M.
Kuzniacka, A.
Brozek, I.
Kozlowski, P.
Limon, J.
Ratajska, M.
Kuzniacka, A.
Matusiak, M.
Brozek, I.
Pilyugin, M.
Debniak, J.
Sniadecki, M.
Wydra, D.
Irminger–Finger, I.
Limon, J.
Lesueur, F.
Damiola, F.
Pertesi, M.
Oliver, J.
Le Calvez–Kelm, F.
Young, E.L.
Roane, T.C.
Williams, G.J.
Registry, B.C.
Hopper, J.L.
Southey, M.C.
Andrulis, I.L.
John, E.M.
Goldgar, D.E.
Tavtigian, S.V.
Bédard, K.
Arcand, S.L.
Alirezaie, N.
Majewski, J.
Nolet, S.
Haffaf, Z.E.
Provencher, D.M.
Mes–Masson, A.-.
Tonin, P.N.
Dutil, J.
Teer, J.K.
Yoder, S.J.
Matta, J.L.
Monteiro, A.
Arcand, S.L.
Akbari, M.R.
Mes–Masson, A.-.
Provencher, D.
Narod, S.A.
Tonin, P.N.
Sawyer, S.D.
Forrest, L.
Mitchell, G.
Hallowell, N.
James, P.A.
Young, M.-.
Lapointe, J.
Simard, J.
Julian–Reynier, C.
Dorval, M.
Trottier, M.
Narod, S.A.
Lunn, J.
Donenberg, T.
Hurley, J.
Curling, D.
Butler, R.
Blouin–Bougie, J.
Amara, N.
Jbilou, J.
Halilem, N.
Simard, J.
Landry, R.
Giannakeas, V.
Narod, S.
Eisen, A.
Prummel, M.
Meschino, W.
Muradali, D.
Horgan, M.
Carroll, J.
Shumak, R.
Warner, E.
Rabeneck, L.
Chiarelli, A.
Armel, S.R.
McCuaig, J.
Gojska, N.
Demsky, R.
Murphy, J.
Rosen, B.
Mazzola, E.
Chipman, J.
Cheng, S.-.
Parmigiani, G.
McGarrigle, S.
Guinan, E.
Hussey, J.
O’Sullivan, J.
Gallagher, D.
Connolly, E.
Guinan, E.M.
McGarrigle, S.A.
Hussey, J.
Healy, L.A.
Gallagher, D.
Connolly, E.
Hastings, V.
Lord, M.
Joanisse, S.
Anderson, K.
Creede, E.
Gilpin, C.
Smith, E.
Rusnak, A.
Tomiak, E.
Agranat, S.
Barris, H.
Kedar, I.
Shohat, M.
Sulkes, A.
Rizel, S.
Perry, S.
Yerushalmi, R.
Hinds, G.
Irwin, G.
McFaul, L.
McGoldrick, P.
Williams, F.
Savage, K.
Harley, I.
McKee, S.
McIntosh, S.A.
Lieberman, S.
Tomer, A.
Raz, A.
Ben-Chetrit, A.
Olsha, O.
Lahad, A.
Levy–Lahad, E.
Viassolo, V.
Ayme, A.
Membrez, V.
Murphy, A.E.
Blouin, J.-.
Rebsamen, M.
Hutter, P.
Chappuis, P.O.
Hassan, N.
Yee, Y.S.
Taib, N.A.
Har, Y.C.
Hwang, T.S.
Lecarpentier, J.
Noguès, C.
Mouret–Fourme, E.
Gauthier–Villars, M.
Bonadona, V.
Fricker, J.-.
Caron, O.
Stoppa–Lyonnet, D.
Berthet, P.
Faivre, L.
Buecher, B.
Coupier, I.
Dugast, C.
Andrieu, N.
Katapodi, M.
Duquette, D.
Milliron, K.
Mendelsohn–Victor, K.
Anderson, B.
Merajver, S.
Leclerc, J.
Bouchard, K.
Chiquette, J.
Larouche, G.
Glendon, G.
Maugard, C.M.
Simard, J.
Dorval, M.
(2014). Proffered papers and posters submitted to the Fifth International Symposium on Hereditary Breast and Ovarian Cancer, BRCA: Twenty Years of Advances. Current oncology (toronto, ont.),
Vol.21
(2),
pp. e358-e391.
show abstract
Objectives:
It is estimated that 1%–2% of individuals of Ashkenazi Jewish (aj) ancestry carry one of three pathogenic founder mutations in BRCA1 and BRCA2. Targeted testing for these mutations (BRCA1 187delAG and 5385insC, and BRCA2 6174delT) is therefore recommended for all aj breast and ovarian cancer patients, regardless of age of diagnosis or family history. Comprehensive analysis of both genes is recommended for a subset of aj patients in whom founder mutations are not identified, but estimates of the yield from comprehensive analysis in this population vary widely.
Methods:
We sought to establish the proportion of non-founder mutations in aj patients undergoing clinical testing in our laboratory from January 2006 through August 2013. Analysis included aj patients for whom: 1) comprehensive testing was ordered as the initial test, or 2) founder mutation testing was ordered with instructions to “reflex” to comprehensive analysis if negative. The latter group was limited to cases where the reflex testing was ordered on the original test request form, and not cancelled for any reason other than the detection of a founder mutation.
Results:
The percentage of non-founder mutations detected in these groups was 13% (104/802) and 7.2% (198/2769) respectively. We detected 189 unique non-founder mutations, 76 in BRCA1 and 113 in BRCA2. BRCA2 4075delGT was detected in 15 patients. The next most common mutations, found in 7 patients each, were BRCA1 5055delG, BRCA2 1982delA, and BRCA2 R3128X.
Conclusions:
Non-founder mutations make up between 13% and 7.2% of BRCA1 and BRCA2 mutations in patients reporting aj ancestry. These numbers may represent underestimates if some patients were ascertained for testing based on the identification of a founder mutation in a relative. These numbers suggest that the prevalence of non-founder mutations in aj individuals may be comparable to the prevalence of BRCA1/2 mutations in non-aj individuals.
Objectives:
The genetic cause of the majority of multiple-case breast cancer families remains unresolved. Next-generation sequencing has emerged as an efficient strategy for identifying predisposing mutations in individuals with inherited cancer. We are conducting whole-exome sequence analysis of germline dna from multiple affected relatives from breast cancer families, with the aim of identifying rare protein truncating and non-synonymous variants that are likely to include novel cancer predisposing mutations. Data from more than 200 exomes show that, on average, each individual carries 30–50 protein truncating mutations and 300–400 rare non-synonymous variants. Heterogeneity among our exome data strongly suggest that numerous moderate penetrance genes remain to be discovered, with each gene individually accounting for only a small fraction of families (∼0.5%). This scenario marks validation of candidate breast cancer predisposing genes in large case–control studies as the rate-limiting step in resolving the missing heritability of breast cancer. The aim of this study is to screen genes that are recurrently mutated among our exome data in a larger cohort of cases and controls to assess the prevalence of inactivating mutations that may be associated with breast cancer risk.
Methods:
We are currently using the Agilent HaloPlex Target Enrichment System to screen the coding regions of 168 genes in 1000 BRCA1/2 mutation-negative familial breast cancer cases and 1000 cancer-naïve controls.
Results:
To date, our interim analysis has identified 23 genes which carry truncating mutations in multiple breast cancer families and do not have corresponding truncating mutations among controls, therefore representing interesting candidate genes for further investigation. Among these genes are established breast cancer susceptibility gene PALB2,dna repair genes ATR, PARP4, TDP1, and gwas snp–associated gene TOX3. Population-based mammographic screening is the main form of detection of breast tumours at a stage where they are more amenable to successful treatment. However women are offered the same age-based screening regime even though it is known that they can differ substantially in their risk of developing breast cancer. We hypothesize that incorporating genetic factors using a polygenic risk score (prs) and non-genetic risk factors, including mammographic density, will improve detection rates. As a first step in building the resources to improve mammographic screening, we have established LifePool (http://www.lifepool.org), which is a prospective cohort of >75,000 healthy women attending BreastScreen Victoria, Australia. LifePool participants give informed consent to access to all screening and cancer incidence data and complete a health and lifestyle questionnaire. More than 50% of women consent to provide dna for use in germline genetic research. Using this cohort, we will identify the optimal weighted combination of prs, breast density, and other non-genetic risk factors to predict observed screen-detected cancer (sdc) and interval cancer (ic) rates in the cohort. Using these data we will specify models of personalized screening strategies and identify which optimize sdc rates and reduce ic rates while containing or reducing false-positive outcomes. Simulations of a hypothetical cohort of 20,000 women provided data highly suggestive of a large benefit associated with inclusion of a prs to screening schedules. For example, making screening annual in the high-risk group could reduce the interval cancer rate by more than half in the top prs quartile group. While these predictions are intriguing, they are based on a number of assumptions that are not necessarily reflective of a real life screen population. Our prospective study will provide robust data from a carefully controlled and representative screened population that can be used to progress to tailored screening trial.
Objective:
Since discovery of the BRCA1 and BRCA2 genes, great strides have been made in understanding the varied impact of testing positive. Significant challenges remain for BRCA-positive patients, which are not always addressed by their medical team. To educate our BRCA community regarding advancements in the field and to address the unique medical and psychological needs of BRCA carriers, the Beaumont Cancer Genetics Program initiated an annual BRCA Symposium.
Methods:
BRCA-positive individuals and their families from Beaumont Health System and the local community were invited to attend a BRCA Symposium initiated in the fall of 2012. A variety of relevant topics were presented, including cancer risks, high-risk surveillance, prophylactic surgery, gynecologic issues, and psychosocial topics. Participants were asked to complete a survey rating the quality, added benefit, and overall impact of the conference at the 2012 and 2013 meetings.
Results:
Survey respondents included 48 of 58 participants (83%) in 2012, and 34 of 47 participants (72%) in 2013. Participants included 30 cancer survivors, 23 previvors, and 13 who had a family member who was BRCA-positive, but had not tested themselves. The majority were Caucasian (73%), with representation from Asian, African, and Arabic Americans. The primary reasons for attending included gathering information regarding BRCA, help with medical decision-making, support, and networking with other individuals who are BRCA-positive. 96% of participants felt that the conference met or exceeded their expectations; 88% felt that their knowledge about BRCA improved significantly.
Conclusion:
This experience demonstrates successful implementation of an annual educational and support symposium for BRCA-positive patients and their families. This approach addresses a significant need in this unique population for continued long-term education and support, and serves as a model for others.
Objectives:
Epidemiologic studies have shown a co-clustering of breast and prostate cancer suggesting that there are germline variants that increase the risk of both hormonally driven neoplasms. Mutations in BRCA1 and BRCA2 genes may explain a small portion of the observed co-occurrence of breast and prostate cancer within families. The current investigation focuses on the delineation of chromosomal regions which may harbour new genes that play a role in the aggregation of breast and prostate cancer among first-degree family members.
Methods:
A genome-wide linkage scan was conducted on 50 families participating in the University of Michigan Prostate Cancer Genetics Project. All families had at least 2 first-degree relatives diagnosed with prostate cancer and at least 1 female relative diagnosed with breast cancer in a first-degree relationship with one of the participating prostate cancer cases. Genome-wide multipoint nonparametric linkage analyses for the combined phenotype of prostate and breast cancer were performed using the software Merlin.
Results:
The strongest evidence for linkage was detected at 16q22 (lod: 3.07 at rs722579), a region previously reported to be in linked to prostate cancer. This region contains several interesting candidate genes including known prostate cancer tumour suppressor genes CDH1, WWOX, and ATBF1, as well as BCAR1, a gene involved in a number of critical carcinogenic processes including cell migration, growth, and differentiation.
Conclusions:
Next-generation sequencing of the genes in this region in our linked families are in progress to identify new mutations that explain clustering of prostate and breast cancer in these families and provide new information on shared genetic pathways between these two common cancers.
Objectives:
In 2011, the High-Risk Ontario Breast Screening Program (obsp) expanded to include organized breast screening with annual mammography and breast mri for women at high risk of developing breast cancer. Eligibility criteria included: ages 30–69 with i) BRCA1/2 mutations, ii) 50% risk of BRCA1/2 mutation, iii) ≥25% lifetime risk of breast cancer (by ibis or boadicea), iv) prior chest irradiation. A standardized pathway with criteria for genetic assessment (ga) was implemented in 29 centres. The objective of this study was to evaluate quality indicators of ga.
Methods:
Data were collected for women assessed July 2011 to June 2012. Variables included demographics, risk factors, breast cancer risk assessment, referral dates for ga, and testing information. Subjects consented to the use of their data for evaluation.
Results:
Of 6835 women referred, 964 (14%) were known high-risk, and 5899 (86%) had ga. Of the 5899, 5201 completed ga and were studied. Median wait time for ga was 62 days (range: 3–145 days). 1852 Women (36%) had genetic counselling (gc) and genetic testing (gt); 3349 (64%) had gc only. Of gt results, 82% were available within 90 days. The median time to disclosure of gt results was 22 days (range: 9–42 days) after results were reported. Wait times were similar for women <50 vs. >50 years. The median wait time for gc was shortest for women with 50% mutation risk (16 days) and longest for women who did not meet high-risk criteria (65 days). Overall, 31% met the high-risk criteria.
Conclusions:
After implementation of the obsp high-risk program, many women received timely ga in Ontario. gc wait time ranged widely and varied by risk criteria. Possible explanations include variability in gc resources, and risk triage by gc centres. Less than one third of women referred met the high-risk criteria. Evaluation of the risk assessment process and referral criteria is needed..
Osorio, A.
Milne, R.L.
Kuchenbaecker, K.
Vaclová, T.
Pita, G.
Alonso, R.
Peterlongo, P.
Blanco, I.
de la Hoya, M.
Duran, M.
Díez, O.
Ramón Y Cajal, T.
Konstantopoulou, I.
Martínez-Bouzas, C.
Andrés Conejero, R.
Soucy, P.
McGuffog, L.
Barrowdale, D.
Lee, A.
SWE-BRCA,
Arver, B.
Rantala, J.
Loman, N.
Ehrencrona, H.
Olopade, O.I.
Beattie, M.S.
Domchek, S.M.
Nathanson, K.
Rebbeck, T.R.
Arun, B.K.
Karlan, B.Y.
Walsh, C.
Lester, J.
John, E.M.
Whittemore, A.S.
Daly, M.B.
Southey, M.
Hopper, J.
Terry, M.B.
Buys, S.S.
Janavicius, R.
Dorfling, C.M.
van Rensburg, E.J.
Steele, L.
Neuhausen, S.L.
Ding, Y.C.
Hansen, T.V.
Jønson, L.
Ejlertsen, B.
Gerdes, A.-.
Infante, M.
Herráez, B.
Moreno, L.T.
Weitzel, J.N.
Herzog, J.
Weeman, K.
Manoukian, S.
Peissel, B.
Zaffaroni, D.
Scuvera, G.
Bonanni, B.
Mariette, F.
Volorio, S.
Viel, A.
Varesco, L.
Papi, L.
Ottini, L.
Tibiletti, M.G.
Radice, P.
Yannoukakos, D.
Garber, J.
Ellis, S.
Frost, D.
Platte, R.
Fineberg, E.
Evans, G.
Lalloo, F.
Izatt, L.
Eeles, R.
Adlard, J.
Davidson, R.
Cole, T.
Eccles, D.
Cook, J.
Hodgson, S.
Brewer, C.
Tischkowitz, M.
Douglas, F.
Porteous, M.
Side, L.
Walker, L.
Morrison, P.
Donaldson, A.
Kennedy, J.
Foo, C.
Godwin, A.K.
Schmutzler, R.K.
Wappenschmidt, B.
Rhiem, K.
Engel, C.
Meindl, A.
Ditsch, N.
Arnold, N.
Plendl, H.J.
Niederacher, D.
Sutter, C.
Wang-Gohrke, S.
Steinemann, D.
Preisler-Adams, S.
Kast, K.
Varon-Mateeva, R.
Gehrig, A.
Stoppa-Lyonnet, D.
Sinilnikova, O.M.
Mazoyer, S.
Damiola, F.
Poppe, B.
Claes, K.
Piedmonte, M.
Tucker, K.
Backes, F.
Rodríguez, G.
Brewster, W.
Wakeley, K.
Rutherford, T.
Caldés, T.
Nevanlinna, H.
Aittomäki, K.
Rookus, M.A.
van Os, T.A.
van der Kolk, L.
de Lange, J.L.
Meijers-Heijboer, H.E.
van der Hout, A.H.
van Asperen, C.J.
Gómez Garcia, E.B.
Hoogerbrugge, N.
Collée, J.M.
van Deurzen, C.H.
van der Luijt, R.B.
Devilee, P.
HEBON,
Olah, E.
Lázaro, C.
Teulé, A.
Menéndez, M.
Jakubowska, A.
Cybulski, C.
Gronwald, J.
Lubinski, J.
Durda, K.
Jaworska-Bieniek, K.
Johannsson, O.T.
Maugard, C.
Montagna, M.
Tognazzo, S.
Teixeira, M.R.
Healey, S.
KConFab Investigators,
Olswold, C.
Guidugli, L.
Lindor, N.
Slager, S.
Szabo, C.I.
Vijai, J.
Robson, M.
Kauff, N.
Zhang, L.
Rau-Murthy, R.
Fink-Retter, A.
Singer, C.F.
Rappaport, C.
Geschwantler Kaulich, D.
Pfeiler, G.
Tea, M.-.
Berger, A.
Phelan, C.M.
Greene, M.H.
Mai, P.L.
Lejbkowicz, F.
Andrulis, I.
Mulligan, A.M.
Glendon, G.
Toland, A.E.
Bojesen, A.
Pedersen, I.S.
Sunde, L.
Thomassen, M.
Kruse, T.A.
Jensen, U.B.
Friedman, E.
Laitman, Y.
Shimon, S.P.
Simard, J.
Easton, D.F.
Offit, K.
Couch, F.J.
Chenevix-Trench, G.
Antoniou, A.C.
Benitez, J.
(2014). DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers. Plos genet,
Vol.10
(4),
p. e1004256.
show abstract
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied..
McBride, K.A.
Ballinger, M.L.
Killick, E.
Kirk, J.
Tattersall, M.H.
Eeles, R.A.
Thomas, D.M.
Mitchell, G.
(2014). Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nat rev clin oncol,
Vol.11
(5),
pp. 260-271.
show abstract
Carriers of germline mutations in the TP53 gene, encoding the cell-cycle regulator and tumour suppressor p53, have a markedly increased risk of cancer-related morbidity and mortality during both childhood and adulthood, and thus require appropriate and effective cancer risk management. However, the predisposition of such patients to multiorgan tumorigenesis presents a specific challenge for cancer risk management programmes. Herein, we review the clinical implications of germline mutations in TP53 and the evidence for cancer screening and prevention strategies in individuals carrying such mutations, as well as examining the potential psychosocial implications of lifelong management for a ubiquitous cancer risk. In addition, we propose an evidence-based framework for the clinical management of TP53 mutation carriers and provide a platform for addressing the management of other cancer predisposition syndromes that can affect multiple organs..
Evans, D.G.
Kesavan, N.
Lim, Y.
Gadde, S.
Hurley, E.
Massat, N.J.
Maxwell, A.J.
Ingham, S.
Eeles, R.
Leach, M.O.
MARIBS Group,
Howell, A.
Duffy, S.W.
(2014). MRI breast screening in high-risk women: cancer detection and survival analysis. Breast cancer res treat,
Vol.145
(3),
pp. 663-672.
show abstract
Women with a genetic predisposition to breast cancer tend to develop the disease at a younger age with denser breasts making mammography screening less effective. The introduction of magnetic resonance imaging (MRI) for familial breast cancer screening programs in recent years was intended to improve outcomes in these women. We aimed to assess whether introduction of MRI surveillance improves 5- and 10-year survival of high-risk women and determine the accuracy of MRI breast cancer detection compared with mammography-only or no enhanced surveillance and compare size and pathology of cancers detected in women screened with MRI + mammography and mammography only. We used data from two prospective studies where asymptomatic women with a very high breast cancer risk were screened by either mammography alone or with MRI also compared with BRCA1/2 carriers with no intensive surveillance. 63 cancers were detected in women receiving MRI + mammography and 76 in women receiving mammography only. Sensitivity of MRI + mammography was 93 % with 63 % specificity. Fewer cancers detected on MRI were lymph node positive compared to mammography/no additional screening. There were no differences in 10-year survival between the MRI + mammography and mammography-only groups, but survival was significantly higher in the MRI-screened group (95.3 %) compared to no intensive screening (73.7 %; p = 0.002). There were no deaths among the 21 BRCA2 carriers receiving MRI. There appears to be benefit from screening with MRI, particularly in BRCA2 carriers. Extended follow-up of larger numbers of high-risk women is required to assess long-term survival..
Chen, Y.
Bancroft, E.
Ashley, S.
Arden-Jones, A.
Thomas, S.
Shanley, S.
Saya, S.
Wakeling, E.
Eeles, R.
(2014). Baseline and post prophylactic tubal-ovarian surgery CA125 levels in BRCA1 and BRCA2 mutation carriers. Familial cancer,
Vol.13
(2),
pp. 197-203.
Pooley, K.A.
McGuffog, L.
Barrowdale, D.
Frost, D.
Ellis, S.D.
Fineberg, E.
Platte, R.
Izatt, L.
Adlard, J.
Bardwell, J.
Brewer, C.
Cole, T.
Cook, J.
Davidson, R.
Donaldson, A.
Dorkins, H.
Douglas, F.
Eason, J.
Houghton, C.
Kennedy, M.J.
McCann, E.
Miedzybrodzka, Z.
Murray, A.
Porteous, M.E.
Rogers, M.T.
Side, L.E.
Tischkowitz, M.
Walker, L.
Hodgson, S.
Eccles, D.M.
Morrison, P.J.
Evans, D.G.
Eeles, R.A.
Antoniou, A.C.
Easton, D.F.
Dunning, A.M.
EMBRACE;,
(2014). Lymphocyte telomere length is long in BRCA1 and BRCA2 mutation carriers regardless of cancer-affected status. Cancer epidemiol biomarkers prev,
Vol.23
(6),
pp. 1018-1024.
show abstract
BACKGROUND: Telomere length has been linked to risk of common diseases, including cancer, and has previously been proposed as a biomarker for cancer risk. Germline BRCA1 and BRCA2 mutations predispose to breast, ovarian, and other cancer types. METHODS: We investigated telomere length in BRCA mutation carriers and their non-carrier relatives and further examined whether telomere length is a modifier of cancer risk in mutation carriers. We measured mean telomere length in DNA extracted from whole blood using high-throughput quantitative PCR. Participants were from the EMBRACE study in United Kingdom and Eire (n = 4,822) and comprised BRCA1 (n = 1,628) and BRCA2 (n = 1,506) mutation carriers and their non-carrier relatives (n = 1,688). RESULTS: We find no significant evidence that mean telomere length is associated with breast or ovarian cancer risk in BRCA mutation carriers. However, we find mutation carriers to have longer mean telomere length than their non-carrier relatives (all carriers vs. non-carriers, Ptrend = 0.0018), particularly in families with BRCA2 mutations (BRCA2 mutation carriers vs. all non-carriers, Ptrend = 0.0016). CONCLUSIONS: Our findings lend little support to the hypothesis that short mean telomere length predisposes to cancer. Conversely, our main and unexpected finding is that BRCA mutation carriers (regardless of cancer status) have longer telomeres than their non-mutation carrier, non-cancer-affected relatives. The longer telomere length in BRCA2 mutation carriers is consistent with its role in DNA damage response. Overall, it seems that increased telomere length may be a consequence of these mutations, but is not itself directly related to the increased cancer risk in carriers. IMPACT: The finding that mutation carriers have longer mean telomere lengths than their non-carrier relatives is unexpected but biologically plausible and could open up new lines of research into the functions of the BRCA proteins. To our knowledge, this is the largest study of telomere length in BRCA mutation carriers and their relatives. The null cancer-risk association supports recent large prospective studies of breast and ovarian cancer and indicates that mean telomere length would not be a useful biomarker in these cancers. Cancer Epidemiol Biomarkers Prev; 23(6); 1018-24. ©2014 AACR..
Copson, E.
Maishman, T.
Gerty, S.
Eccles, B.
Stanton, L.
Cutress, R.I.
Altman, D.G.
Durcan, L.
Simmonds, P.
Jones, L.
Tapper, W.
POSH study steering group,
Eccles, D.
(2014). Ethnicity and outcome of young breast cancer patients in the United Kingdom: the POSH study. Br j cancer,
Vol.110
(1),
pp. 230-241.
show abstract
BACKGROUND: Black ethnic groups have a higher breast cancer mortality than Whites. American studies have identified variations in tumour biology and unequal health-care access as causative factors. We compared tumour pathology, treatment and outcomes in three ethnic groups in young breast cancer patients treated in the United Kingdom. METHODS: Women aged ≤ 40 years at breast cancer diagnosis were recruited to the POSH national cohort study (MREC: 00/06/69). Personal characteristics, tumour pathology and treatment data were collected at diagnosis. Follow-up data were collected annually. Overall survival (OS) and distant relapse-free survival (DRFS) were assessed using Kaplan-Meier curves, and multivariate analyses were performed using Cox regression. RESULTS: Ethnicity data were available for 2915 patients including 2690 (91.0%) Whites, 118 (4.0%) Blacks and 87 (2.9%) Asians. Median tumour diameter at presentation was greater in Blacks than Whites (26.0 mm vs 22.0 mm, P=0.0103), and multifocal tumours were more frequent in both Blacks (43.4%) and Asians (37.0%) than Whites (28.9%). ER/PR/HER2-negative tumours were significantly more frequent in Blacks (26.1%) than Whites (18.6%, P=0.043). Use of chemotherapy was similarly high in all ethnic groups (89% B vs 88.6% W vs 89.7% A). A 5-year DRFS was significantly lower in Blacks than Asians (62.8% B vs 77.0% A, P=0.0473) or Whites (62.8 B% vs 77.0% W, P=0.0053) and a 5-year OS for Black patients, 71.1% (95% CI: 61.0-79.1%), was significantly lower than that of Whites (82.4%, 95% CI: 80.8-83.9%, W vs B: P=0.0160). In multivariate analysis, Black ethnicity had an effect on DRFS in oestrogen receptor (ER)-positive patients that is independent of body mass index, tumour size, grade or nodal status, HR: 1.60 (95% CI: 1.03-2.47, P=0.035). CONCLUSION: Despite equal access to health care, young Black women in the United Kingdom have a significantly poorer outcome than White patients. Black ethnicity is an independent risk factor for reduced DRFS particularly in ER-positive patients..
Knipe, D.W.
Evans, D.M.
Kemp, J.P.
Eeles, R.
Easton, D.F.
Kote-Jarai, Z.
Al Olama, A.A.
Benlloch, S.
Donovan, J.L.
Hamdy, F.C.
Neal, D.E.
Smith, G.D.
Lathrop, M.
Martin, R.M.
(2014). Genetic variation in prostate-specific antigen-detected prostate cancer and the effect of control selection on genetic association studies. Cancer epidemiol biomarkers prev,
Vol.23
(7),
pp. 1356-1365.
show abstract
BACKGROUND: Only a minority of the genetic components of prostate cancer risk have been explained. Some observed associations of SNPs with prostate cancer might arise from associations of these SNPs with circulating prostate-specific antigen (PSA) because PSA values are used to select controls. METHODS: We undertook a genome-wide association study (GWAS) of screen-detected prostate cancer (ProtecT: 1,146 cases and 1,804 controls); meta-analyzed the results with those from the previously published UK Genetic Prostate Cancer Study (1,854 cases and 1,437 controls); investigated associations of SNPs with prostate cancer using either "low" (PSA < 0.5 ng/mL) or "high" (PSA ≥ 3 ng/mL, biopsy negative) PSA controls; and investigated associations of SNPs with PSA. RESULTS: The ProtecT GWAS confirmed previously reported associations of prostate cancer at three loci: 10q11.23, 17q24.3, and 19q13.33. The meta-analysis confirmed associations of prostate cancer with SNPs near four previously identified loci (8q24.21,10q11.23, 17q24.3, and 19q13.33). When comparing prostate cancer cases with low PSA controls, alleles at genetic markers rs1512268, rs445114, rs10788160, rs11199874, rs17632542, rs266849, and rs2735839 were associated with an increased risk of prostate cancer, but the effect-estimates were attenuated to the null when using high PSA controls (Pheterogeneity in effect-estimates < 0.04). We found a novel inverse association of rs9311171-T with circulating PSA. CONCLUSIONS: Differences in effect-estimates for prostate cancer observed when comparing low versus high PSA controls may be explained by associations of these SNPs with PSA. IMPACT: These findings highlight the need for inferences from genetic studies of prostate cancer risk to carefully consider the influence of control selection criteria..
Annels, N.E.
Simpson, G.R.
Denyer, M.
McGrath, S.E.
Falgari, G.
Killick, E.
Eeles, R.
Stebbing, J.
Pchejetski, D.
Cutress, R.
Murray, N.
Michael, A.
Pandha, H.
(2014). Spontaneous antibodies against Engrailed-2 (EN2) protein in patients with prostate cancer. Clinical and experimental immunology,
Vol.177
(2),
pp. 428-438.
Andreassen, O.A.
Zuber, V.
Thompson, W.K.
Schork, A.J.
Bettella, F.
PRACTICAL Consortium,
CRUK GWAS,
Djurovic, S.
Desikan, R.S.
Mills, I.G.
Dale, A.M.
(2014). Shared common variants in prostate cancer and blood lipids. Int j epidemiol,
Vol.43
(4),
pp. 1205-1214.
show abstract
BACKGROUND: Epidemiological and clinical studies suggest comorbidity between prostate cancer (PCA) and cardiovascular disease (CVD) risk factors. However, the relationship between these two phenotypes is still not well understood. Here we sought to identify shared genetic loci between PCA and CVD risk factors. METHODS: We applied a genetic epidemiology method based on conjunction false discovery rate (FDR) that combines summary statistics from different genome-wide association studies (GWAS), and allows identification of genetic overlap between two phenotypes. We evaluated summary statistics from large, multi-centre GWA studies of PCA (n=50 000) and CVD risk factors (n=200 000) [triglycerides (TG), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes (T2D)]. Enrichment of single nucleotide polymorphisms (SNPs) associated with PCA and CVD risk factors was assessed with conditional quantile-quantile plots and the Anderson-Darling test. Moreover, we pinpointed shared loci using conjunction FDR. RESULTS: We found the strongest enrichment of P-values in PCA was conditional on LDL and conditional on TG. In contrast, we found only weak enrichment conditional on HDL or conditional on the other traits investigated. Conjunction FDR identified altogether 17 loci; 10 loci were associated with PCA and LDL, 3 loci were associated with PCA and TG and additionally 4 loci were associated with PCA, LDL and TG jointly (conjunction FDR <0.01). For T2D, we detected one locus adjacent to HNF1B. CONCLUSIONS: We found polygenic overlap between PCA predisposition and blood lipids, in particular LDL and TG, and identified 17 pleiotropic gene loci between PCA and LDL, and PCA and TG, respectively. These findings provide novel pathobiological insights and may have implications for trials using targeting lipid-lowering agents in a prevention or cancer setting..
Bancroft, E.K.
Page, E.C.
Castro, E.
Lilja, H.
Vickers, A.
Sjoberg, D.
Assel, M.
Foster, C.S.
Mitchell, G.
Drew, K.
Mæhle, L.
Axcrona, K.
Evans, D.G.
Bulman, B.
Eccles, D.
McBride, D.
van Asperen, C.
Vasen, H.
Kiemeney, L.A.
Ringelberg, J.
Cybulski, C.
Wokolorczyk, D.
Selkirk, C.
Hulick, P.J.
Bojesen, A.
Skytte, A.-.
Lam, J.
Taylor, L.
Oldenburg, R.
Cremers, R.
Verhaegh, G.
van Zelst-Stams, W.A.
Oosterwijk, J.C.
Blanco, I.
Salinas, M.
Cook, J.
Rosario, D.J.
Buys, S.
Conner, T.
Ausems, M.G.
Ong, K.-.
Hoffman, J.
Domchek, S.
Powers, J.
Teixeira, M.R.
Maia, S.
Foulkes, W.D.
Taherian, N.
Ruijs, M.
Helderman-van den Enden, A.T.
Izatt, L.
Davidson, R.
Adank, M.A.
Walker, L.
Schmutzler, R.
Tucker, K.
Kirk, J.
Hodgson, S.
Harris, M.
Douglas, F.
Lindeman, G.J.
Zgajnar, J.
Tischkowitz, M.
Clowes, V.E.
Susman, R.
Ramón y Cajal, T.
Patcher, N.
Gadea, N.
Spigelman, A.
van Os, T.
Liljegren, A.
Side, L.
Brewer, C.
Brady, A.F.
Donaldson, A.
Stefansdottir, V.
Friedman, E.
Chen-Shtoyerman, R.
Amor, D.J.
Copakova, L.
Barwell, J.
Giri, V.N.
Murthy, V.
Nicolai, N.
Teo, S.-.
Greenhalgh, L.
Strom, S.
Henderson, A.
McGrath, J.
Gallagher, D.
Aaronson, N.
Ardern-Jones, A.
Bangma, C.
Dearnaley, D.
Costello, P.
Eyfjord, J.
Rothwell, J.
Falconer, A.
Gronberg, H.
Hamdy, F.C.
Johannsson, O.
Khoo, V.
Kote-Jarai, Z.
Lubinski, J.
Axcrona, U.
Melia, J.
McKinley, J.
Mitra, A.V.
Moynihan, C.
Rennert, G.
Suri, M.
Wilson, P.
Killick, E.
IMPACT Collaborators,
Moss, S.
Eeles, R.A.
(2014). Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study. Eur urol,
Vol.66
(3),
pp. 489-499.
show abstract
full text
BACKGROUND: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. OBJECTIVE: To report the first year's screening results for all men at enrollment in the study. DESIGN, SETTING AND PARTICIPANTS: We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrollment, and those men with PSA >3 ng/ml were offered prostate biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. RESULTS AND LIMITATIONS: We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. CONCLUSIONS: The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease. PATIENT SUMMARY: In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment..
Cuzick, J.
Thorat, M.A.
Andriole, G.
Brawley, O.W.
Brown, P.H.
Culig, Z.
Eeles, R.A.
Ford, L.G.
Hamdy, F.C.
Holmberg, L.
Ilic, D.
Key, T.J.
La Vecchia, C.
Lilja, H.
Marberger, M.
Meyskens, F.L.
Minasian, L.M.
Parker, C.
Parnes, H.L.
Perner, S.
Rittenhouse, H.
Schalken, J.
Schmid, H.-.
Schmitz-Dräger, B.J.
Schröder, F.H.
Stenzl, A.
Tombal, B.
Wilt, T.J.
Wolk, A.
(2014). Prevention and early detection of prostate cancer. Lancet oncol,
Vol.15
(11),
pp. e484-e492.
show abstract
Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-specific antigen (PSA) screening is controversial, but changes in the PSA threshold, frequency of screening, and the use of other biomarkers have the potential to minimise the overdiagnosis associated with PSA screening. Several new biomarkers for individuals with raised PSA concentrations or those diagnosed with prostate cancer are likely to identify individuals who can be spared aggressive treatment. Several pharmacological agents such as 5α-reductase inhibitors and aspirin could prevent development of prostate cancer. In this Review, we discuss the present evidence and research questions regarding prevention, early detection of prostate cancer, and management of men either at high risk of prostate cancer or diagnosed with low-grade prostate cancer..
Al Olama, A.A.
Kote-Jarai, Z.
Berndt, S.I.
Conti, D.V.
Schumacher, F.
Han, Y.
Benlloch, S.
Hazelett, D.J.
Wang, Z.
Saunders, E.
Leongamornlert, D.
Lindstrom, S.
Jugurnauth-Little, S.
Dadaev, T.
Tymrakiewicz, M.
Stram, D.O.
Rand, K.
Wan, P.
Stram, A.
Sheng, X.
Pooler, L.C.
Park, K.
Xia, L.
Tyrer, J.
Kolonel, L.N.
Le Marchand, L.
Hoover, R.N.
Machiela, M.J.
Yeager, M.
Burdette, L.
Chung, C.C.
Hutchinson, A.
Yu, K.
Goh, C.
Ahmed, M.
Govindasami, K.
Guy, M.
Tammela, T.L.
Auvinen, A.
Wahlfors, T.
Schleutker, J.
Visakorpi, T.
Leinonen, K.A.
Xu, J.
Aly, M.
Donovan, J.
Travis, R.C.
Key, T.J.
Siddiq, A.
Canzian, F.
Khaw, K.-.
Takahashi, A.
Kubo, M.
Pharoah, P.
Pashayan, N.
Weischer, M.
Nordestgaard, B.G.
Nielsen, S.F.
Klarskov, P.
Røder, M.A.
Iversen, P.
Thibodeau, S.N.
McDonnell, S.K.
Schaid, D.J.
Stanford, J.L.
Kolb, S.
Holt, S.
Knudsen, B.
Coll, A.H.
Gapstur, S.M.
Diver, W.R.
Stevens, V.L.
Maier, C.
Luedeke, M.
Herkommer, K.
Rinckleb, A.E.
Strom, S.S.
Pettaway, C.
Yeboah, E.D.
Tettey, Y.
Biritwum, R.B.
Adjei, A.A.
Tay, E.
Truelove, A.
Niwa, S.
Chokkalingam, A.P.
Cannon-Albright, L.
Cybulski, C.
Wokołorczyk, D.
Kluźniak, W.
Park, J.
Sellers, T.
Lin, H.-.
Isaacs, W.B.
Partin, A.W.
Brenner, H.
Dieffenbach, A.K.
Stegmaier, C.
Chen, C.
Giovannucci, E.L.
Ma, J.
Stampfer, M.
Penney, K.L.
Mucci, L.
John, E.M.
Ingles, S.A.
Kittles, R.A.
Murphy, A.B.
Pandha, H.
Michael, A.
Kierzek, A.M.
Blot, W.
Signorello, L.B.
Zheng, W.
Albanes, D.
Virtamo, J.
Weinstein, S.
Nemesure, B.
Carpten, J.
Leske, C.
Wu, S.-.
Hennis, A.
Kibel, A.S.
Rybicki, B.A.
Neslund-Dudas, C.
Hsing, A.W.
Chu, L.
Goodman, P.J.
Klein, E.A.
Zheng, S.L.
Batra, J.
Clements, J.
Spurdle, A.
Teixeira, M.R.
Paulo, P.
Maia, S.
Slavov, C.
Kaneva, R.
Mitev, V.
Witte, J.S.
Casey, G.
Gillanders, E.M.
Seminara, D.
Riboli, E.
Hamdy, F.C.
Coetzee, G.A.
Li, Q.
Freedman, M.L.
Hunter, D.J.
Muir, K.
Gronberg, H.
Neal, D.E.
Southey, M.
Giles, G.G.
Severi, G.
Breast and Prostate Cancer Cohort Consortium (BPC3),
PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium,
COGS (Collaborative Oncological Gene-environment Study) Consortium,
GAME-ON/ELLIPSE Consortium,
Cook, M.B.
Nakagawa, H.
Wiklund, F.
Kraft, P.
Chanock, S.J.
Henderson, B.E.
Easton, D.F.
Eeles, R.A.
Haiman, C.A.
(2014). A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat genet,
Vol.46
(10),
pp. 1103-1109.
show abstract
Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease..
Chai, X.
Friebel, T.M.
Singer, C.F.
Evans, D.G.
Lynch, H.T.
Isaacs, C.
Garber, J.E.
Neuhausen, S.L.
Matloff, E.
Eeles, R.
Tung, N.
Weitzel, J.N.
Couch, F.J.
Hulick, P.J.
Ganz, P.A.
Daly, M.B.
Olopade, O.I.
Tomlinson, G.
Blum, J.L.
Domchek, S.M.
Chen, J.
Rebbeck, T.R.
(2014). Use of risk-reducing surgeries in a prospective cohort of 1,499 BRCA1 and BRCA2 mutation carriers. Breast cancer research and treatment,
Vol.148
(2),
pp. 397-406.
full text
Bancroft, E.K.
Castro, E.
Ardern-Jones, A.
Moynihan, C.
Page, E.
Taylor, N.
Eeles, R.A.
Rowley, E.
Cox, K.
(2014). "It's all very well reading the letters in the genome, but it's a long way to being able to write": Men's interpretations of undergoing genetic profiling to determine future risk of prostate cancer. Fam cancer,
Vol.13
(4),
pp. 625-635.
show abstract
A family history of prostate cancer (PC) is one of the main risk factors for the disease. A number of common single nucleotide polymorphisms (SNPs) that confer small but cumulatively substantial risks of PC have been identified, opening the possibility for the use of SNPs in PC risk stratification for targeted screening and prevention in the future. The objective of this study was to explore the psychosocial impact of receiving information about genetic risk of PC. The participants were men who had a family history of PC and were enrolled in a screening study providing research genetic profiling alongside screening for PC. A combination of questionnaires and in-depth interviews were used. Questionnaires were completed by men at two time points: both before and after joining the study and going through the genetic profiling process. The interviews were completed after all study process were complete and were analysed using a framework analysis. In total 95 men completed both questionnaires and 26 men were interviewed. A number of issues facing men at risk of PC were identified. The results fell into two main categories: personal relevance and societal relevance. The strength of men's innate beliefs about their risk, shaped by genetic and environmental assumptions, outweigh the information provided by genetic testing. Men felt genetic profile results would have future use for accessing prostate screening, being aware of symptoms and in communicating with others. The findings reinforce the importance of providing contextual information alongside genetic profiling test results, and emphasises the importance of the counselling process in providing genetic risk information. This research raises some key issues to facilitate clinical practice and future research related to the use of genetic profiling to determine risk of PC and other diseases..
Lalonde, E.
Ishkanian, A.S.
Sykes, J.
Fraser, M.
Ross-Adams, H.
Erho, N.
Dunning, M.J.
Halim, S.
Lamb, A.D.
Moon, N.C.
Zafarana, G.
Warren, A.Y.
Meng, X.
Thoms, J.
Grzadkowski, M.R.
Berlin, A.
Have, C.L.
Ramnarine, V.R.
Yao, C.Q.
Malloff, C.A.
Lam, L.L.
Xie, H.
Harding, N.J.
Mak, D.Y.
Chu, K.C.
Chong, L.C.
Sendorek, D.H.
P'ng, C.
Collins, C.C.
Squire, J.A.
Jurisica, I.
Cooper, C.
Eeles, R.
Pintilie, M.
Dal Pra, A.
Davicioni, E.
Lam, W.L.
Milosevic, M.
Neal, D.E.
van der Kwast, T.
Boutros, P.C.
Bristow, R.G.
(2014). Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet oncol,
Vol.15
(13),
pp. 1521-1532.
show abstract
BACKGROUND: Clinical prognostic groupings for localised prostate cancers are imprecise, with 30-50% of patients recurring after image-guided radiotherapy or radical prostatectomy. We aimed to test combined genomic and microenvironmental indices in prostate cancer to improve risk stratification and complement clinical prognostic factors. METHODS: We used DNA-based indices alone or in combination with intra-prostatic hypoxia measurements to develop four prognostic indices in 126 low-risk to intermediate-risk patients (Toronto cohort) who will receive image-guided radiotherapy. We validated these indices in two independent cohorts of 154 (Memorial Sloan Kettering Cancer Center cohort [MSKCC] cohort) and 117 (Cambridge cohort) radical prostatectomy specimens from low-risk to high-risk patients. We applied unsupervised and supervised machine learning techniques to the copy-number profiles of 126 pre-image-guided radiotherapy diagnostic biopsies to develop prognostic signatures. Our primary endpoint was the development of a set of prognostic measures capable of stratifying patients for risk of biochemical relapse 5 years after primary treatment. FINDINGS: Biochemical relapse was associated with indices of tumour hypoxia, genomic instability, and genomic subtypes based on multivariate analyses. We identified four genomic subtypes for prostate cancer, which had different 5-year biochemical relapse-free survival. Genomic instability is prognostic for relapse in both image-guided radiotherapy (multivariate analysis hazard ratio [HR] 4·5 [95% CI 2·1-9·8]; p=0·00013; area under the receiver operator curve [AUC] 0·70 [95% CI 0·65-0·76]) and radical prostatectomy (4·0 [1·6-9·7]; p=0·0024; AUC 0·57 [0·52-0·61]) patients with prostate cancer, and its effect is magnified by intratumoral hypoxia (3·8 [1·2-12]; p=0·019; AUC 0·67 [0·61-0·73]). A novel 100-loci DNA signature accurately classified treatment outcome in the MSKCC low-risk to intermediate-risk cohort (multivariate analysis HR 6·1 [95% CI 2·0-19]; p=0·0015; AUC 0·74 [95% CI 0·65-0·83]). In the independent MSKCC and Cambridge cohorts, this signature identified low-risk to high-risk patients who were most likely to fail treatment within 18 months (combined cohorts multivariate analysis HR 2·9 [95% CI 1·4-6·0]; p=0·0039; AUC 0·68 [95% CI 0·63-0·73]), and was better at predicting biochemical relapse than 23 previously published RNA signatures. INTERPRETATION: This is the first study of cancer outcome to integrate DNA-based and microenvironment-based failure indices to predict patient outcome. Patients exhibiting these aggressive features after biopsy should be entered into treatment intensification trials. FUNDING: Movember Foundation, Prostate Cancer Canada, Ontario Institute for Cancer Research, Canadian Institute for Health Research, NIHR Cambridge Biomedical Research Centre, The University of Cambridge, Cancer Research UK, Cambridge Cancer Charity, Prostate Cancer UK, Hutchison Whampoa Limited, Terry Fox Research Institute, Princess Margaret Cancer Centre Foundation, PMH-Radiation Medicine Program Academic Enrichment Fund, Motorcycle Ride for Dad (Durham), Canadian Cancer Society..
Milne, R.L.
Burwinkel, B.
Michailidou, K.
Arias-Perez, J.-.
Zamora, M.P.
Menéndez-Rodríguez, P.
Hardisson, D.
Mendiola, M.
González-Neira, A.
Pita, G.
Alonso, M.R.
Dennis, J.
Wang, Q.
Bolla, M.K.
Swerdlow, A.
Ashworth, A.
Orr, N.
Schoemaker, M.
Ko, Y.-.
Brauch, H.
Hamann, U.
GENICA Network,
Andrulis, I.L.
Knight, J.A.
Glendon, G.
Tchatchou, S.
kConFab Investigators,
Australian Ovarian Cancer Study Group,
Matsuo, K.
Ito, H.
Iwata, H.
Tajima, K.
Li, J.
Brand, J.S.
Brenner, H.
Dieffenbach, A.K.
Arndt, V.
Stegmaier, C.
Lambrechts, D.
Peuteman, G.
Christiaens, M.-.
Smeets, A.
Jakubowska, A.
Lubinski, J.
Jaworska-Bieniek, K.
Durda, K.
Hartman, M.
Hui, M.
Yen Lim, W.
Wan Chan, C.
Marme, F.
Yang, R.
Bugert, P.
Lindblom, A.
Margolin, S.
García-Closas, M.
Chanock, S.J.
Lissowska, J.
Figueroa, J.D.
Bojesen, S.E.
Nordestgaard, B.G.
Flyger, H.
Hooning, M.J.
Kriege, M.
van den Ouweland, A.M.
Koppert, L.B.
Fletcher, O.
Johnson, N.
dos-Santos-Silva, I.
Peto, J.
Zheng, W.
Deming-Halverson, S.
Shrubsole, M.J.
Long, J.
Chang-Claude, J.
Rudolph, A.
Seibold, P.
Flesch-Janys, D.
Winqvist, R.
Pylkäs, K.
Jukkola-Vuorinen, A.
Grip, M.
Cox, A.
Cross, S.S.
Reed, M.W.
Schmidt, M.K.
Broeks, A.
Cornelissen, S.
Braaf, L.
Kang, D.
Choi, J.-.
Park, S.K.
Noh, D.-.
Simard, J.
Dumont, M.
Goldberg, M.S.
Labrèche, F.
Fasching, P.A.
Hein, A.
Ekici, A.B.
Beckmann, M.W.
Radice, P.
Peterlongo, P.
Azzollini, J.
Barile, M.
Sawyer, E.
Tomlinson, I.
Kerin, M.
Miller, N.
Hopper, J.L.
Schmidt, D.F.
Makalic, E.
Southey, M.C.
Hwang Teo, S.
Har Yip, C.
Sivanandan, K.
Tay, W.-.
Shen, C.-.
Hsiung, C.-.
Yu, J.-.
Hou, M.-.
Guénel, P.
Truong, T.
Sanchez, M.
Mulot, C.
Blot, W.
Cai, Q.
Nevanlinna, H.
Muranen, T.A.
Aittomäki, K.
Blomqvist, C.
Wu, A.H.
Tseng, C.-.
Van Den Berg, D.
Stram, D.O.
Bogdanova, N.
Dörk, T.
Muir, K.
Lophatananon, A.
Stewart-Brown, S.
Siriwanarangsan, P.
Mannermaa, A.
Kataja, V.
Kosma, V.-.
Hartikainen, J.M.
Shu, X.-.
Lu, W.
Gao, Y.-.
Zhang, B.
Couch, F.J.
Toland, A.E.
TNBCC,
Yannoukakos, D.
Sangrajrang, S.
McKay, J.
Wang, X.
Olson, J.E.
Vachon, C.
Purrington, K.
Severi, G.
Baglietto, L.
Haiman, C.A.
Henderson, B.E.
Schumacher, F.
Le Marchand, L.
Devilee, P.
Tollenaar, R.A.
Seynaeve, C.
Czene, K.
Eriksson, M.
Humphreys, K.
Darabi, H.
Ahmed, S.
Shah, M.
Pharoah, P.D.
Hall, P.
Giles, G.G.
Benítez, J.
Dunning, A.M.
Chenevix-Trench, G.
Easton, D.F.
(2014). Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium. Hum mol genet,
Vol.23
(22),
pp. 6096-6111.
show abstract
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act..
Rosenstein, B.S.
West, C.M.
Bentzen, S.M.
Alsner, J.
Andreassen, C.N.
Azria, D.
Barnett, G.C.
Baumann, M.
Burnet, N.
Chang-Claude, J.
Chuang, E.Y.
Coles, C.E.
Dekker, A.
De Ruyck, K.
De Ruysscher, D.
Drumea, K.
Dunning, A.M.
Easton, D.
Eeles, R.
Fachal, L.
Gutiérrez-Enríquez, S.
Haustermans, K.
Henríquez-Hernández, L.A.
Imai, T.
Jones, G.D.
Kerns, S.L.
Liao, Z.
Onel, K.
Ostrer, H.
Parliament, M.
Pharoah, P.D.
Rebbeck, T.R.
Talbot, C.J.
Thierens, H.
Vega, A.
Witte, J.S.
Wong, P.
Zenhausern, F.
Radiogenomics Consortium,
(2014). Radiogenomics: radiobiology enters the era of big data and team science. Int j radiat oncol biol phys,
Vol.89
(4),
pp. 709-713.
Agarwal, D.
Pineda, S.
Michailidou, K.
Herranz, J.
Pita, G.
Moreno, L.T.
Alonso, M.R.
Dennis, J.
Wang, Q.
Bolla, M.K.
Meyer, K.B.
Menéndez-Rodríguez, P.
Hardisson, D.
Mendiola, M.
González-Neira, A.
Lindblom, A.
Margolin, S.
Swerdlow, A.
Ashworth, A.
Orr, N.
Jones, M.
Matsuo, K.
Ito, H.
Iwata, H.
Kondo, N.
kConFab Investigators,
Australian Ovarian Cancer Study Group,
Hartman, M.
Hui, M.
Lim, W.Y.
Iau, P.T.
Sawyer, E.
Tomlinson, I.
Kerin, M.
Miller, N.
Kang, D.
Choi, J.-.
Park, S.K.
Noh, D.-.
Hopper, J.L.
Schmidt, D.F.
Makalic, E.
Southey, M.C.
Teo, S.H.
Yip, C.H.
Sivanandan, K.
Tay, W.-.
Brauch, H.
Brüning, T.
Hamann, U.
GENICA Network,
Dunning, A.M.
Shah, M.
Andrulis, I.L.
Knight, J.A.
Glendon, G.
Tchatchou, S.
Schmidt, M.K.
Broeks, A.
Rosenberg, E.H.
van't Veer, L.J.
Fasching, P.A.
Renner, S.P.
Ekici, A.B.
Beckmann, M.W.
Shen, C.-.
Hsiung, C.-.
Yu, J.-.
Hou, M.-.
Blot, W.
Cai, Q.
Wu, A.H.
Tseng, C.-.
Van Den Berg, D.
Stram, D.O.
Cox, A.
Brock, I.W.
Reed, M.W.
Muir, K.
Lophatananon, A.
Stewart-Brown, S.
Siriwanarangsan, P.
Zheng, W.
Deming-Halverson, S.
Shrubsole, M.J.
Long, J.
Shu, X.-.
Lu, W.
Gao, Y.-.
Zhang, B.
Radice, P.
Peterlongo, P.
Manoukian, S.
Mariette, F.
Sangrajrang, S.
McKay, J.
Couch, F.J.
Toland, A.E.
TNBCC,
Yannoukakos, D.
Fletcher, O.
Johnson, N.
dos Santos Silva, I.
Peto, J.
Marme, F.
Burwinkel, B.
Guénel, P.
Truong, T.
Sanchez, M.
Mulot, C.
Bojesen, S.E.
Nordestgaard, B.G.
Flyer, H.
Brenner, H.
Dieffenbach, A.K.
Arndt, V.
Stegmaier, C.
Mannermaa, A.
Kataja, V.
Kosma, V.-.
Hartikainen, J.M.
Lambrechts, D.
Yesilyurt, B.T.
Floris, G.
Leunen, K.
Chang-Claude, J.
Rudolph, A.
Seibold, P.
Flesch-Janys, D.
Wang, X.
Olson, J.E.
Vachon, C.
Purrington, K.
Giles, G.G.
Severi, G.
Baglietto, L.
Haiman, C.A.
Henderson, B.E.
Schumacher, F.
Marchand, L.L.
Simard, J.
Dumont, M.
Goldberg, M.S.
Labréche, F.
Winqvist, R.
Pylkäs, K.
Jukkola-Vuorinen, A.
Grip, M.
Devilee, P.
Tollenaar, R.A.
Seynaeve, C.
García-Closas, M.
Chanock, S.J.
Lissowska, J.
Figueroa, J.D.
Czene, K.
Eriksson, M.
Humphreys, K.
Darabi, H.
Hooning, M.J.
Kriege, M.
Collée, J.M.
Tilanus-Linthorst, M.
Li, J.
Jakubowska, A.
Lubinski, J.
Jaworska-Bieniek, K.
Durda, K.
Nevanlinna, H.
Muranen, T.A.
Aittomäki, K.
Blomqvist, C.
Bogdanova, N.
Dörk, T.
Hall, P.
Chenevix-Trench, G.
Easton, D.F.
Pharroah, P.D.
Arias-Perez, J.I.
Zamora, P.
Benítez, J.
Milne, R.L.
(2014). FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium. Br j cancer,
Vol.110
(4),
pp. 1088-1100.
show abstract
BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2..
Leongamornlert, D.
Saunders, E.
Dadaev, T.
Tymrakiewicz, M.
Goh, C.
Jugurnauth-Little, S.
Kozarewa, I.
Fenwick, K.
Assiotis, I.
Barrowdale, D.
Govindasami, K.
Guy, M.
Sawyer, E.
Wilkinson, R.
UKGPCS Collaborators,
Antoniou, A.C.
Eeles, R.
Kote-Jarai, Z.
(2014). Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. Br j cancer,
Vol.110
(6),
pp. 1663-1672.
show abstract
BACKGROUND: Prostate cancer (PrCa) is one of the most common diseases to affect men worldwide and among the leading causes of cancer-related death. The purpose of this study was to use second-generation sequencing technology to assess the frequency of deleterious mutations in 22 tumour suppressor genes in familial PrCa and estimate the relative risk of PrCa if these genes are mutated. METHODS: Germline DNA samples from 191 men with 3 or more cases of PrCa in their family were sequenced for 22 tumour suppressor genes using Agilent target enrichment and Illumina technology. Analysis for genetic variation was carried out by using a pipeline consisting of BWA, Genome Analysis Toolkit (GATK) and ANNOVAR. Clinical features were correlated with mutation status using standard statistical tests. Modified segregation analysis was used to determine the relative risk of PrCa conferred by the putative loss-of-function (LoF) mutations identified. RESULTS: We discovered 14 putative LoF mutations in 191 samples (7.3%) and these mutations were more frequently associated with nodal involvement, metastasis or T4 tumour stage (P=0.00164). Segregation analysis of probands with European ancestry estimated that LoF mutations in any of the studied genes confer a relative risk of PrCa of 1.94 (95% CI: 1.56-2.42). CONCLUSIONS: These findings show that LoF mutations in DNA repair pathway genes predispose to familial PrCa and advanced disease and therefore warrants further investigation. The clinical utility of these findings will become increasingly important as targeted screening and therapies become more widespread..
Spurdle, A.B.
Couch, F.J.
Parsons, M.T.
McGuffog, L.
Barrowdale, D.
Bolla, M.K.
Wang, Q.
Healey, S.
Schmutzler, R.
Wappenschmidt, B.
Rhiem, K.
Hahnen, E.
Engel, C.
Meindl, A.
Ditsch, N.
Arnold, N.
Plendl, H.
Niederacher, D.
Sutter, C.
Wang-Gohrke, S.
Steinemann, D.
Preisler-Adams, S.
Kast, K.
Varon-Mateeva, R.
Ellis, S.
Frost, D.
Platte, R.
Perkins, J.
Evans, D.G.
Izatt, L.
Eeles, R.
Adlard, J.
Davidson, R.
Cole, T.
Scuvera, G.
Manoukian, S.
Bonanni, B.
Mariette, F.
Fortuzzi, S.
Viel, A.
Pasini, B.
Papi, L.
Varesco, L.
Balleine, R.
Nathanson, K.L.
Domchek, S.M.
Offitt, K.
Jakubowska, A.
Lindor, N.
Thomassen, M.
Jensen, U.B.
Rantala, J.
Borg, Å.
Andrulis, I.L.
Miron, A.
Hansen, T.V.
Caldes, T.
Neuhausen, S.L.
Toland, A.E.
Nevanlinna, H.
Montagna, M.
Garber, J.
Godwin, A.K.
Osorio, A.
Factor, R.E.
Terry, M.B.
Rebbeck, T.R.
Karlan, B.Y.
Southey, M.
Rashid, M.U.
Tung, N.
Pharoah, P.D.
Blows, F.M.
Dunning, A.M.
Provenzano, E.
Hall, P.
Czene, K.
Schmidt, M.K.
Broeks, A.
Cornelissen, S.
Verhoef, S.
Fasching, P.A.
Beckmann, M.W.
Ekici, A.B.
Slamon, D.J.
Bojesen, S.E.
Nordestgaard, B.G.
Nielsen, S.F.
Flyger, H.
Chang-Claude, J.
Flesch-Janys, D.
Rudolph, A.
Seibold, P.
Aittomäki, K.
Muranen, T.A.
Heikkilä, P.
Blomqvist, C.
Figueroa, J.
Chanock, S.J.
Brinton, L.
Lissowska, J.
Olson, J.E.
Pankratz, V.S.
John, E.M.
Whittemore, A.S.
West, D.W.
Hamann, U.
Torres, D.
Ulmer, H.U.
Rüdiger, T.
Devilee, P.
Tollenaar, R.A.
Seynaeve, C.
Van Asperen, C.J.
Eccles, D.M.
Tapper, W.J.
Durcan, L.
Jones, L.
Peto, J.
dos-Santos-Silva, I.
Fletcher, O.
Johnson, N.
Dwek, M.
Swann, R.
Bane, A.L.
Glendon, G.
Mulligan, A.M.
Giles, G.G.
Milne, R.L.
Baglietto, L.
McLean, C.
Carpenter, J.
Clarke, C.
Scott, R.
Brauch, H.
Brüning, T.
Ko, Y.-.
Cox, A.
Cross, S.S.
Reed, M.W.
Lubinski, J.
Jaworska-Bieniek, K.
Durda, K.
Gronwald, J.
Dörk, T.
Bogdanova, N.
Park-Simon, T.-.
Hillemanns, P.
Haiman, C.A.
Henderson, B.E.
Schumacher, F.
Le Marchand, L.
Burwinkel, B.
Marme, F.
Surovy, H.
Yang, R.
Anton-Culver, H.
Ziogas, A.
Hooning, M.J.
Collée, J.M.
Martens, J.W.
Tilanus-Linthorst, M.M.
Brenner, H.
Dieffenbach, A.K.
Arndt, V.
Stegmaier, C.
Winqvist, R.
Pylkäs, K.
Jukkola-Vuorinen, A.
Grip, M.
Lindblom, A.
Margolin, S.
Joseph, V.
Robson, M.
Rau-Murthy, R.
González-Neira, A.
Arias, J.I.
Zamora, P.
Benítez, J.
Mannermaa, A.
Kataja, V.
Kosma, V.-.
Hartikainen, J.M.
Peterlongo, P.
Zaffaroni, D.
Barile, M.
Capra, F.
Radice, P.
Teo, S.H.
Easton, D.F.
Antoniou, A.C.
Chenevix-Trench, G.
Goldgar, D.E.
ABCTB Investigators,
EMBRACE Group,
GENICA Network,
HEBON Group,
kConFab Investigators,
(2014). Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia. Breast cancer res,
Vol.16
(6),
p. 3419.
show abstract
full text
INTRODUCTION: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. METHODS: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. RESULTS: ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). CONCLUSIONS: These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management..
Kuchenbaecker, K.B.
Neuhausen, S.L.
Robson, M.
Barrowdale, D.
McGuffog, L.
Mulligan, A.M.
Andrulis, I.L.
Spurdle, A.B.
Schmidt, M.K.
Schmutzler, R.K.
Engel, C.
Wappenschmidt, B.
Nevanlinna, H.
Thomassen, M.
Southey, M.
Radice, P.
Ramus, S.J.
Domchek, S.M.
Nathanson, K.L.
Lee, A.
Healey, S.
Nussbaum, R.L.
Rebbeck, T.R.
Arun, B.K.
James, P.
Karlan, B.Y.
Lester, J.
Cass, I.
Breast Cancer Family Registry,
Terry, M.B.
Daly, M.B.
Goldgar, D.E.
Buys, S.S.
Janavicius, R.
Tihomirova, L.
Tung, N.
Dorfling, C.M.
van Rensburg, E.J.
Steele, L.
v O Hansen, T.
Ejlertsen, B.
Gerdes, A.-.
Nielsen, F.C.
Dennis, J.
Cunningham, J.
Hart, S.
Slager, S.
Osorio, A.
Benitez, J.
Duran, M.
Weitzel, J.N.
Tafur, I.
Hander, M.
Peterlongo, P.
Manoukian, S.
Peissel, B.
Roversi, G.
Scuvera, G.
Bonanni, B.
Mariani, P.
Volorio, S.
Dolcetti, R.
Varesco, L.
Papi, L.
Tibiletti, M.G.
Giannini, G.
Fostira, F.
Konstantopoulou, I.
Garber, J.
Hamann, U.
Donaldson, A.
Brewer, C.
Foo, C.
Evans, D.G.
Frost, D.
Eccles, D.
EMBRACE Study,
Douglas, F.
Brady, A.
Cook, J.
Tischkowitz, M.
Adlard, J.
Barwell, J.
Ong, K.-.
Walker, L.
Izatt, L.
Side, L.E.
Kennedy, M.J.
Rogers, M.T.
Porteous, M.E.
Morrison, P.J.
Platte, R.
Eeles, R.
Davidson, R.
Hodgson, S.
Ellis, S.
Godwin, A.K.
Rhiem, K.
Meindl, A.
Ditsch, N.
Arnold, N.
Plendl, H.
Niederacher, D.
Sutter, C.
Steinemann, D.
Bogdanova-Markov, N.
Kast, K.
Varon-Mateeva, R.
Wang-Gohrke, S.
Gehrig, A.
Markiefka, B.
Buecher, B.
Lefol, C.
Stoppa-Lyonnet, D.
Rouleau, E.
Prieur, F.
Damiola, F.
GEMO Study Collaborators,
Barjhoux, L.
Faivre, L.
Longy, M.
Sevenet, N.
Sinilnikova, O.M.
Mazoyer, S.
Bonadona, V.
Caux-Moncoutier, V.
Isaacs, C.
Van Maerken, T.
Claes, K.
Piedmonte, M.
Andrews, L.
Hays, J.
Rodriguez, G.C.
Caldes, T.
de la Hoya, M.
Khan, S.
Hogervorst, F.B.
Aalfs, C.M.
de Lange, J.L.
Meijers-Heijboer, H.E.
van der Hout, A.H.
Wijnen, J.T.
van Roozendaal, K.E.
Mensenkamp, A.R.
van den Ouweland, A.M.
van Deurzen, C.H.
van der Luijt, R.B.
HEBON,
Olah, E.
Diez, O.
Lazaro, C.
Blanco, I.
Teulé, A.
Menendez, M.
Jakubowska, A.
Lubinski, J.
Cybulski, C.
Gronwald, J.
Jaworska-Bieniek, K.
Durda, K.
Arason, A.
Maugard, C.
Soucy, P.
Montagna, M.
Agata, S.
Teixeira, M.R.
KConFab Investigators,
Olswold, C.
Lindor, N.
Pankratz, V.S.
Hallberg, E.
Wang, X.
Szabo, C.I.
Vijai, J.
Jacobs, L.
Corines, M.
Lincoln, A.
Berger, A.
Fink-Retter, A.
Singer, C.F.
Rappaport, C.
Kaulich, D.G.
Pfeiler, G.
Tea, M.-.
Phelan, C.M.
Mai, P.L.
Greene, M.H.
Rennert, G.
Imyanitov, E.N.
Glendon, G.
Toland, A.E.
Bojesen, A.
Pedersen, I.S.
Jensen, U.B.
Caligo, M.A.
Friedman, E.
Berger, R.
Laitman, Y.
Rantala, J.
Arver, B.
Loman, N.
Borg, A.
Ehrencrona, H.
Olopade, O.I.
Simard, J.
Easton, D.F.
Chenevix-Trench, G.
Offit, K.
Couch, F.J.
Antoniou, A.C.
CIMBA,
(2014). Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers. Breast cancer res,
Vol.16
(6),
p. 3416.
show abstract
INTRODUCTION: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. METHODS: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. RESULTS: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. CONCLUSIONS: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction..
Goh, C.L.
Eeles, R.A.
(2014). Germline genetic variants associated with prostate cancer and potential relevance to clinical practice. Recent results cancer res,
Vol.202,
pp. 9-26.
show abstract
The inherited link of prostate cancer predisposition has been supported using data from early epidemiological studies, as well as from familial and twin studies. Early linkage analyses and candidate gene approaches to identify these variants yielded mixed results. Since then, multiple genetic variants associated with prostate cancer susceptibility have now been found from genome-wide association studies (GWAS). Their clinical utility, however, remains unknown. It is recognised that collaborative efforts are needed to ensure adequate sample sizes are available to definitively investigate the genetic-clinical interactions. These could have important implications for public health as well as individualised prostate cancer management strategies. With the costs of genotyping decreasing and direct-to-consumer testing already offered for these common variants, it is envisaged that a lot of attention will be focussed in this area. These results will enable more refined risk stratification which will be important for targeting screening and prevention to higher risk groups. Ascertaining their clinical role remains an important goal for the GWAS community with international consortia now established, pooling efforts and resources to move this field forward..
deSouza, N.M.
Morgan, V.A.
Bancroft, E.
Sohaib, S.A.
Giles, S.L.
Kote-Jarai, Z.
Castro, E.
Hazell, S.
Jafar, M.
Eeles, R.
(2014). Diffusion-weighted MRI for detecting prostate tumour in men at increased genetic risk. Eur j radiol open,
Vol.1,
pp. 22-27.
show abstract
full text
BACKGROUND: Diffusion-weighted (DW)-MRI is invaluable in detecting prostate cancer. We determined its sensitivity and specificity and established interobserver agreement for detecting tumour in men with a family history of prostate cancer stratified by genetic risk. METHODS: 51 men with a family history of prostate cancer underwent T2-W + DW-endorectal MRI at 3.0 T. Presence of tumour was noted at right and left apex, mid and basal prostate sextants by 2 independent observers, 1 experienced and the other inexperienced in endorectal MRI. Sensitivity and specificity against a 10-core sampling technique (lateral and medial cores at each level considered together) in men with >2× population risk based on 71 SNP analysis versus those with lower genetic risk scores was established. Interobserver agreement was determined at a subject level. RESULTS: Biopsies indicated cancer in 28 sextants in 13/51 men; 32 of 51 men had twice the population risk (>0.25) based on 71 SNP profiling. Sensitivity/specificity per-subject for patients was 90.0%/86.4% (high-risk) vs. 66.7%/100% (low-risk, observer 1) and 60.0%/86.3% (high-risk) vs. 33.3%/93.8% (low-risk, observer 2) with moderate overall inter-observer agreement (kappa = 0.42). Regional sensitivities/specificities for high-risk vs. low-risk for observer 1 apex 72.2%/100% [33.3%/100%], mid 100%/93.1% [100%/97.3%], base 16.7%/98.3% [0%/100%] and for observer 2 apex 36.4%/98.1% [0%/100%], mid 28.6%/96.5% [100%/100%], base 20%/100% [0%/97.3%] were poorer as they failed to detect multiple lesions. CONCLUSION: Endorectal T2W + DW-MRI at 3.0 T yields high sensitivity and specificity for tumour detection by an experienced observer in screening men with a family history of prostate cancer and increased genetic risk..
Mikropoulos, C.
Goh, C.
Leongamornlert, D.
Kote-Jarai, Z.
Eeles, R.
(2014). Translating genetic risk factors for prostate cancer to the clinic: 2013 and beyond. Future oncol,
Vol.10
(9),
pp. 1679-1694.
show abstract
Prostate cancer (PrCa) is the most commonly diagnosed cancer in the male UK population, with over 40,000 new cases per year. PrCa has a complex, polygenic predisposition, due to rare variants such as BRCA and common variants such as single nucleotide polymorphisms (SNPs). With the introduction of genome-wide association studies, 78 susceptibility loci (SNPs) associated with PrCa risk have been identified. Genetic profiling could risk-stratify a population, leading to the discovery of a higher proportion of clinically significant disease and a reduction in the morbidity related to age-based prostate-specific antigen screening. Based on the combined risk of the 78 SNPs identified so far, the top 1% of the risk distribution has a 4.7-times higher risk of developing PrCa compared with the average of the general population..
Weng, P.-.
Huang, Y.-.
Page, J.H.
Chen, J.-.
Xu, J.
Koutros, S.
Berndt, S.
Chanock, S.
Yeager, M.
Witte, J.S.
Eeles, R.A.
Easton, D.F.
Neal, D.E.
Donovan, J.
Hamdy, F.C.
Muir, K.R.
Giles, G.
Severi, G.
Smith, J.R.
Balistreri, C.R.
Shui, I.M.
Chen, Y.-.
(2014). Polymorphisms of an innate immune gene, toll-like receptor 4, and aggressive prostate cancer risk: a systematic review and meta-analysis. Plos one,
Vol.9
(10),
p. e110569.
show abstract
BACKGROUND: Toll-like receptor 4 (TLR4) is one of the best known TLR members expressed on the surface of several leukocytes and tissue cells and has a key function in detecting pathogen and danger-associated molecular patterns. The role of TLR4 in the pathophysiology of several age-related diseases is also well recognized, such as prostate cancer (PCa). TLR4 polymorphisms have been related to PCa risk, but the relationship between TLR4 genotypes and aggressive PCa risk has not been evaluated by any systematic reviews. METHODS: We performed a systematic review and meta-analysis of candidate-gene and genome-wide association studies analyzing this relationship and included only white population. Considering appropriate criteria, only nine studies were analyzed in the meta-analysis, including 3,937 aggressive PCa and 7,382 controls. RESULTS: Using random effects model, no significant association was found in the ten TLR4 SNPs reported by at least four included studies under any inheritance model (rs2737191, rs1927914, rs10759932, rs1927911, rs11536879, rs2149356, rs4986790, rs11536889, rs7873784, and rs1554973). Pooled estimates from another ten TLR4 SNPs reported by three studies also showed no significant association (rs10759930, rs10116253, rs11536869, rs5030717, rs4986791, rs11536897, rs1927906, rs913930, rs1927905, and rs7045953). Meta-regression revealed that study type was not a significant source of between-study heterogeneity. CONCLUSIONS: TLR4 polymorphisms were not significantly associated with the risk of aggressive PCa..
Killick, E.
Tymrakiewicz, M.
Cieza-Borrella, C.
Smith, P.
Thompson, D.J.
Pooley, K.A.
Easton, D.F.
Bancroft, E.
Page, E.
Leongamornlert, D.
IMPACT collaborators,
Kote-Jarai, Z.
Eeles, R.A.
(2014). Telomere length shows no association with BRCA1 and BRCA2 mutation status. Plos one,
Vol.9
(1),
p. e86659.
show abstract
This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy at time of enrollment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrollment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL..
Tree, A.C.
Khoo, V.S.
Eeles, R.A.
Ahmed, M.
Dearnaley, D.P.
Hawkins, M.A.
Huddart, R.A.
Nutting, C.M.
Ostler, P.J.
van As, N.J.
(2013). Stereotactic body radiotherapy for oligometastases. Lancet oncol,
Vol.14
(1),
pp. e28-e37.
show abstract
The management of metastatic solid tumours has historically focused on systemic treatment given with palliative intent. However, radical surgical treatment of oligometastases is now common practice in some settings. The development of stereotactic body radiotherapy (SBRT), building on improvements in delivery achieved by intensity-modulated and image-guided radiotherapy, now allows delivery of ablative doses of radiation to extracranial sites. Many non-randomised studies have shown that SBRT for oligometastases is safe and effective, with local control rates of about 80%. Importantly, these studies also suggest that the natural history of the disease is changing, with 2-5 year progression-free survival of about 20%. Although complete cure might be possible in a few patients with oligometastases, the aim of SBRT in this setting is to achieve local control and delay progression, and thereby also postpone the need for further treatment. We review published work showing that SBRT offers durable local control and the potential for progression-free survival in non-liver, non-lung oligometastatic disease at a range of sites. However, to test whether SBRT really does improve progression-free survival, randomised trials will be essential..
Tilanus-Linthorst, M.M.
Lingsma, H.F.
Evans, D.G.
Thompson, D.
Kaas, R.
Manders, P.
van Asperen, C.J.
Adank, M.
Hooning, M.J.
Lim, G.E.
Eeles, R.
Oosterwijk, J.C.
Leach, M.O.
Steyerberg, E.W.
(2013). Optimal age to start preventive measures in women with BRCA1/2 mutations or high familial breast cancer risk. International journal of cancer,
Vol.133
(1),
pp. 156-163.
Donnelly, L.
Watson, M.
Moynihan, C.
Bancroft, E.
Evans, D.G.
Eeles, R.
Lavery, S.
Ormondroyd, E.
(2013). Reproductive decision-making in young female carriers of a BRCA mutation. Human reproduction,
Vol.0,
pp. 1-7.
Copson, E.
Eccles, B.
Maishman, T.
Gerty, S.
Stanton, L.
Cutress, R.I.
Altman, D.G.
Durcan, L.
Simmonds, P.
Lawrence, G.
Jones, L.
Bliss, J.
Eccles, D.
POSH Study Steering Group,
(2013). Prospective observational study of breast cancer treatment outcomes for UK women aged 18-40 years at diagnosis: the POSH study. J natl cancer inst,
Vol.105
(13),
pp. 978-988.
show abstract
BACKGROUND: Breast cancer at a young age is associated with poor prognosis. The Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH) was designed to investigate factors affecting prognosis in this patient group. METHODS: Between 2000 and 2008, 2956 patients aged 40 years or younger were recruited to a UK multicenter prospective observational cohort study (POSH). Details of tumor pathology, disease stage, treatment received, and outcome were recorded. Overall survival (OS) and distant disease-free interval (DDFI) were assessed using Kaplan-Meier curves. All statistical tests were two-sided. RESULTS: Median age of patients was 36 years. Median tumor diameter was 22 mm, and 50% of patients had positive lymph nodes; 59% of tumors were grade 3, 33.7% were estrogen receptor (ER) negative, and 24% were human epidermal growth factor receptor 2 (HER2) positive. Five-year OS was higher for patients with ER-positive than ER-negative tumors (85.0%, 95% confidence interval [CI] = 83.2% to 86.7% vs 75.7%, 95% CI = 72.8% to 78.4%; P < .001), but by eight years, survival was almost equal. The eight-year OS of patients with ER-positive tumors was similar to that of patients with ER-negative tumors in both HER2-positive and HER2-negative subgroups. The flexible parametric survival model for OS shows that the risk of death increases steadily over time for patients with ER-positive tumors in contrast to patients with ER-negative tumors, where risk of death peaked at two years. CONCLUSIONS: These results confirm the increased frequency of ER-negative tumors and early relapse in young patients and also demonstrate the equally poor longer-term outlook of young patients who have ER-positive tumors with HER2-negative or -positive disease..
Couch, F.J.
Wang, X.
McGuffog, L.
Lee, A.
Olswold, C.
Kuchenbaecker, K.B.
Soucy, P.
Fredericksen, Z.
Barrowdale, D.
Dennis, J.
Gaudet, M.M.
Dicks, E.
Kosel, M.
Healey, S.
Sinilnikova, O.M.
Lee, A.
Bacot, F.
Vincent, D.
Hogervorst, F.B.
Peock, S.
Stoppa-Lyonnet, D.
Jakubowska, A.
Radice, P.
Schmutzler, R.K.
Domchek, S.M.
Piedmonte, M.
Singer, C.F.
Friedman, E.
Thomassen, M.
Hansen, T.V.
Neuhausen, S.L.
Szabo, C.I.
Blanco, I.
Greene, M.H.
Karlan, B.Y.
Garber, J.
Phelan, C.M.
Weitzel, J.N.
Montagna, M.
Olah, E.
Andrulis, I.L.
Godwin, A.K.
Yannoukakos, D.
Goldgar, D.E.
Caldes, T.
Nevanlinna, H.
Osorio, A.
Terry, M.B.
Daly, M.B.
van Rensburg, E.J.
Hamann, U.
Ramus, S.J.
Toland, A.E.
Caligo, M.A.
Olopade, O.I.
Tung, N.
Claes, K.
Beattie, M.S.
Southey, M.C.
Imyanitov, E.N.
Tischkowitz, M.
Janavicius, R.
John, E.M.
Kwong, A.
Diez, O.
Balmana, J.
Barkardottir, R.B.
Arun, B.K.
Rennert, G.
Teo, S.-.
Ganz, P.A.
Campbell, I.
van der Hout, A.H.
van Deurzen, C.H.
Seynaeve, C.
Garcia, E.B.
van Leeuwen, F.E.
Meijers-Heijboer, H.E.
Gille, J.J.
Ausems, M.G.
Blok, M.J.
Ligtenberg, M.J.
Rookus, M.A.
Devilee, P.
Verhoef, S.
van Os, T.A.
Wijnen, J.T.
Frost, D.
Ellis, S.
Fineberg, E.
Platte, R.
Evans, D.G.
Izatt, L.
Eeles, R.A.
Adlard, J.
Eccles, D.M.
Cook, J.
Brewer, C.
Douglas, F.
Hodgson, S.
Morrison, P.J.
Side, L.E.
Donaldson, A.
Houghton, C.
Rogers, M.T.
Dorkins, H.
Eason, J.
Gregory, H.
McCann, E.
Murray, A.
Calender, A.
Hardouin, A.
Berthet, P.
Delnatte, C.
Nogues, C.
Lasset, C.
Houdayer, C.
Leroux, D.
Rouleau, E.
Prieur, F.
Damiola, F.
Sobol, H.
Coupier, I.
Venat-Bouvet, L.
Castera, L.
Gauthier-Villars, M.
Leone, M.
Pujol, P.
Mazoyer, S.
Bignon, Y.-.
Zlowocka-Perlowska, E.
Gronwald, J.
Lubinski, J.
Durda, K.
Jaworska, K.
Huzarski, T.
Spurdle, A.B.
Viel, A.
Peissel, B.
Bonanni, B.
Melloni, G.
Ottini, L.
Papi, L.
Varesco, L.
Tibiletti, M.G.
Peterlongo, P.
Volorio, S.
Manoukian, S.
Pensotti, V.
Arnold, N.
Engel, C.
Deissler, H.
Gadzicki, D.
Gehrig, A.
Kast, K.
Rhiem, K.
Meindl, A.
Niederacher, D.
Ditsch, N.
Plendl, H.
Preisler-Adams, S.
Engert, S.
Sutter, C.
Varon-Mateeva, R.
Wappenschmidt, B.
Weber, B.H.
Arver, B.
Stenmark-Askmalm, M.
Loman, N.
Rosenquist, R.
Einbeigi, Z.
Nathanson, K.L.
Rebbeck, T.R.
Blank, S.V.
Cohn, D.E.
Rodriguez, G.C.
Small, L.
Friedlander, M.
Bae-Jump, V.L.
Fink-Retter, A.
Rappaport, C.
Gschwantler-Kaulich, D.
Pfeiler, G.
Tea, M.-.
Lindor, N.M.
Kaufman, B.
Paluch, S.S.
Laitman, Y.
Skytte, A.-.
Gerdes, A.-.
Pedersen, I.S.
Moeller, S.T.
Kruse, T.A.
Jensen, U.B.
Vijai, J.
Sarrel, K.
Robson, M.
Kauff, N.
Mulligan, A.M.
Glendon, G.
Ozcelik, H.
Ejlertsen, B.
Nielsen, F.C.
Jonson, L.
Andersen, M.K.
Ding, Y.C.
Steele, L.
Foretova, L.
Teule, A.
Lazaro, C.
Brunet, J.
Angel Pujana, M.
Mai, P.L.
Loud, J.T.
Walsh, C.
Lester, J.
Orsulic, S.
Narod, S.A.
Herzog, J.
Sand, S.R.
Tognazzo, S.
Agata, S.
Vaszko, T.
Weaver, J.
Stavropoulou, A.V.
Buys, S.S.
Romero, A.
de la Hoya, M.
Aittomaki, K.
Muranen, T.A.
Duran, M.
Chung, W.K.
Lasa, A.
Dorfling, C.M.
Miron, A.
Benitez, J.
Senter, L.
Huo, D.
Chan, S.B.
Sokolenko, A.P.
Chiquette, J.
Tihomirova, L.
Friebel, T.M.
Agnarsson, B.A.
Lu, K.H.
Lejbkowicz, F.
James, P.A.
Hall, P.
Dunning, A.M.
Tessier, D.
Cunningham, J.
Slager, S.L.
Wang, C.
Hart, S.
Stevens, K.
Simard, J.
Pastinen, T.
Pankratz, V.S.
Offit, K.
Easton, D.F.
Chenevix-Trench, G.
Antoniou, A.C.
Investigators, K.
SWE-BRCA,
Network, O.C.
HEBON,
EMBRACE,
Collaborators, G.E.
BCFR,
CIMBA,
(2013). Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk. Plos genetics,
Vol.9
(3).
Eeles, R.A.
Olama, A.A.
Benlloch, S.
Saunders, E.J.
Leongamornlert, D.A.
Tymrakiewicz, M.
Ghoussaini, M.
Luccarini, C.
Dennis, J.
Jugurnauth-Little, S.
Dadaev, T.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Muir, K.
Giles, G.G.
Severi, G.
Wiklund, F.
Gronberg, H.
Haiman, C.A.
Schumacher, F.
Henderson, B.E.
Le Marchand, L.
Lindstrom, S.
Kraft, P.
Hunter, D.J.
Gapstur, S.
Chanock, S.J.
Berndt, S.I.
Albanes, D.
Andriole, G.
Schleutker, J.
Weischer, M.
Canzian, F.
Riboli, E.
Key, T.J.
Travis, R.C.
Campa, D.
Ingles, S.A.
John, E.M.
Hayes, R.B.
Pharoah, P.D.
Pashayan, N.
Khaw, K.-.
Stanford, J.L.
Ostrander, E.A.
Signorello, L.B.
Thibodeau, S.N.
Schaid, D.
Maier, C.
Vogel, W.
Kibel, A.S.
Cybulski, C.
Lubinski, J.
Cannon-Albright, L.
Brenner, H.
Park, J.Y.
Kaneva, R.
Batra, J.
Spurdle, A.B.
Clements, J.A.
Teixeira, M.R.
Dicks, E.
Lee, A.
Dunning, A.M.
Baynes, C.
Conroy, D.
Maranian, M.J.
Ahmed, S.
Govindasami, K.
Guy, M.
Wilkinson, R.A.
Sawyer, E.J.
Morgan, A.
Dearnaley, D.P.
Horwich, A.
Huddart, R.A.
Khoo, V.S.
Parker, C.C.
Van As, N.J.
Woodhouse, C.J.
Thompson, A.
Dudderidge, T.
Ogden, C.
Cooper, C.S.
Lophatananon, A.
Cox, A.
Southey, M.C.
Hopper, J.L.
English, D.R.
Aly, M.
Adolfsson, J.
Xu, J.
Zheng, S.L.
Yeager, M.
Kaaks, R.
Diver, W.R.
Gaudet, M.M.
Stern, M.C.
Corral, R.
Joshi, A.D.
Shahabi, A.
Wahlfors, T.
Tammela, T.L.
Auvinen, A.
Virtamo, J.
Klarskov, P.
Nordestgaard, B.G.
Røder, M.A.
Nielsen, S.F.
Bojesen, S.E.
Siddiq, A.
Fitzgerald, L.M.
Kolb, S.
Kwon, E.M.
Karyadi, D.M.
Blot, W.J.
Zheng, W.
Cai, Q.
McDonnell, S.K.
Rinckleb, A.E.
Drake, B.
Colditz, G.
Wokolorczyk, D.
Stephenson, R.A.
Teerlink, C.
Muller, H.
Rothenbacher, D.
Sellers, T.A.
Lin, H.-.
Slavov, C.
Mitev, V.
Lose, F.
Srinivasan, S.
Maia, S.
Paulo, P.
Lange, E.
Cooney, K.A.
Antoniou, A.C.
Vincent, D.
Bacot, F.
Tessier, D.C.
COGS–Cancer Research UK GWAS–ELLIPSE (part of GAME-ON) Initiative,
Australian Prostate Cancer Bioresource,
UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology,
UK ProtecT (Prostate testing for cancer and Treatment) Study Collaborators,
PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium,
Kote-Jarai, Z.
Easton, D.F.
(2013). Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat genet,
Vol.45
(4),
pp. 385-391e2.
show abstract
Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies..
Mavaddat, N.
Peock, S.
Frost, D.
Ellis, S.
Platte, R.
Fineberg, E.
Evans, D.G.
Izatt, L.
Eeles, R.A.
Adlard, J.
Davidson, R.
Eccles, D.
Cole, T.
Cook, J.
Brewer, C.
Tischkowitz, M.
Douglas, F.
Hodgson, S.
Walker, L.
Porteous, M.E.
Morrison, P.J.
Side, L.E.
Kennedy, M.J.
Houghton, C.
Donaldson, A.
Rogers, M.T.
Dorkins, H.
Miedzybrodzka, Z.
Gregory, H.
Eason, J.
Barwell, J.
McCann, E.
Murray, A.
Antoniou, A.C.
Easton, D.F.
EMBRACE,
(2013). Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J natl cancer inst,
Vol.105
(11),
pp. 812-822.
show abstract
BACKGROUND: Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles. METHODS: Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided. RESULTS: The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02). CONCLUSIONS: Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers..
Creak, A.
Hall, E.
Horwich, A.
Eeles, R.
Khoo, V.
Huddart, R.
Parker, C.
Griffin, C.
Bidmead, M.
Warrington, J.
Dearnaley, D.
(2013). Randomised pilot study of dose escalation using conformal radiotherapy in prostate cancer: long-term follow-up. Br j cancer,
Vol.109
(3),
pp. 651-657.
show abstract
BACKGROUND: Radical three-dimensional conformal radiotherapy (CFRT) with initial androgen suppression (AS) is a standard management for localised prostate cancer (PC). This pilot study evaluated the role of dose escalation and appropriate target volume margin. Here, we report long-term follow-up. METHODS: Eligible patients had T1b-T3b N0 M0 PC. After neoadjuvant AS, they were randomised to CFRT, giving (a) 64 Gy with either a 1.0- or 1.5-cm margin and (b) ±10 Gy boost to the prostate alone. RESULTS: One hundred and twenty-six men were randomised and treated. Median follow-up was 13.7 years. The median age was 66.6 years at randomisation. Median presenting prostate-specific antigen (PSA) was 14 ng ml(-1). Sixty-four out of 126 patients developed PSA failure. Forty-nine out of 126 patients restarted AS, 34 out of 126 developed metastases and 28 out of 126 developed castrate-resistant prostate cancer (CRPC). Fifty-one out of 126 patients died; 19 out of 51 died of PC. Median overall survival (OS) was 14.4 years. Although escalated dose results were favourable, no statistically significant differences were seen between the randomised groups; PSA control (hazard ratio (HR): 0.77 (95% confidence interval (CI): 0.47-1.26)), development of CRPC (HR: 0.81 (95% CI: 0.40-1.65)), PC-specific survival (HR: 0.59 (95% CI:0.23-1.49)) and OS (HR: 0.81 (95% CI: 0.47-1.40)). There was no evidence of a difference in PSA control according to margin size (HR: 1.01 (95% CI: 0.61-1.66)). INTERPRETATION: Long-term follow-up of this small pilot study is compatible with a benefit from dose escalation, but confirmation from larger trials is required. There was no obvious detriment using the smaller radiotherapy margin..
Orozco, G.
Goh, C.L.
Al Olama, A.A.
Benlloch-Garcia, S.
Govindasami, K.
Guy, M.
Muir, K.R.
Giles, G.G.
Severi, G.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Kote-Jarai, Z.
Easton, D.F.
Eyre, S.
Eeles, R.A.
(2013). Common genetic variants associated with disease from genome-wide association studies are mutually exclusive in prostate cancer and rheumatoid arthritis. Bju int,
Vol.111
(7),
pp. 1148-1155.
show abstract
full text
UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The link between inflammation and cancer has long been reported and inflammation is thought to play a role in the pathogenesis of many cancers, including prostate cancer (PrCa). Over the last 5 years, genome-wide association studies (GWAS) have reported numerous susceptibility loci that predispose individuals to many different traits. The present study aims to ascertain if there are common genetic risk profiles that might predispose individuals to both PrCa and the autoimmune inflammatory condition, rheumatoid arthritis. These results could have potential public heath impact in terms of screening and chemoprevention. OBJECTIVES: To investigate if potential common pathways exist for the pathogenesis of autoimmune disease and prostate cancer (PrCa). To ascertain if the single nucleotide polymorphisms (SNPs) reported by genome-wide association studies (GWAS) as being associated with susceptibility to PrCa are also associated with susceptibility to the autoimmune disease rheumatoid arthritis (RA). MATERIALS AND METHODS: The original Wellcome Trust Case Control Consortium (WTCCC) UK RA GWAS study was expanded to include a total of 3221 cases and 5272 controls. In all, 37 germline autosomal SNPs at genome-wide significance associated with PrCa risk were identified from a UK/Australian PrCa GWAS. Allele frequencies were compared for these 37 SNPs between RA cases and controls using a chi-squared trend test and corrected for multiple testing (Bonferroni). RESULTS: In all, 33 SNPs were able to be analysed in the RA dataset. Proxies could not be located for the SNPs in 3q26, 5p15 and for two SNPs in 17q12. After applying a Bonferroni correction for the number of SNPs tested, the SNP mapping to CCHCR1 (rs130067) retained statistically significant evidence for association (P = 6 × 10(-4) ; odds ratio [OR] = 1.15, 95% CI: 1.06-1.24); this has also been associated with psoriasis. However, further analyses showed that the association of this allele was due to confounding by RA-associated HLA-DRB1 alleles. CONCLUSIONS: There is currently no evidence that SNPs associated with PrCa at genome-wide significance are associated with the development of RA. Studies like this are important in determining if common genetic risk profiles might predispose individuals to many diseases, which could have implications for public health in terms of screening and chemoprevention..
(2013). Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression. Human molecular genetics,
Vol.22
(20),
pp. 4239-4239.
Lose, F.
Batra, J.
O'Mara, T.
Fahey, P.
Marquart, L.
Eeles, R.A.
Easton, D.F.
Al Olama, A.A.
Kote-Jarai, Z.
Guy, M.
Muir, K.
Lophatananon, A.
Rahman, A.A.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Chambers, S.
Gardiner, R.A.
Aitken, J.F.
Yaxley, J.
Alexander, K.
Clements, J.A.
Spurdle, A.B.
Kedda, M.-.
Australian Prostate Cancer BioResource,
(2013). Common variation in Kallikrein genes KLK5, KLK6, KLK12, and KLK13 and risk of prostate cancer and tumor aggressiveness. Urol oncol,
Vol.31
(5),
pp. 635-643.
show abstract
The human tissue Kallikrein family consists of 15 genes with the majority shown to be differentially expressed in cancers and/or indicators of cancer prognosis. We sought to elucidate the role of common genetic variation in four of the Kallikrein genes, KLK5, KLK6, KLK12, and KLK13, in prostate cancer risk and tumor aggressiveness. Genotyping of all 22 tagging single nucleotide polymorphisms (tagSNPs) in the KLK5, KLK6, KLK12, and KLK13 genes was performed in approximately 1,000 prostate cancer cases and 1,300 male controls from Australia. Data from any positive results were also accessed for 1,844 cases and 1,886 controls from a previously published prostate cancer genome-wide association study set from the United Kingdom. For one SNP in KLK12, rs3865443, there was evidence for association with prostate cancer risk of similar direction and magnitude in the replication set to that seen in the Australian cohort. We conducted genotyping of a further 309 prostate cancer cases, and combined analyses revealed an increased risk of prostate cancer for carriers of the rare homozygous genotype for rs3865443 (OR 1.28, 95% CI 1.04-1.57; P = 0.018). No other tagSNPs in the KLK5, KLK6, and KLK13 genes were consistently associated with prostate cancer risk or tumor aggressiveness. Analysis of a combined sample of 3,153 cases and 3,199 controls revealed the KLK12 tagSNP rs3865443 to be marginally statistically significantly associated with risk of prostate cancer. Considering the total number of SNPs investigated in this study, this finding should be interpreted cautiously and requires additional validation from very large datasets such as those of the Prostate Cancer Association group to investigate cancer associated alterations (PRACTICAL) Consortium..
Yu, O.H.
Foulkes, W.D.
Dastani, Z.
Martin, R.M.
Eeles, R.
PRACTICAL Consortium,
CRUK GWAS Investigators,
Richards, J.B.
(2013). An assessment of the shared allelic architecture between type II diabetes and prostate cancer. Cancer epidemiol biomarkers prev,
Vol.22
(8),
pp. 1473-1475.
show abstract
BACKGROUND: To determine whether the alleles that influence type II diabetes risk and glycemic traits also influence prostate cancer risk. METHODS: We used a multiple single-nucleotide polymorphisms (SNP) genotypic risk score to assess the average effect of alleles that increase type II diabetes risk or worsen glycemic traits on risk of prostate cancer in 19,662 prostate cancer cases and 19,715 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium and 5,504 prostate cancer cases and 5,834 controls from the Cancer Research UK (CRUK) prostate cancer study. RESULTS: Calculating the average additive effect of type II diabetes or glycemic trait risk alleles on prostate cancer risk using a logistic model revealed no evidence of a shared allelic architecture between type II diabetes, or worsened glycemic status, with prostate cancer risk [OR for type II diabetes alleles: 1.00 (P = 0.58), fasting glycemia alleles: 1.00 (P = 0.67), HbA1c alleles: 1.00 (P = 0.93), 2-hour OGTT alleles: 1.01 (P = 0.14), and HOMA-B alleles: 0.99 (P = 0.57)]. CONCLUSIONS: Using genetic data from large consortia, we found no evidence for a shared genetic etiology of type II diabetes or glycemic risk with prostate cancer. IMPACT: Our results showed that alleles influencing type II diabetes and related glycemic traits were not found to be associated with the risk of prostate cancer..
Goh, C.L.
Saunders, E.J.
Leongamornlert, D.A.
Tymrakiewicz, M.
Thomas, K.
Selvadurai, E.D.
Woode-Amissah, R.
Dadaev, T.
Mahmud, N.
Castro, E.
Olmos, D.
Guy, M.
Govindasami, K.
O'Brien, L.T.
Hall, A.L.
Wilkinson, R.A.
Sawyer, E.J.
Al Olama, A.A.
Easton, D.F.
Kote-Jarai, Z.
Parker, C.C.
Eeles, R.A.
(2013). Clinical implications of family history of prostate cancer and genetic risk single nucleotide polymorphism (SNP) profiles in an active surveillance cohort. Bju international,
Vol.112
(5),
pp. 666-673.
Castro, E.
Goh, C.
Olmos, D.
Saunders, E.
Leongamornlert, D.
Tymrakiewicz, M.
Mahmud, N.
Dadaev, T.
Govindasami, K.
Guy, M.
Sawyer, E.
Wilkinson, R.
Ardern-Jones, A.
Ellis, S.
Frost, D.
Peock, S.
Evans, D.G.
Tischkowitz, M.
Cole, T.
Davidson, R.
Eccles, D.
Brewer, C.
Douglas, F.
Porteous, M.E.
Donaldson, A.
Dorkins, H.
Izatt, L.
Cook, J.
Hodgson, S.
Kennedy, M.J.
Side, L.E.
Eason, J.
Murray, A.
Antoniou, A.C.
Easton, D.F.
Kote-Jarai, Z.
Eeles, R.
(2013). Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J clin oncol,
Vol.31
(14),
pp. 1748-1757.
show abstract
PURPOSE: To analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 (BRCA1/2) mutations and the prognostic value of those mutations on prostate cancer (PCa) outcomes. PATIENTS AND METHODS: This study analyzed the tumor features and outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 noncarriers). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival (OS), cause-specific OS (CSS), CSS in localized PCa (CSS_M0), metastasis-free survival (MFS), and CSS from metastasis (CSS_M1). RESULTS: PCa with germline BRCA1/2 mutations were more frequently associated with Gleason ≥ 8 (P = .00003), T3/T4 stage (P = .003), nodal involvement (P = .00005), and metastases at diagnosis (P = .005) than PCa in noncarriers. CSS was significantly longer in noncarriers than in carriers (15.7 v 8.6 years, multivariable analyses [MVA] P = .015; hazard ratio [HR] = 1.8). For localized PCa, 5-year CSS and MFS were significantly higher in noncarriers (96% v 82%; MVA P = .01; HR = 2.6%; and 93% v 77%; MVA P = .009; HR = 2.7, respectively). Subgroup analyses confirmed the poor outcomes in BRCA2 patients, whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup. CONCLUSION: Our results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis. BRCA mutations are associated with poor survival outcomes and this should be considered for tailoring clinical management of these patients..
Rudolph, A.
Hein, R.
Lindström, S.
Beckmann, L.
Behrens, S.
Liu, J.
Aschard, H.
Bolla, M.K.
Wang, J.
Truong, T.
Cordina-Duverger, E.
Menegaux, F.
Brüning, T.
Harth, V.
GENICA Network,
Severi, G.
Baglietto, L.
Southey, M.
Chanock, S.J.
Lissowska, J.
Figueroa, J.D.
Eriksson, M.
Humpreys, K.
Darabi, H.
Olson, J.E.
Stevens, K.N.
Vachon, C.M.
Knight, J.A.
Glendon, G.
Mulligan, A.M.
Ashworth, A.
Orr, N.
Schoemaker, M.
Webb, P.M.
kConFab Investigators,
AOCS Management Group,
Guénel, P.
Brauch, H.
Giles, G.
García-Closas, M.
Czene, K.
Chenevix-Trench, G.
Couch, F.J.
Andrulis, I.L.
Swerdlow, A.
Hunter, D.J.
Flesch-Janys, D.
Easton, D.F.
Hall, P.
Nevanlinna, H.
Kraft, P.
Chang-Claude, J.
Breast Cancer Association Consortium,
(2013). Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study. Endocr relat cancer,
Vol.20
(6),
pp. 875-887.
show abstract
Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case-control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showing P values for interaction (Pint) <3.0 × 10(-3) were selected for replication using pooled case-control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combined Pint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined Pint≤8.9 × 10(-6)), two SNPs in SLC25A21 (combined Pint≤4.8 × 10(-5)), and three SNPs in PLCG2 (combined Pint≤4.5 × 10(-5)). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint≤2.7 × 10(-5)), one SNP in CD80 (combined Pint≤8.2 × 10(-6)), three SNPs on chr17 near TMEM132E (combined Pint≤2.2×10(-6)), and two SNPs on chr18 near SLC25A52 (combined Pint≤4.6 × 10(-5)). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies..
Amin Al Olama, A.
Kote-Jarai, Z.
Schumacher, F.R.
Wiklund, F.
Berndt, S.I.
Benlloch, S.
Giles, G.G.
Severi, G.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Hunter, D.J.
Henderson, B.E.
Thun, M.J.
Gaziano, M.
Giovannucci, E.L.
Siddiq, A.
Travis, R.C.
Cox, D.G.
Canzian, F.
Riboli, E.
Key, T.J.
Andriole, G.
Albanes, D.
Hayes, R.B.
Schleutker, J.
Auvinen, A.
Tammela, T.L.
Weischer, M.
Stanford, J.L.
Ostrander, E.A.
Cybulski, C.
Lubinski, J.
Thibodeau, S.N.
Schaid, D.J.
Sorensen, K.D.
Batra, J.
Clements, J.A.
Chambers, S.
Aitken, J.
Gardiner, R.A.
Maier, C.
Vogel, W.
Dörk, T.
Brenner, H.
Habuchi, T.
Ingles, S.
John, E.M.
Dickinson, J.L.
Cannon-Albright, L.
Teixeira, M.R.
Kaneva, R.
Zhang, H.-.
Lu, Y.-.
Park, J.Y.
Cooney, K.A.
Muir, K.R.
Leongamornlert, D.A.
Saunders, E.
Tymrakiewicz, M.
Mahmud, N.
Guy, M.
Govindasami, K.
O'Brien, L.T.
Wilkinson, R.A.
Hall, A.L.
Sawyer, E.J.
Dadaev, T.
Morrison, J.
Dearnaley, D.P.
Horwich, A.
Huddart, R.A.
Khoo, V.S.
Parker, C.C.
Van As, N.
Woodhouse, C.J.
Thompson, A.
Dudderidge, T.
Ogden, C.
Cooper, C.S.
Lophatonanon, A.
Southey, M.C.
Hopper, J.L.
English, D.
Virtamo, J.
Le Marchand, L.
Campa, D.
Kaaks, R.
Lindstrom, S.
Diver, W.R.
Gapstur, S.
Yeager, M.
Cox, A.
Stern, M.C.
Corral, R.
Aly, M.
Isaacs, W.
Adolfsson, J.
Xu, J.
Zheng, S.L.
Wahlfors, T.
Taari, K.
Kujala, P.
Klarskov, P.
Nordestgaard, B.G.
Røder, M.A.
Frikke-Schmidt, R.
Bojesen, S.E.
FitzGerald, L.M.
Kolb, S.
Kwon, E.M.
Karyadi, D.M.
Orntoft, T.F.
Borre, M.
Rinckleb, A.
Luedeke, M.
Herkommer, K.
Meyer, A.
Serth, J.
Marthick, J.R.
Patterson, B.
Wokolorczyk, D.
Spurdle, A.
Lose, F.
McDonnell, S.K.
Joshi, A.D.
Shahabi, A.
Pinto, P.
Santos, J.
Ray, A.
Sellers, T.A.
Lin, H.-.
Stephenson, R.A.
Teerlink, C.
Muller, H.
Rothenbacher, D.
Tsuchiya, N.
Narita, S.
Cao, G.-.
Slavov, C.
Mitev, V.
UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology,
UK ProtecT Study Collaborators,
Australian Prostate Cancer Bioresource,
PRACTICAL Consortium,
Chanock, S.
Gronberg, H.
Haiman, C.A.
Kraft, P.
Easton, D.F.
Eeles, R.A.
(2013). A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease. Hum mol genet,
Vol.22
(2),
pp. 408-415.
show abstract
Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis..
Pooley, K.A.
Bojesen, S.E.
Weischer, M.
Nielsen, S.F.
Thompson, D.
Al Olama, A.A.
Michailidou, K.
Tyrer, J.P.
Benlloch, S.
Brown, J.
Audley, T.
Luben, R.
Khaw, K.-.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Kote-Jarai, Z.
Baynes, C.
Shah, M.
Bolla, M.K.
Wang, Q.
Dennis, J.
Dicks, E.
Yang, R.
Rudolph, A.
Schildkraut, J.
Chang-Claude, J.
Burwinkel, B.
Chenevix-Trench, G.
Pharoah, P.D.
Berchuck, A.
Eeles, R.A.
Easton, D.F.
Dunning, A.M.
Nordestgaard, B.G.
(2013). A genome-wide association scan (GWAS) for mean telomere length within the COGS project: identified loci show little association with hormone-related cancer risk. Human molecular genetics,
Vol.22
(24),
pp. 5056-5064.
Kote-Jarai, Z.
Saunders, E.J.
Leongamornlert, D.A.
Tymrakiewicz, M.
Dadaev, T.
Jugurnauth-Little, S.
Ross-Adams, H.
Al Olama, A.A.
Benlloch, S.
Halim, S.
Russell, R.
Dunning, A.M.
Luccarini, C.
Dennis, J.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Muir, K.
Giles, G.G.
Severi, G.
Wiklund, F.
Gronberg, H.
Haiman, C.A.
Schumacher, F.
Henderson, B.E.
Le Marchand, L.
Lindstrom, S.
Kraft, P.
Hunter, D.J.
Gapstur, S.
Chanock, S.
Berndt, S.I.
Albanes, D.
Andriole, G.
Schleutker, J.
Weischer, M.
Canzian, F.
Riboli, E.
Key, T.J.
Travis, R.C.
Campa, D.
Ingles, S.A.
John, E.M.
Hayes, R.B.
Pharoah, P.
Khaw, K.-.
Stanford, J.L.
Ostrander, E.A.
Signorello, L.B.
Thibodeau, S.N.
Schaid, D.
Maier, C.
Vogel, W.
Kibel, A.S.
Cybulski, C.
Lubinski, J.
Cannon-Albright, L.
Brenner, H.
Park, J.Y.
Kaneva, R.
Batra, J.
Spurdle, A.
Clements, J.A.
Teixeira, M.R.
Govindasami, K.
Guy, M.
Wilkinson, R.A.
Sawyer, E.J.
Morgan, A.
Dicks, E.
Baynes, C.
Conroy, D.
Bojesen, S.E.
Kaaks, R.
Vincent, D.
Bacot, F.
Tessier, D.C.
COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative,
UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology,
UK ProtecT Study Collaborators,
PRACTICAL Consortium,
Easton, D.F.
Eeles, R.A.
(2013). Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression. Hum mol genet,
Vol.22
(12),
pp. 2520-2528.
show abstract
Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease..
Ruark, E.
Snape, K.
Humburg, P.
Loveday, C.
Bajrami, I.
Brough, R.
Rodrigues, D.N.
Renwick, A.
Seal, S.
Ramsay, E.
Duarte, S.D.
Rivas, M.A.
Warren-Perry, M.
Zachariou, A.
Campion-Flora, A.
Hanks, S.
Murray, A.
Ansari Pour, N.
Douglas, J.
Gregory, L.
Rimmer, A.
Walker, N.M.
Yang, T.-.
Adlard, J.W.
Barwell, J.
Berg, J.
Brady, A.F.
Brewer, C.
Brice, G.
Chapman, C.
Cook, J.
Davidson, R.
Donaldson, A.
Douglas, F.
Eccles, D.
Evans, D.G.
Greenhalgh, L.
Henderson, A.
Izatt, L.
Kumar, A.
Lalloo, F.
Miedzybrodzka, Z.
Morrison, P.J.
Paterson, J.
Porteous, M.
Rogers, M.T.
Shanley, S.
Walker, L.
Gore, M.
Houlston, R.
Brown, M.A.
Caufield, M.J.
Deloukas, P.
McCarthy, M.I.
Todd, J.A.
Breast and Ovarian Cancer Susceptibility Collaboration,
Wellcome Trust Case Control Consortium,
Turnbull, C.
Reis-Filho, J.S.
Ashworth, A.
Antoniou, A.C.
Lord, C.J.
Donnelly, P.
Rahman, N.
(2013). Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature,
Vol.493
(7432),
pp. 406-410.
show abstract
Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification..
Rebbeck, T.R.
Devesa, S.S.
Chang, B.-.
Bunker, C.H.
Cheng, I.
Cooney, K.
Eeles, R.
Fernandez, P.
Giri, V.N.
Gueye, S.M.
Haiman, C.A.
Henderson, B.E.
Heyns, C.F.
Hu, J.J.
Ingles, S.A.
Isaacs, W.
Jalloh, M.
John, E.M.
Kibel, A.S.
Kidd, L.R.
Layne, P.
Leach, R.J.
Neslund-Dudas, C.
Okobia, M.N.
Ostrander, E.A.
Park, J.Y.
Patrick, A.L.
Phelan, C.M.
Ragin, C.
Roberts, R.A.
Rybicki, B.A.
Stanford, J.L.
Strom, S.
Thompson, I.M.
Witte, J.
Xu, J.
Yeboah, E.
Hsing, A.W.
Zeigler-Johnson, C.M.
(2013). Global patterns of prostate cancer incidence, aggressiveness, and mortality in men of african descent. Prostate cancer,
Vol.2013,
p. 560857.
show abstract
Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world..
Mikropoulos, C.
Eeles, R.A.
(2013). IMPACT Study: Targeted Prostate Cancer Screening. Oncologist,
Vol.18
(8),
p. e28.
show abstract
This letter to the editor clarifies the difference between two similarly named studies and expands on the progress of one—the Identification of Men with a Genetic Predisposition to Prostate Cancer study (IMPACT): Targeted screening in BRCA1/2 mutation carriers and controls..
Dent, T.
Jbilou, J.
Rafi, I.
Segnan, N.
Tornberg, S.
Chowdhury, S.
Hall, A.
Lyratzopoulos, G.
Eeles, R.
Eccles, D.
Hallowell, N.
Pashayan, N.
Pharoah, P.
Burton, H.
(2013). Stratified Cancer Screening: The Practicalities of Implementation. Public health genomics,
Vol.16
(3),
pp. 94-99.
Killick, E.
Morgan, R.
Launchbury, F.
Bancroft, E.
Page, E.
Castro, E.
Kote-Jarai, Z.
Aprikian, A.
Blanco, I.
Clowes, V.
Domchek, S.
Douglas, F.
Eccles, D.
Evans, D.G.
Harris, M.
Kirk, J.
Lam, J.
Lindeman, G.
Mitchell, G.
Pachter, N.
Selkirk, C.
Tucker, K.
Zgajnar, J.
Eeles, R.
Pandha, H.
(2013). Role of Engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men. Sci rep,
Vol.3,
p. 2059.
show abstract
Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0 ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals..
Shen, H.
Fridley, B.L.
Song, H.
Lawrenson, K.
Cunningham, J.M.
Ramus, S.J.
Cicek, M.S.
Tyrer, J.
Stram, D.
Larson, M.C.
Köbel, M.
PRACTICAL Consortium,
Ziogas, A.
Zheng, W.
Yang, H.P.
Wu, A.H.
Wozniak, E.L.
Woo, Y.L.
Winterhoff, B.
Wik, E.
Whittemore, A.S.
Wentzensen, N.
Weber, R.P.
Vitonis, A.F.
Vincent, D.
Vierkant, R.A.
Vergote, I.
Van Den Berg, D.
Van Altena, A.M.
Tworoger, S.S.
Thompson, P.J.
Tessier, D.C.
Terry, K.L.
Teo, S.-.
Templeman, C.
Stram, D.O.
Southey, M.C.
Sieh, W.
Siddiqui, N.
Shvetsov, Y.B.
Shu, X.-.
Shridhar, V.
Wang-Gohrke, S.
Severi, G.
Schwaab, I.
Salvesen, H.B.
Rzepecka, I.K.
Runnebaum, I.B.
Rossing, M.A.
Rodriguez-Rodriguez, L.
Risch, H.A.
Renner, S.P.
Poole, E.M.
Pike, M.C.
Phelan, C.M.
Pelttari, L.M.
Pejovic, T.
Paul, J.
Orlow, I.
Omar, S.Z.
Olson, S.H.
Odunsi, K.
Nickels, S.
Nevanlinna, H.
Ness, R.B.
Narod, S.A.
Nakanishi, T.
Moysich, K.B.
Monteiro, A.N.
Moes-Sosnowska, J.
Modugno, F.
Menon, U.
McLaughlin, J.R.
McGuire, V.
Matsuo, K.
Adenan, N.A.
Massuger, L.F.
Lurie, G.
Lundvall, L.
Lubiński, J.
Lissowska, J.
Levine, D.A.
Leminen, A.
Lee, A.W.
Le, N.D.
Lambrechts, S.
Lambrechts, D.
Kupryjanczyk, J.
Krakstad, C.
Konecny, G.E.
Kjaer, S.K.
Kiemeney, L.A.
Kelemen, L.E.
Keeney, G.L.
Karlan, B.Y.
Karevan, R.
Kalli, K.R.
Kajiyama, H.
Ji, B.-.
Jensen, A.
Jakubowska, A.
Iversen, E.
Hosono, S.
Høgdall, C.K.
Høgdall, E.
Hoatlin, M.
Hillemanns, P.
Heitz, F.
Hein, R.
Harter, P.
Halle, M.K.
Hall, P.
Gronwald, J.
Gore, M.
Goodman, M.T.
Giles, G.G.
Gentry-Maharaj, A.
Garcia-Closas, M.
Flanagan, J.M.
Fasching, P.A.
Ekici, A.B.
Edwards, R.
Eccles, D.
Easton, D.F.
Dürst, M.
du Bois, A.
Dörk, T.
Doherty, J.A.
Despierre, E.
Dansonka-Mieszkowska, A.
Cybulski, C.
Cramer, D.W.
Cook, L.S.
Chen, X.
Charbonneau, B.
Chang-Claude, J.
Campbell, I.
Butzow, R.
Bunker, C.H.
Brueggmann, D.
Brown, R.
Brooks-Wilson, A.
Brinton, L.A.
Bogdanova, N.
Block, M.S.
Benjamin, E.
Beesley, J.
Beckmann, M.W.
Bandera, E.V.
Baglietto, L.
Bacot, F.
Armasu, S.M.
Antonenkova, N.
Anton-Culver, H.
Aben, K.K.
Liang, D.
Wu, X.
Lu, K.
Hildebrandt, M.A.
Australian Ovarian Cancer Study Group,
Australian Cancer Study,
Schildkraut, J.M.
Sellers, T.A.
Huntsman, D.
Berchuck, A.
Chenevix-Trench, G.
Gayther, S.A.
Pharoah, P.D.
Laird, P.W.
Goode, E.L.
Pearce, C.L.
(2013). Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer. Nat commun,
Vol.4,
p. 1628.
show abstract
HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes..
Ormondroyd, E.
Donnelly, L.
Moynihan, C.
Savona, C.
Bancroft, E.
Evans, D.G.
Eeles, R.A.
Lavery, S.
Watson, M.
(2012). Attitudes to reproductive genetic testing in women who had a positive BRCA test before having children: a qualitative analysis. European journal of human genetics,
Vol.20
(1),
pp. 4-10.
Spurdle, A.B.
Healey, S.
Devereau, A.
Hogervorst, F.B.
Monteiro, A.N.
Nathanson, K.L.
Radice, P.
Stoppa-Lyonnet, D.
Tavtigian, S.
Wappenschmidt, B.
Couch, F.J.
Goldgar, D.E.
ENIGMA,
(2012). ENIGMA--evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes. Hum mutat,
Vol.33
(1),
pp. 2-7.
show abstract
As genetic testing for predisposition to human diseases has become an increasingly common practice in medicine, the need for clear interpretation of the test results is apparent. However, for many disease genes, including the breast cancer susceptibility genes BRCA1 and BRCA2, a significant fraction of tests results in the detection of a genetic variant for which disease association is not known. The finding of an "unclassified" variant (UV)/variant of uncertain significance (VUS) complicates genetic test reporting and counseling. As these variants are individually rare, a large collaboration of researchers and clinicians will facilitate studies to assess their association with cancer predisposition. It was with this in mind that the ENIGMA consortium (www.enigmaconsortium.org) was initiated in 2009. The membership is both international and interdisciplinary, and currently includes more than 100 research scientists and clinicians from 19 countries. Within ENIGMA, there are presently six working groups focused on the following topics: analysis, clinical, database, functional, tumor histopathology, and mRNA splicing. ENIGMA provides a mechanism to pool resources, exchange methods and data, and coordinately develop and apply algorithms for classification of variants in BRCA1 and BRCA2. It is envisaged that the research and clinical application of models developed by ENIGMA will be relevant to the interpretation of sequence variants in other disease genes..
Mavaddat, N.
Barrowdale, D.
Andrulis, I.L.
Domchek, S.M.
Eccles, D.
Nevanlinna, H.
Ramus, S.J.
Spurdle, A.
Robson, M.
Sherman, M.
Mulligan, A.M.
Couch, F.J.
Engel, C.
McGuffog, L.
Healey, S.
Sinilnikova, O.M.
Southey, M.C.
Terry, M.B.
Goldgar, D.
O'Malley, F.
John, E.M.
Janavicius, R.
Tihomirova, L.
Hansen, T.V.
Nielsen, F.C.
Osorio, A.
Stavropoulou, A.
Benítez, J.
Manoukian, S.
Peissel, B.
Barile, M.
Volorio, S.
Pasini, B.
Dolcetti, R.
Putignano, A.L.
Ottini, L.
Radice, P.
Hamann, U.
Rashid, M.U.
Hogervorst, F.B.
Kriege, M.
van der Luijt, R.B.
HEBON,
Peock, S.
Frost, D.
Evans, D.G.
Brewer, C.
Walker, L.
Rogers, M.T.
Side, L.E.
Houghton, C.
EMBRACE,
Weaver, J.
Godwin, A.K.
Schmutzler, R.K.
Wappenschmidt, B.
Meindl, A.
Kast, K.
Arnold, N.
Niederacher, D.
Sutter, C.
Deissler, H.
Gadzicki, D.
Preisler-Adams, S.
Varon-Mateeva, R.
Schönbuchner, I.
Gevensleben, H.
Stoppa-Lyonnet, D.
Belotti, M.
Barjhoux, L.
GEMO Study Collaborators,
Isaacs, C.
Peshkin, B.N.
Caldes, T.
de la Hoya, M.
Cañadas, C.
Heikkinen, T.
Heikkilä, P.
Aittomäki, K.
Blanco, I.
Lazaro, C.
Brunet, J.
Agnarsson, B.A.
Arason, A.
Barkardottir, R.B.
Dumont, M.
Simard, J.
Montagna, M.
Agata, S.
D'Andrea, E.
Yan, M.
Fox, S.
kConFab Investigators,
Rebbeck, T.R.
Rubinstein, W.
Tung, N.
Garber, J.E.
Wang, X.
Fredericksen, Z.
Pankratz, V.S.
Lindor, N.M.
Szabo, C.
Offit, K.
Sakr, R.
Gaudet, M.M.
Singer, C.F.
Tea, M.-.
Rappaport, C.
Mai, P.L.
Greene, M.H.
Sokolenko, A.
Imyanitov, E.
Toland, A.E.
Senter, L.
Sweet, K.
Thomassen, M.
Gerdes, A.-.
Kruse, T.
Caligo, M.
Aretini, P.
Rantala, J.
von Wachenfeld, A.
Henriksson, K.
SWE-BRCA Collaborators,
Steele, L.
Neuhausen, S.L.
Nussbaum, R.
Beattie, M.
Odunsi, K.
Sucheston, L.
Gayther, S.A.
Nathanson, K.
Gross, J.
Walsh, C.
Karlan, B.
Chenevix-Trench, G.
Easton, D.F.
Antoniou, A.C.
Consortium of Investigators of Modifiers of BRCA1/2,
(2012). Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer epidemiol biomarkers prev,
Vol.21
(1),
pp. 134-147.
show abstract
BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers. RESULTS: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%). CONCLUSIONS/IMPACT: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis..
Kohut, K.
D'Mello, L.
Bancroft, E.K.
Thomas, S.
Young, M.-.
Myhill, K.
Shanley, S.
Briggs, B.H.
Newman, M.
Saraf, I.M.
Cox, P.
Scambler, S.
Wagman, L.
Wyndham, M.T.
Eeles, R.A.
Ferris, M.
(2012). Implications for cancer genetics practice of pro-actively assessing family history in a General Practice cohort in North West London. Fam cancer,
Vol.11
(1),
pp. 107-113.
show abstract
At present cancer genetics referrals are reactive to individuals asking for a referral and providing a family history thereafter. A previous pilot study in a single General Practice (GP) catchment area in North London showed a 1.5-fold increase in breast cancer risk in the Ashkenazi Jewish population compared with the non-Ashkenazi mixed population. The breast cancer incidence was equal in the Ashkenazim in both pre- and postmenopausal groups. We wanted to investigate the effect of proactively seeking family history data from the entire female population of the practice to determine the effect on cancer genetics referral. Objectives To determine the need for cancer genetics intervention for women in a single GP catchment area. (1) to determine the incidence and strength of family history of cancer in women aged over 18 in the practice, (2) to offer cancer genetics advice and determine the uptake of counselling in those with a positive family history, (3) to identify potential BRCA1/BRCA2 gene mutation carriers who can be offered clinical follow up with appropriate translational research studies. Design Population-based cohort study of one General Practice female population. Participants Three hundred and eighty-three women over the age of 18 from one General Practice who responded to a questionnaire about family history of cancer. The whole female adult GP population was the target and the total number sampled was 3,820. Results 10% of patients completed the questionnaire (n = 383). A family history of cancer was present in 338 cases, 95 went on to have genetic counselling or had previously had counselling and 47 were genetically tested. We identified three carriers of an Ashkenazi Jewish founder mutation in BRCA1. Conclusions Response rate to a family history questionnaire such as that used in genetics centres was low (10%) and other approaches will be needed to proactively assess family history. Although the Ashkenazim are present in 39% of the GP catchment area, 62% of those who returned a family history questionnaire were from this ethnic group and of those returned, 44% warranted referral to a cancer genetics unit. In the non Ashkenazim, the questionnaire return rate was 38% and 18% of those warranted referral to cancer genetics..
Lu, L.
Cancel-Tassin, G.
Valeri, A.
Cussenot, O.
Lange, E.M.
Cooney, K.A.
Farnham, J.M.
Camp, N.J.
Cannon-Albright, L.A.
Tammela, T.L.
Schleutker, J.
Hoegel, J.
Herkommer, K.
Maier, C.
Vogel, W.
Wiklund, F.
Emanuelsson, M.
Groenberg, H.
Wiley, K.E.
Isaacs, S.D.
Walsh, P.C.
Helfand, B.T.
Kan, D.
Catalona, W.J.
Stanford, J.L.
FitzGerald, L.M.
Johanneson, B.
Deutsch, K.
McIntosh, L.
Ostrander, E.A.
Thibodeau, S.N.
McDonnell, S.K.
Hebbring, S.
Schaid, D.J.
Whittemore, A.S.
Oakley-Girvan, I.
Hsieh, C.-.
Powell, I.
Bailey-Wilson, J.E.
Cropp, C.D.
Simpson, C.
Carpten, J.D.
Seminara, D.
Zheng, S.L.
Xu, J.
Giles, G.G.
Severi, G.
Hopper, J.L.
English, D.R.
Foulkes, W.D.
Maehle, L.
Moller, P.
Badzioch, M.D.
Edwards, S.
Guy, M.
Eeles, R.
Easton, D.
Isaacs, W.B.
Canc, I.C.
(2012). Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG. Prostate,
Vol.72
(4),
pp. 410-426.
Laitman, Y.
Kuchenbaecker, K.B.
Rantala, J.
Hogervorst, F.
Peock, S.
Godwin, A.K.
Arason, A.
Kirchhoff, T.
Offit, K.
Isaacs, C.
Schmutzler, R.K.
Wappenschmidt, B.
Nevanlinna, H.
Chen, X.
Chenevix-Trench, G.
Healey, S.
Couch, F.
Peterlongo, P.
Radice, P.
Nathanson, K.L.
Caligo, M.A.
Neuhausen, S.L.
Ganz, P.
Sinilnikova, O.M.
McGuffog, L.
Easton, D.F.
Antoniou, A.C.
Wolf, I.
Friedman, E.
(2012). The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers. Breast cancer res treat,
Vol.132
(3),
pp. 1119-1126.
show abstract
Klotho (KL) is a putative tumor suppressor gene in breast and pancreatic cancers located at chromosome 13q12. A functional sequence variant of Klotho (KL-VS) was previously reported to modify breast cancer risk in Jewish BRCA1 mutation carriers. The effect of this variant on breast and ovarian cancer risks in non-Jewish BRCA1/BRCA2 mutation carriers has not been reported. The KL-VS variant was genotyped in women of European ancestry carrying a BRCA mutation: 5,741 BRCA1 mutation carriers (2,997 with breast cancer, 705 with ovarian cancer, and 2,039 cancer free women) and 3,339 BRCA2 mutation carriers (1,846 with breast cancer, 207 with ovarian cancer, and 1,286 cancer free women) from 16 centers. Genotyping was accomplished using TaqMan(®) allelic discrimination or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data were analyzed within a retrospective cohort approach, stratified by country of origin and Ashkenazi Jewish origin. The per-allele hazard ratio (HR) for breast cancer was 1.02 (95% CI 0.93-1.12, P = 0.66) for BRCA1 mutation carriers and 0.92 (95% CI 0.82-1.04, P = 0.17) for BRCA2 mutation carriers. Results remained unaltered when analysis excluded prevalent breast cancer cases. Similarly, the per-allele HR for ovarian cancer was 1.01 (95% CI 0.84-1.20, P = 0.95) for BRCA1 mutation carriers and 0.9 (95% CI 0.66-1.22, P = 0.45) for BRCA2 mutation carriers. The risk did not change when carriers of the 6174delT mutation were excluded. There was a lack of association of the KL-VS Klotho variant with either breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers..
Richter, S.
Graham, T.
Haroun, I.
Eisen, A.
Warner, E.
Greenberg, R.A.
Domchek, S.M.
Winqvist, R.
Reis-Filho, J.S.
Natrajan, R.
Mackay, A.
Lambros, M.B.
Weigelt, B.
Manie, E.
Grigoriadis, A.
van der Groep, P.
Kozarewa, I.
Popova, T.
Mariani, O.
Turajlic, S.
Furney, S.J.
Marais, R.
Wilkerson, P.M.
Rodrigues, D.N.
Flora, A.C.
Wai, P.
Pawar, V.
McDade, S.
Carrol, J.
Stoppa-Lyonnet, D.
Green, A.R.
Ellis, I.O.
van Diest, P.
Delattre, O.
Lord, C.J.
Foulkes, W.D.
Vincent-Salomon, A.
Ashworth, A.
Stern, M.H.
Castro, E.
Goh, C.
Olmos, D.
Saunders, E.
Leongamornlert, D.
Tymrakiewicz, M.
Govindasami, K.
Guy, M.
Sawyer, E.
Wilkinson, R.
UKGPCS collaborators,
EMBRACE collaborators,
Easton, D.F.
Kote-Jarai, Z.
Eeles, R.
Vencken, P.M.
Reitsma, W.
Mourits, M.J.
de Bock, G.H.
de Hullu, J.A.
Gaarenstroom, K.N.
Biemans, D.
Brood, M.
Schmidt, M.K.
Zweemer, R.P.
Fons, G.
Slangen, B.F.
Burger, C.W.
Kriege, M.G.
Seynaeve, C.M.
Pathania, S.
Burke, K.
Kharbanda, A.
Feunteun, J.
Garber, J.
Livingston, D.M.
Kang, P.
KANG, I.N.
Phuah, S.Y.
Yoon, S.-.
Thong, M.K.
Lee, D.
Sivanandan, K.
Mohd Taib, N.A.
Yip, C.-.
Teo, S.-.
de Bock, G.H.
Vermeulen, K.M.
Jansen, L.
Oosterwijk, J.C.
Siesling, S.
Kok, T.
Jansen-van der Weide, M.C.
Houssami, N.
Greuter., M.J.
Eeles, R.
Bancroft, E.
Castro, E.
Page, E.
MacDonald, D.J.
Hurley, K.
Garcia, N.
Bowen, D.J.
Grant, M.
Weitzel, J.N.
Ferrell, B.R.
Pruski-Clark, J.
Trivedi, A.
Sutphen, R.
Moncoutier, V.
Zeitouni, B.
Barillot, E.
Stern, M.-.
Stoppa-Lyonnet, D.
Houdayer, C.
van der Groep, P.
van Diest, P.J.
Ausems, M.G.
van der Luijt, R.B.
Menko, F.H.
Bart, J.
de Vries, E.G.
van der Wall, E.
Bacha, O.M.
Plante, M.
Gregoire, J.
Grondin, K.
Edelweiss, M.I.
Laframboise, R.
Simard, J.
Chapman, J.
Panighetti, A.
Hwang, E.S.
Crawford, B.
Powell, C.B.
Chan, J.K.
Chen., L.
Dorval, M.
Foulkes, W.
Hamet, P.
Chiquette, J.
Simard, J.
Wong, N.
Côté, S.
Haffaf, Z.E.
Rhéaume, J.
Pelletier, S.
Valentini, A.
Ng, J.
Poll, A.
Llacuachaqui, M.
Iqbal, J.
Narod, S.
Irwin, G.W.
Morrison, P.J.
McIntosh, S.A.
Larouche, G.
Côté, C.
Simard, J.
Desbiens, C.
Chiquette, J.
Dorval, M.
Ramon y Cajal, T.
Llort, G.
Lasa, A.
Stradella, A.
Murata, P.
Calvo, N.
Sulivan, I.
Arcusa, Â.
Barnadas, A.
Alonso, M.
Eisen, A.
Carroll, J.
Chiarelli, A.M.
Heale, E.
Horgan, M.
Meschino, W.
Plewes, D.
Rabeneck, L.
Shumak, R.
Warner, E.
Enmore, M.
Narod, S.
Metcalfe, K.
Kerachian, M.A.
Rooyadeh, M.
Sharifi, N.
Naseri, S.
Shakeri, M.T.
Shandiz, F.H.
Houdayer, C.
Kristoffersson, U.
Osorio, A.
Stoppa-Lyonnet, D.
Kamarainen, O.
Patton, S.
Müller, C.
Johannes, B.
Lui, M.
Ben-Yishay, M.
Klugman, S.
Lee, R.
Joseph, G.
Moseley, M.
Banks, P.
Batiste, W.
Brown, G.
DePuit, M.
Pasick, R.
Russ, H.
Rimel, B.J.
Walsh, C.
Lester, J.
Bresee, C.
Cook-Wiens, G.
Karlan, B.Y.
Mitchell, G.
Willems, A.
Kavanagh, L.
Campbell, I.
Bolton, D.
Li, J.
Clouston, D.
Fox, S.
Thorne, H.
Quinn, J.E.
Irwin, G.W.
Lamers, E.
Haddock, P.
Gorski, J.J.
Savage, K.
Blayney, J.
McDyer, F.A.
McCabe, N.
Mulligan, J.M.
Mullan, P.B.
Couch, F.J.
Kennedy, R.D.
Harkin, D.P.
McAlpine, J.N.
McCluggage, W.G.
Quinn, J.E.
Harley, I.
Kalloger, S.E.
Salto-Tellez, M.
Maxwell, P.
Gilks, C.B.
Lasa, A.
Ramón y Cajal, T.
López, C.
Cornet, M.
Iturbe, A.
Barnadas, A.
Baiget, M.
Alonso, C.
Matchett, K.
Savage, K.
Cooper, K.
Gorski, J.
Manti, L.
Richard, D.
Barrros, E.
Mullan, P.
Elliott, C.
Harkin, P.
Rothenmund, H.
Hall, A.
Chong, G.
Foulkes, W.
Zogopoulos, G.
Hamdi, Y.
Soucy, P.
Goldgar, D.
Feng, B.-.
Pastinen, T.
Reimnitz, G.
Sinnett, D.
Cassart, P.
Leclerc, M.
Lakhal Chaieb, M.L.
Stoppa-Lyonnet, D.
Verny-Pierre, C.
Barjhoux, L.
Sinilnikova, O.
Simard, J.
Bignon, Y.-.
Bidet, Y.
Viala, S.
Uhrhammer, N.
Alvarez, R.M.
Vaca, F.
Fragoso, V.
Vidal, S.
Herrera, L.
Cantu, D.
Bargalló, J.E.
Mohar, A.
Pérez, C.
Diez, O.
Balmaña, J.
Rue, M.
Bosch, N.
Gadea, N.
Gutiérrez-Enríquez, S.
Romero, A.
Pérez-Segura, P.
Rubio, E.D.
Caldés, T.
de la Hoya, M.
Alonso, C.
Cajal, T.R.
Baiget, M.
Lasa, A.
Blanco, A.
Santamariña, M.
Fachal, L.
Vega, A.
Infante, M.
Durán, M.
Velasco, E.
Chirivella, I.
Osorio, A.
Benítez, J.
Barroso, A.
Domingo, S.
Esteban-Cardeñosa, E.
Bolufer, P.
Segura, A.
Brunet, J.
Darder, E.
Izquierdo, A.
Guillén, C.
Andrés, R.
Torres, A.
de Dueñas, E.M.
García-Casado, Z.
Llort, G.
Dolman, L.
Belanger, M.H.
Arcand, S.L.
Shen, Z.
Chong, G.
Foulkes, W.D.
Ghadirian, P.
#,
#,
Tonin, P.N.
Belanger, M.H.
Dolman, L.
Arcand, S.L.
Shen, Z.
Chong, G.
Foulkes, W.D.
Ghadirian, P.
Mes-Masson, A.-.
Provencher, D.
Tonin, P.N.
Ragone, A.
Llacuachaqui, M.
Iqbal, J.
Sun, P.
Narod, S.
Pal, T.
Bonner, D.
Kim, J.
Monteiro, A.
Kessler, L.
Royer, R.
Narod, S.
Vadaparampil, S.T.
Semple, J.L.
Metcalfe, K.
Sun, P.
Narod, S.A.
Taylor, A.
Molenda, A.
Drummond, J.
Oakhill, K.
Treacy, R.
Whittaker, J.
Tischkowitz, M.
Chun, K.
Brown, A.
Ng, K.
Denroche, R.
McPherson, J.
Dohany, L.
Zakalik, D.
Beattie, M.S.
Ganschow, P.
Gabram-Mendola, S.
Lee, R.
Loranger, K.
Fehniger, J.
Seelaus, C.
Bressler, L.
Stanislaw, C.
Trim, L.
Luce, J.
Moore, R.
Bosdet, I.
Docking, R.
Butterfield, Y.
Chan, S.
Young, S.
Kirkpatrick, R.
Hirst, M.
Mungall, A.
Zhao, Y.
Birol, I.
Holt, R.
Karsan, A.
Kotsopoulos, J.
Sukiennicki, G.
Muszyńka, M.
Gackowski, D.
Kaklewski, K.
Durda, K.
Jaworska, K.
Huzarski, T.
Gronwald, J.
Byrski, T.
Ashuryk, O.
Dęniak, T.
Tołczko-Grabarek, A.
Stawicka, M.
Godlewski, D.
Olinski, R.
Jakubowska, A.
Narod, S.
Lubinski, J.
Bakker, J.L.
Mil, S.E.
Crossan, G.
Sabbaghian, N.
Claes, K.
Foulkes, W.
De Leeneer, K.
Poppe, B.
Gille, H.
Verheul, H.
Meijers, H.
de Winter, J.P.
Waisfisz, Q.
Diez, O.
Balmaña, J.
Gutiérrez-Enríquez, S.
Tenés, A.
Masas, M.
Gadea, N.
Bosch, N.
Vega, A.
Blanco, A.
Bonache, S.
Moreno, R.
Montalbán, G.
Hanna, D.
Glendon, G.
Knight, J.
Lilge, L.
Bordeleau, L.
Terespolsky, D.
Andrulis, I.
Tomiak, E.
Osher, D.
De Leeneer, K.
Michils, G.
Hamel, N.
Poppe, B.
Leunen, K.
Leguis, E.
Shuen, A.
Arseneau, J.
Tonin, P.
Matthijs, G.
Claes, K.
Tischkowitz, M.
Foulkes, W.
Navarro de Souza, A.
Loiselle, C.
Foulkes, W.
Wong, N.
Bosch, N.
Junyent, N.
Gadea, N.
Brunet, J.
Ramon y Cajal, T.
Torres, A.
Graña, B.
Velasco, A.
Darder, E.
Mensa, I.
Balmaña, J.
Vaisman, A.
Elser, C.
Panchal, S.
Barrault, M.
Grados, C.
Ostrovsky, R.
M’Baïlara, K.
Longy, M.
Barouk, E.
Floquet, A.
Wenzel, L.
Osann, K.
Gross-Lester, J.
Kurz, R.
Hsieh, S.
Nelson, E.L.
Karlan, B.Y.
Rimel, B.J.
Phuah, S.-.
Looi, L.-.
Rhodes, A.
Dean, S.
Mohd Taib, N.A.
Yip, C.-.
Colizza, K.
Spriggs, E.
Marles, S.
Nielsen, H.R.
Skytte, A.-.
Sugano, K.
Ando, J.
Sekiguchi, I.
Kamata, H.
Makishima, K.
Haneda, E.
Jinno, H.
Kitagawa, Y.
Hirasawa, A.
Aoki, D.
Shimizu, C.
Hojyo, T.
Kinoshita, T.
Kasamatsu, T.
Yoshida, T.
Lee, R.
Joseph, G.
Stewart, S.
Luce, J.
Kaplan, C.
Marquez, T.
Davis, S.
Guerra, C.
Pasick, R.J.
McClellan, K.A.
Kleiderman, E.
Black, L.
Bouchard, K.
Dorval, M.
Knoppers, B.M.
Avard, D.
Duffy, J.
Greening, S.
Warwick, L.
Tucker, K.
Creighton, B.
Au, A.
Schwartz, D.
Huang, M.
Finch, A.
Tierney, M.
Hampson, E.
Narod, S.
Einstein, G.
van der Merwe, N.C.
Schneider, S.-.
Visser, B.
Milewski, B.
McKenna, D.
Parker, M.
Somerman, C.
Catts, Z.A.
Boman, B.
Fehniger, J.
Lin, F.
Beattie, M.S.
Volenik, A.
Foulkes, W.D.
Palma, L.
Bell, K.
Learn, L.
Parpia, S.
Piccinin, C.
Bordeleau, L.
Zbuk, K.
Chappuis, P.O.
Ayme, A.
Murphy, A.E.
Membrez, V.
Cina, V.
Monnerat, C.
Benais-Pont, G.
Rebsamen, M.
Tamura, C.
Murakami, S.
Nakamura, S.
Gammon, A.
Kohlmann, W.
Jasperson, K.
Champine, M.
Kinney, A.
Hayden, R.
Woike, A.
Thomas, M.
Tsai, E.
Herschorn, S.
(2012). Selected abstracts submitted to the Fourth International Symposium on Hereditary Breast and Ovarian Cancer. Current oncology (toronto, ont.),
Vol.19
(2),
pp. e84-e111.
show abstract
Background:
Nearly 15% of DNA tests for BRCA1/2 results in the identification of an unclassified variant (UV). In DNA diagnostic laboratories in The Netherlands, a 4-group classification system (class I to IV) is in use (Bell et al.). Aim of this study was to investigate whether the UVs in different classes showed a significant difference in their in silico characteristics and would justify current differences in protocols for counselling with respect to communication to the counselees.
Methods:
Missense UVs in BRCA1/2 identified between 2002 and 2010 (n = 88) were analyzed. In silico analysis of UVs was performed using SIFT– analysis Grantham score and AGVGD for the predicted severity of amino acid substitutions. Each UV was classified to one of the four classes.
Results:
More than half of the UVs (n = 50) were predicted to be tolerated using SIFT-analysis. Accordingly, all these variants are scored as neutral (C0) by AGVGD. Of the remaining 38 UVs not tolerated using SIFT-analysis, 19 were scored as C0 (neutral), 8 were scored C15–C25 (intermediate) and 11 were scored C35 or higher (likely to be pathogenic). Although class III UVs more frequently show in silico parameter outcomes that are suspicious for a pathogenic effect, the observed differences are not absolute. Seven UVs classified in class II had similar in silico profiles with 7 UVs in class III.
Conclusion:
This study showed that, in general, in silico analysis is consistently applied and proved to be able to discriminate between the different classes of UVs. However, additional analyses will be required to classify the UVs with more accuracy. In order to reduce psychological distress in families in which a UV is identified, we propose that communication of a UV should not primarily depend on its class, but also on the possibility to perform additional research in the family.
Objectives:
BRCA+ women are strongly advised to have their ovaries removed upon completion of childbearing, preferably by age 35–40. Our clinical observations and preliminary research indicate that this recommendation raises significant psychosocial concerns for younger BRCA+ women, particularly regarding loss of fertility and premature menopause. Yet little research has been conducted to thoroughly assess these outcomes. This ongoing study describes salient issues of psychosocial well-being (PSWB) related to fertility and menopause in ethnically diverse reproductive age BRCA+ women who do and do not undergo oophorectomy.
Methods:
Thus far, we have conducted 10 qualitative individual in-person or phone audio-recorded semi-structured interviews regarding PSWB related to recommendation for early oophorectomy. The sample is ethnically diverse (including 1 monolingual Spanish-speaker), BRCA1/2+ women ages 29–45, 3–36 months post-result notification who have never had cancer.
Results:
Seven were partnered, 7 had children, 4 opted for risk-reducing mastectomies, and 2 underwent risk-reducing oophorectomy. Thematic analysis thus far revealed the following themes: adverse effects of premature menopause (“can’t focus,” mood swings, lack of desire, relationship strain); developmental issues (“too young for menopause,” hurrying childbirth), use of hormone replacement (lack of provider knowledge, “am I trading one set of problems for another?”), and concern for relatives who choose not to test. Positive themes also emerged, including benefits of genetic testing (“saved our lives,” emotional growth) and importance of peer support (“speak[ing] with the younger women my own age, I started to get more comfortable with the idea”).
Conclusion:
Findings to date provide rich in-depth data about a critical untapped area of inquiry relevant to cancer prevention and control. As genetic testing is increasingly utilized, addressing the interrelated fertility and menopausal needs of reproductive age BRCA+ women will become increasingly important in clinical care.
Objectives:
Shortened telomeres are associated with a significant increase in cancer risk. The objective of our study was to identify differences in telomere length between BRCA mutation carriers with and without cancer, and between ovarian/fallopian tube/primary peritoneal cancer (OC/FTC/PPC) patients with and without germline BRCA mutations.
Methods:
277 patients met inclusion criteria for this study. Serum and clinical data were collected through a Hereditary Cancer Program and other IRB approved studies at a single institution. Pre-diagnostic germline DNA from peripheral blood leukocytes was obtained from women at diagnosis of OC/FTC/ PPC, and from healthy women who were undergoing risk reducing salpingo-oophorectomy. All subjects were screened for BRCA1 or BRCA2 mutations. Telomere length was assessed in triplicate by PCR according to standard methods. Statistical analysis was performed using linear regression.
Results:
The mean age-adjusted telomere length at the time of diagnosis of OC/FTC/PPC was significantly shorter (p = 0.02) for BRCA mutation carriers compared to WT-BRCA patients with ovarian cancer. As expected, increasing age was associated with decreasing telomere length, but was not significant (p = 0.22). However, there was no difference in age-adjusted mean telomere length between BRCA mutation carriers with ovarian, fallopian tube, or peritoneal cancer compared with healthy women with germline BRCA mutations (p = 0.43).
Conclusion:
Shortened telomere length is more frequent in BRCA-associated ovarian/fallopian tube/peritoneal cancer compared with sporadic cases. These data suggest cancer predisposition of the BRCA mutation carrier is likely influenced by other known causes of telomere shortening, such as obesity and stress.
Objectives:
Clinical data from BRCA testing programs is largely based on Caucasian populations from tertiary care centres. As BRCA testing becomes more available and accepted in diverse communities, it is necessary to study clinical outcomes from these populations. The overarching objectives of the Consortium of Underserved BRCA testers (CUB) are to: 1) Describe population characteristics, referral patterns, and BRCA results in diverse and underserved BRCA testers; and 2) Create a database of point-of-care clinical outcomes in diverse and underserved BRCA testers
Methods:
CUB was founded in October 2010 from 3 US public hospitals: San Francisco General Hospital (SFGH), Stroger Hospital of Cook County (Chicago) and Grady Memorial (Atlanta). We pooled retrospective data (2002–2010) from all 3 sites to compare referral patterns, population characteristics, and BRCA test results. We developed common data collection protocols and instruments which have been used prospectively since 2011 during phone and in-person visits.
Results:
2942 total underserved patients were referred to genetic counselling, and 636 received BRCA testing at CUB sites within the last 10 years. The overall racial/ethnicity of CUB includes: 37% African American, 5% Asian, 41% Caucasian, and 17% Hispanic. Race, ethnicity, and referral patterns differ significantly between sites. SFGH receives most referrals from a family history screening questionnaire, administered during mammography. In Chicago, primary care networks provide many referrals. In Atlanta, most CUB patients are identified in the breast clinic. Despite these significant differences, BRCA-positive rates are remarkably similar between sites: 18% (SFGH), 16% (Chicago), and 13% (Atlanta).
Conclusions:
Although each CUB site has unique populations and referral patterns, their similar BRCA-positive rates suggest a common testing threshold. Despite the heterogeneity in site characteristics, and the challenges of combining data, our research demonstrates the feasibility of pooling data from 3 diverse public US hospitals. We welcome collaborations with other researchers and/or clinical sites. BRCA carriers are often counseled to undergo a bilateral salpingo oophorectomy (BSO). It is known that cognitive changes exist in the domains of verbal and spatial memory in women post-BSO (Sherwin et al., 1988). Recent epidemiological literature reports that women who undergo BSO before natural menopause have a higher incidence of Alzheimer’s and Parkinson’s dementias (Rocca et al., 2008), suggesting a relatively steady decline from BSO to old age. To better understand the trajectory of possible decline, we have undertaken a 3-year longitudinal study designed to observe changes in cognitive function over time, relative to concentrations of endogenous estrogens and progesterone in women with BRCA1/2 mutations who elected a BSO prior to natural menopause. Three groups of women were recruited: women with BRCA1/2 and BSO, BRCA carriers with no BSO, and age-matched controls. All were administered psychometric tasks assessing attention, verbal and spatial memory, working memory, and a self-report scale of mood. Task performance was correlated to estrogen (E1G) and progesterone metabolite (PdG) concentrations measured from urine, and also compared between groups. Preliminary results show cognitive changes in women with BSO compared to both age-matched and BRCA controls. The BSO group performed more poorly on tasks of verbal memory and attention relative to controls. However, a significant, negative association of E1G and performance on a spatial memory task was observed, and concentrations of E1G correlated negatively to a fluency clustering task assessing functioning of the frontal cortex. Furthermore, there was a significant negative association between verbal memory and time since BSO. Results indicate both positive and negative group differences in cognitive functioning of BRCA carriers with BSO. Based on previous studies reporting cognitive decline 6 months post-BSO and reversal of that decline with administration of 17β-estradiol, we believe changes observed are attributable to the absence of ovarian 17β-estradiol following BSO..
Goh, C.L.
Schumacher, F.R.
Easton, D.
Muir, K.
Henderson, B.
Kote-Jarai, Z.
Eeles, R.A.
(2012). Genetic variants associated with predisposition to prostate cancer and potential clinical implications. J intern med,
Vol.271
(4),
pp. 353-365.
show abstract
Prostate cancer is the commonest cancer in the developed world. There is an inherited component to this disease as shown in familial and twin studies. However, the discovery of these variants has been difficult. The emergence of genome-wide association studies has led to the identification of over 46 susceptibility loci. Their clinical utility to predict risk, response to treatment, or treatment toxicity, remains undefined. Large consortia are needed to achieve adequate statistical power to answer these genetic-clinical and genetic-epidemiological questions. International collaborations are currently underway to link genetic with clinical/epidemiological data to develop risk prediction models, which could direct screening and treatment programs..
Barnes, D.R.
Lee, A.
EMBRACE Investigators,
kConFab Investigators,
Easton, D.F.
Antoniou, A.C.
(2012). Evaluation of association methods for analysing modifiers of disease risk in carriers of high-risk mutations. Genet epidemiol,
Vol.36
(3),
pp. 274-291.
show abstract
There is considerable evidence indicating that disease risk in carriers of high-risk mutations (e.g. BRCA1 and BRCA2) varies by other genetic factors. Such mutations tend to be rare in the population and studies of genetic modifiers of risk have focused on sampling mutation carriers through clinical genetics centres. Genetic testing targets affected individuals from high-risk families, making ascertainment of mutation carriers non-random with respect to disease phenotype. Standard analytical methods can lead to biased estimates of associations. Methods proposed to address this problem include a weighted-cohort (WC) and retrospective likelihood (RL) approach. Their performance has not been evaluated systematically. We evaluate these methods by simulation and extend the RL to analysing associations of two diseases simultaneously (competing risks RL-CRRL). The standard cohort approach (Cox regression) yielded the most biased risk ratio (RR) estimates (relative bias-RB: -25% to -17%) and had the lowest power. The WC and RL approaches provided similar RR estimates, were least biased (RB: -2.6% to 2.5%), and had the lowest mean-squared errors. The RL method generally had more power than WC. When analysing associations with two diseases, ignoring a potential association with one disease leads to inflated type I errors for inferences with respect to the second disease and biased RR estimates. The CRRL generally gave unbiased RR estimates for both disease risks and had correct nominal type I errors. These methods are illustrated by analyses of genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers..
Couch, F.J.
Gaudet, M.M.
Antoniou, A.C.
Ramus, S.J.
Kuchenbaecker, K.B.
Soucy, P.
Beesley, J.
Chen, X.
Wang, X.
Kirchhoff, T.
McGuffog, L.
Barrowdale, D.
Lee, A.
Healey, S.
Sinilnikova, O.M.
Andrulis, I.L.
OCGN,
Ozcelik, H.
Mulligan, A.M.
Thomassen, M.
Gerdes, A.-.
Jensen, U.B.
Skytte, A.-.
Kruse, T.A.
Caligo, M.A.
von Wachenfeldt, A.
Barbany-Bustinza, G.
Loman, N.
Soller, M.
Ehrencrona, H.
Karlsson, P.
SWE-BRCA,
Nathanson, K.L.
Rebbeck, T.R.
Domchek, S.M.
Jakubowska, A.
Lubinski, J.
Jaworska, K.
Durda, K.
Zlowocka, E.
Huzarski, T.
Byrski, T.
Gronwald, J.
Cybulski, C.
Górski, B.
Osorio, A.
Durán, M.
Tejada, M.I.
Benitez, J.
Hamann, U.
Hogervorst, F.B.
HEBON,
van Os, T.A.
van Leeuwen, F.E.
Meijers-Heijboer, H.E.
Wijnen, J.
Blok, M.J.
Kets, M.
Hooning, M.J.
Oldenburg, R.A.
Ausems, M.G.
Peock, S.
Frost, D.
Ellis, S.D.
Platte, R.
Fineberg, E.
Evans, D.G.
Jacobs, C.
Eeles, R.A.
Adlard, J.
Davidson, R.
Eccles, D.M.
Cole, T.
Cook, J.
Paterson, J.
Brewer, C.
Douglas, F.
Hodgson, S.V.
Morrison, P.J.
Walker, L.
Porteous, M.E.
Kennedy, M.J.
Side, L.E.
EMBRACE,
Bove, B.
Godwin, A.K.
Stoppa-Lyonnet, D.
GEMO Study Collaborators,
Fassy-Colcombet, M.
Castera, L.
Cornelis, F.
Mazoyer, S.
Léoné, M.
Boutry-Kryza, N.
Bressac-de Paillerets, B.
Caron, O.
Pujol, P.
Coupier, I.
Delnatte, C.
Akloul, L.
Lynch, H.T.
Snyder, C.L.
Buys, S.S.
Daly, M.B.
Terry, M.
Chung, W.K.
John, E.M.
Miron, A.
Southey, M.C.
Hopper, J.L.
Goldgar, D.E.
Singer, C.F.
Rappaport, C.
Tea, M.-.
Fink-Retter, A.
Hansen, T.V.
Nielsen, F.C.
Arason, A.
Vijai, J.
Shah, S.
Sarrel, K.
Robson, M.E.
Piedmonte, M.
Phillips, K.
Basil, J.
Rubinstein, W.S.
Boggess, J.
Wakeley, K.
Ewart-Toland, A.
Montagna, M.
Agata, S.
Imyanitov, E.N.
Isaacs, C.
Janavicius, R.
Lazaro, C.
Blanco, I.
Feliubadalo, L.
Brunet, J.
Gayther, S.A.
Pharoah, P.P.
Odunsi, K.O.
Karlan, B.Y.
Walsh, C.S.
Olah, E.
Teo, S.H.
Ganz, P.A.
Beattie, M.S.
van Rensburg, E.J.
Dorfling, C.M.
Diez, O.
Kwong, A.
Schmutzler, R.K.
Wappenschmidt, B.
Engel, C.
Meindl, A.
Ditsch, N.
Arnold, N.
Heidemann, S.
Niederacher, D.
Preisler-Adams, S.
Gadzicki, D.
Varon-Mateeva, R.
Deissler, H.
Gehrig, A.
Sutter, C.
Kast, K.
Fiebig, B.
Heinritz, W.
Caldes, T.
de la Hoya, M.
Muranen, T.A.
Nevanlinna, H.
Tischkowitz, M.D.
Spurdle, A.B.
Neuhausen, S.L.
Ding, Y.C.
Lindor, N.M.
Fredericksen, Z.
Pankratz, V.S.
Peterlongo, P.
Manoukian, S.
Peissel, B.
Zaffaroni, D.
Barile, M.
Bernard, L.
Viel, A.
Giannini, G.
Varesco, L.
Radice, P.
Greene, M.H.
Mai, P.L.
Easton, D.F.
Chenevix-Trench, G.
kConFab investigators,
Offit, K.
Simard, J.
Consortium of Investigators of Modifiers of BRCA1/2,
(2012). Common variants at the 19p13 1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer epidemiol biomarkers prev,
Vol.21
(4),
pp. 645-657.
show abstract
BACKGROUND: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). METHODS: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. RESULTS: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)). CONCLUSIONS: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. IMPACT: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers..
Ramus, S.J.
Antoniou, A.C.
Kuchenbaecker, K.B.
Soucy, P.
Beesley, J.
Chen, X.
McGuffog, L.
Sinilnikova, O.M.
Healey, S.
Barrowdale, D.
Lee, A.
Thomassen, M.
Gerdes, A.-.
Kruse, T.A.
Jensen, U.B.
Skytte, A.-.
Caligo, M.A.
Liljegren, A.
Lindblom, A.
Olsson, H.
Kristoffersson, U.
Stenmark-Askmalm, M.
Melin, B.
SWE-BRCA,
Domchek, S.M.
Nathanson, K.L.
Rebbeck, T.R.
Jakubowska, A.
Lubinski, J.
Jaworska, K.
Durda, K.
Złowocka, E.
Gronwald, J.
Huzarski, T.
Byrski, T.
Cybulski, C.
Toloczko-Grabarek, A.
Osorio, A.
Benitez, J.
Duran, M.
Tejada, M.-.
Hamann, U.
Rookus, M.
van Leeuwen, F.E.
Aalfs, C.M.
Meijers-Heijboer, H.E.
van Asperen, C.J.
van Roozendaal, K.E.
Hoogerbrugge, N.
Collée, J.M.
Kriege, M.
van der Luijt, R.B.
HEBON,
EMBRACE,
Peock, S.
Frost, D.
Ellis, S.D.
Platte, R.
Fineberg, E.
Evans, D.G.
Lalloo, F.
Jacobs, C.
Eeles, R.
Adlard, J.
Davidson, R.
Eccles, D.
Cole, T.
Cook, J.
Paterson, J.
Douglas, F.
Brewer, C.
Hodgson, S.
Morrison, P.J.
Walker, L.
Porteous, M.E.
Kennedy, M.J.
Pathak, H.
Godwin, A.K.
Stoppa-Lyonnet, D.
Caux-Moncoutier, V.
de Pauw, A.
Gauthier-Villars, M.
Mazoyer, S.
Léoné, M.
Calender, A.
Lasset, C.
Bonadona, V.
Hardouin, A.
Berthet, P.
Bignon, Y.-.
Uhrhammer, N.
Faivre, L.
Loustalot, C.
GEMO,
Buys, S.
Daly, M.
Miron, A.
Terry, M.B.
Chung, W.K.
John, E.M.
Southey, M.
Goldgar, D.
Singer, C.F.
Tea, M.-.
Pfeiler, G.
Fink-Retter, A.
Hansen, T.V.
Ejlertsen, B.
Johannsson, O.T.
Offit, K.
Kirchhoff, T.
Gaudet, M.M.
Vijai, J.
Robson, M.
Piedmonte, M.
Phillips, K.-.
Van Le, L.
Hoffman, J.S.
Ewart Toland, A.
Montagna, M.
Tognazzo, S.
Imyanitov, E.
Issacs, C.
Janavicius, R.
Lazaro, C.
Blanco, I.
Tornero, E.
Navarro, M.
Moysich, K.B.
Karlan, B.Y.
Gross, J.
Olah, E.
Vaszko, T.
Teo, S.-.
Ganz, P.A.
Beattie, M.S.
Dorfling, C.M.
van Rensburg, E.J.
Diez, O.
Kwong, A.
Schmutzler, R.K.
Wappenschmidt, B.
Engel, C.
Meindl, A.
Ditsch, N.
Arnold, N.
Heidemann, S.
Niederacher, D.
Preisler-Adams, S.
Gadzicki, D.
Varon-Mateeva, R.
Deissler, H.
Gehrig, A.
Sutter, C.
Kast, K.
Fiebig, B.
Schäfer, D.
Caldes, T.
de la Hoya, M.
Nevanlinna, H.
Aittomäki, K.
Plante, M.
Spurdle, A.B.
kConFab,
Neuhausen, S.L.
Ding, Y.C.
Wang, X.
Lindor, N.
Fredericksen, Z.
Pankratz, V.S.
Peterlongo, P.
Manoukian, S.
Peissel, B.
Zaffaroni, D.
Bonanni, B.
Bernard, L.
Dolcetti, R.
Papi, L.
Ottini, L.
Radice, P.
Greene, M.H.
Mai, P.L.
Andrulis, I.L.
Glendon, G.
Ozcelik, H.
OCGN,
Pharoah, P.D.
Gayther, S.A.
Simard, J.
Easton, D.F.
Couch, F.J.
Chenevix-Trench, G.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA),
(2012). Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Hum mutat,
Vol.33
(4),
pp. 690-702.
show abstract
Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer..
Jakubowska, A.
Rozkrut, D.
Antoniou, A.
Hamann, U.
Scott, R.J.
McGuffog, L.
Healy, S.
Sinilnikova, O.M.
Rennert, G.
Lejbkowicz, F.
Flugelman, A.
Andrulis, I.L.
Glendon, G.
Ozcelik, H.
Thomassen, M.
Paligo, M.
Aretini, P.
Kantala, J.
Aroer, B.
Von Wachenfeldt, A.
Liljegren, A.
Loman, N.
Herbst, K.
Kristoffersson, U.
Rosenquist, R.
Karlsson, P.
Stenmark-Askmalm, M.
Melin, B.
Nathanson, K.L.
Domchek, S.M.
Byrski, T.
Huzarski, T.
Gronwald, J.
Menkiszak, J.
Cybulski, C.
Serrano, P.
Osorio, A.
Cajal, T.R.
Tsitlaidou, M.
Benitez, J.
Gilbert, M.
Rookus, M.
Aalfs, C.M.
Kluijt, I.
Boessenkool-Pape, J.L.
Meijers-Heijboer, H.E.
Oosterwijk, J.C.
van Asperen, C.J.
Blok, M.J.
Nelen, M.R.
van den Ouweland, A.M.
Seynaeve, C.
van der Luijt, R.B.
Devilee, P.
Easton, D.F.
Peock, S.
Frost, D.
Platte, R.
Ellis, S.D.
Fineberg, E.
Evans, D.G.
Lalloo, F.
Eeles, R.
Jacobs, C.
Adlard, J.
Davidson, R.
Eccles, D.
Cole, T.
Cook, J.
Godwin, A.
Bove, B.
Stoppa-Lyonnet, D.
Caux-Moncoutier, V.
Belotti, M.
Tirapo, C.
Mazoyer, S.
Barjhoux, L.
Boutry-Kryza, N.
Pujol, P.
Coupier, I.
Peyrat, J.-.
Vennin, P.
Muller, D.
Fricker, J.-.
Venat-Bouvet, L.
Johannsson, O.
Isaacs, C.
Schmutzler, R.
Wappenschmidt, B.
Meindl, A.
Arnold, N.
Varon-Mateeva, R.
Niederacher, D.
Sutter, C.
Deissler, H.
Preisler-Adams, S.
Simard, J.
Soucy, P.
Durocher, F.
Chenevix-Trench, G.
Beesley, J.
Chen, X.
Rebbeck, T.
Couch, F.
Wang, X.
Lindor, N.
Fredericksen, Z.
Pankratz, V.S.
Peterlongo, P.
Bonanni, B.
Fortuzzi, S.
Peissel, B.
Szabo, C.
Mai, P.L.
Loud, J.T.
Lubinski, J.
OCGN,
BRCA, S.W.
HEBON,
EMBRACE,
Collaborators, G.E.
KConFab,
CIMBA,
(2012). Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study. British journal of cancer,
Vol.106
(12),
pp. 2016-2024.
Pijpe, A.
Andrieu, N.
Easton, D.F.
Kesminiene, A.
Cardis, E.
Nogues, C.
Gauthier-Villars, M.
Lasset, C.
Fricker, J.-.
Peock, S.
Frost, D.
Evans, D.G.
Eeles, R.A.
Paterson, J.
Manders, P.
van Asperen, C.J.
Ausems, M.G.
Meijers-Heijboer, H.
Thierry-Chef, I.
Hauptmann, M.
Goldgar, D.
Rookus, M.A.
van Leeuwen, F.E.
GENEPSO,
EMBRACE,
HEBON,
(2012). Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK). Bmj-british medical journal,
Vol.345.
Vachon, C.M.
Scott, C.G.
Fasching, P.A.
Hall, P.
Tamimi, R.M.
Li, J.
Stone, J.
Apicella, C.
Odefrey, F.
Gierach, G.L.
Jud, S.M.
Heusinger, K.
Beckmann, M.W.
Pollan, M.
Fernández-Navarro, P.
Gonzalez-Neira, A.
Benitez, J.
van Gils, C.H.
Lokate, M.
Onland-Moret, N.C.
Peeters, P.H.
Brown, J.
Leyland, J.
Varghese, J.S.
Easton, D.F.
Thompson, D.J.
Luben, R.N.
Warren, R.M.
Wareham, N.J.
Loos, R.J.
Khaw, K.-.
Ursin, G.
Lee, E.
Gayther, S.A.
Ramus, S.J.
Eeles, R.A.
Leach, M.O.
Kwan-Lim, G.
Couch, F.J.
Giles, G.G.
Baglietto, L.
Krishnan, K.
Southey, M.C.
Le Marchand, L.
Kolonel, L.N.
Woolcott, C.
Maskarinec, G.
Haiman, C.A.
Walker, K.
Johnson, N.
McCormack, V.A.
Biong, M.
Alnaes, G.I.
Gram, I.T.
Kristensen, V.N.
Børresen-Dale, A.-.
Lindström, S.
Hankinson, S.E.
Hunter, D.J.
Andrulis, I.L.
Knight, J.A.
Boyd, N.F.
Figuero, J.D.
Lissowska, J.
Wesolowska, E.
Peplonska, B.
Bukowska, A.
Reszka, E.
Liu, J.
Eriksson, L.
Czene, K.
Audley, T.
Wu, A.H.
Pankratz, V.S.
Hopper, J.L.
dos-Santos-Silva, I.
(2012). Common breast cancer susceptibility variants in LSP1 and RAD51L1 are associated with mammographic density measures that predict breast cancer risk. Cancer epidemiol biomarkers prev,
Vol.21
(7),
pp. 1156-1166.
show abstract
BACKGROUND: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures. METHODS: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status. RESULTS: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07). CONCLUSION: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland. IMPACT: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association..
Jin, G.
Lu, L.
Cooney, K.A.
Ray, A.M.
Zuhlke, K.A.
Lange, E.M.
Cannon-Albright, L.A.
Camp, N.J.
Teerlink, C.C.
FitzGerald, L.M.
Stanford, J.L.
Wiley, K.E.
Isaacs, S.D.
Walsh, P.C.
Foulkes, W.D.
Giles, G.G.
Hopper, J.L.
Severi, G.
Eeles, R.
Easton, D.
Kote-Jarai, Z.
Guy, M.
Rinckleb, A.
Maier, C.
Vogel, W.
Cancel-Tassin, G.
Egrot, C.
Cussenot, O.
Thibodeau, S.N.
McDonnell, S.K.
Schaid, D.J.
Wiklund, F.
Gronberg, H.
Emanuelsson, M.
Whittemore, A.S.
Oakley-Girvan, I.
Hsieh, C.-.
Wahlfors, T.
Tammela, T.
Schleutker, J.
Catalona, W.J.
Zheng, S.L.
Ostrander, E.A.
Isaacs, W.B.
Xu, J.
(2012). Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: evidence from the International Consortium for Prostate Cancer Genetics (ICPCG). Human genetics,
Vol.131
(7),
pp. 1095-1103.
Leongamornlert, D.
Mahmud, N.
Tymrakiewicz, M.
Saunders, E.
Dadaev, T.
Castro, E.
Goh, C.
Govindasami, K.
Guy, M.
O'Brien, L.
Sawyer, E.
Hall, A.
Wilkinson, R.
Easton, D.
UKGPCS Collaborators,
Goldgar, D.
Eeles, R.
Kote-Jarai, Z.
(2012). Germline BRCA1 mutations increase prostate cancer risk. Br j cancer,
Vol.106
(10),
pp. 1697-1701.
show abstract
BACKGROUND: Prostate cancer (PrCa) is one of the most common cancers affecting men but its aetiology is poorly understood. Family history of PrCa, particularly at a young age, is a strong risk factor. There have been previous reports of increased PrCa risk in male BRCA1 mutation carriers in female breast cancer families, but there is a controversy as to whether this risk is substantiated. We sought to evaluate the role of germline BRCA1 mutations in PrCa predisposition by performing a candidate gene study in a large UK population sample set. METHODS: We screened 913 cases aged 36–86 years for germline BRCA1 mutation, with the study enriched for cases with an early age of onset. We analysed the entire coding region of the BRCA1 gene using Sanger sequencing. Multiplex ligation-dependent probe amplification was also used to assess the frequency of large rearrangements in 460 cases. RESULTS: We identified 4 deleterious mutations and 45 unclassified variants (UV). The frequency of deleterious BRCA1 mutation in this study is 0.45%; three of the mutation carriers were affected at age 65 years and one developed PrCa at 69 years. Using previously estimated population carrier frequencies, deleterious BRCA1 mutations confer a relative risk of PrCa of ~3.75-fold, (95% confidence interval 1.02–9.6) translating to a 8.6% cumulative risk by age 65. CONCLUSION: This study shows evidence for an increased risk of PrCa in men who harbour germline mutations in BRCA1. This could have a significant impact on possible screening strategies and targeted treatments..
Ding, Y.C.
McGuffog, L.
Healey, S.
Friedman, E.
Laitman, Y.
Paluch-Shimon, S.
Kaufman, B.
SWE-BRCA,
Liljegren, A.
Lindblom, A.
Olsson, H.
Kristoffersson, U.
Stenmark-Askmalm, M.
Melin, B.
Domchek, S.M.
Nathanson, K.L.
Rebbeck, T.R.
Jakubowska, A.
Lubinski, J.
Jaworska, K.
Durda, K.
Gronwald, J.
Huzarski, T.
Cybulski, C.
Byrski, T.
Osorio, A.
Cajal, T.R.
Stavropoulou, A.V.
Benítez, J.
Hamann, U.
HEBON,
Rookus, M.
Aalfs, C.M.
de Lange, J.L.
Meijers-Heijboer, H.E.
Oosterwijk, J.C.
van Asperen, C.J.
Gómez García, E.B.
Hoogerbrugge, N.
Jager, A.
van der Luijt, R.B.
EMBRACE,
Easton, D.F.
Peock, S.
Frost, D.
Ellis, S.D.
Platte, R.
Fineberg, E.
Evans, D.G.
Lalloo, F.
Izatt, L.
Eeles, R.
Adlard, J.
Davidson, R.
Eccles, D.
Cole, T.
Cook, J.
Brewer, C.
Tischkowitz, M.
Godwin, A.K.
Pathak, H.
GEMO Study Collaborators,
Stoppa-Lyonnet, D.
Sinilnikova, O.M.
Mazoyer, S.
Barjhoux, L.
Léoné, M.
Gauthier-Villars, M.
Caux-Moncoutier, V.
de Pauw, A.
Hardouin, A.
Berthet, P.
Dreyfus, H.
Ferrer, S.F.
Collonge-Rame, M.-.
Sokolowska, J.
Buys, S.
Daly, M.
Miron, A.
Terry, M.B.
Chung, W.
John, E.M.
Southey, M.
Goldgar, D.
Singer, C.F.
Tea, M.-.
Gschwantler-Kaulich, D.
Fink-Retter, A.
Hansen, T.V.
Ejlertsen, B.
Johannsson, O.T.
Offit, K.
Sarrel, K.
Gaudet, M.M.
Vijai, J.
Robson, M.
Piedmonte, M.R.
Andrews, L.
Cohn, D.
DeMars, L.R.
DiSilvestro, P.
Rodriguez, G.
Toland, A.E.
Montagna, M.
Agata, S.
Imyanitov, E.
Isaacs, C.
Janavicius, R.
Lazaro, C.
Blanco, I.
Ramus, S.J.
Sucheston, L.
Karlan, B.Y.
Gross, J.
Ganz, P.A.
Beattie, M.S.
Schmutzler, R.K.
Wappenschmidt, B.
Meindl, A.
Arnold, N.
Niederacher, D.
Preisler-Adams, S.
Gadzicki, D.
Varon-Mateeva, R.
Deissler, H.
Gehrig, A.
Sutter, C.
Kast, K.
Nevanlinna, H.
Aittomäki, K.
Simard, J.
KConFab Investigators,
Spurdle, A.B.
Beesley, J.
Chen, X.
Tomlinson, G.E.
Weitzel, J.
Garber, J.E.
Olopade, O.I.
Rubinstein, W.S.
Tung, N.
Blum, J.L.
Narod, S.A.
Brummel, S.
Gillen, D.L.
Lindor, N.
Fredericksen, Z.
Pankratz, V.S.
Couch, F.J.
Radice, P.
Peterlongo, P.
Greene, M.H.
Loud, J.T.
Mai, P.L.
Andrulis, I.L.
Glendon, G.
Ozcelik, H.
OCGN,
Gerdes, A.-.
Thomassen, M.
Jensen, U.B.
Skytte, A.-.
Caligo, M.A.
Lee, A.
Chenevix-Trench, G.
Antoniou, A.C.
Neuhausen, S.L.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA),
(2012). A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers. Cancer epidemiol biomarkers prev,
Vol.21
(8),
pp. 1362-1370.
show abstract
BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. IMPACT: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers..
Heijnsdijk, E.A.
Warner, E.
Gilbert, F.J.
Tilanus-Linthorst, M.M.
Evans, G.
Causer, P.A.
Eeles, R.A.
Kaas, R.
Draisma, G.
Ramsay, E.A.
Warren, R.M.
Hill, K.A.
Hoogerbrugge, N.
Wasser, M.N.
Bergers, E.
Oosterwijk, J.C.
Hooning, M.J.
Rutgers, E.J.
Klijn, J.G.
Plewes, D.B.
Leach, M.O.
de Koning, H.J.
(2012). Differences in natural history between breast cancers in BRCA1 and BRCA2 mutation carriers and effects of MRI screening-MRISC, MARIBS, and Canadian studies combined. Cancer epidemiol biomarkers prev,
Vol.21
(9),
pp. 1458-1468.
show abstract
BACKGROUND: It is recommended that BRCA1/2 mutation carriers undergo breast cancer screening using MRI because of their very high cancer risk and the high sensitivity of MRI in detecting invasive cancers. Clinical observations suggest important differences in the natural history between breast cancers due to mutations in BRCA1 and BRCA2, potentially requiring different screening guidelines. METHODS: Three studies of mutation carriers using annual MRI and mammography were analyzed. Separate natural history models for BRCA1 and BRCA2 were calibrated to the results of these studies and used to predict the impact of various screening protocols on detection characteristics and mortality. RESULTS: BRCA1/2 mutation carriers (N = 1,275) participated in the studies and 124 cancers (99 invasive) were diagnosed. Cancers detected in BRCA2 mutation carriers were smaller [80% ductal carcinoma in situ (DCIS) or ≤10 mm vs. 49% for BRCA1, P < 0.001]. Below the age of 40, one (invasive) cancer of the 25 screen-detected cancers in BRCA1 mutation carriers was detected by mammography alone, compared with seven (three invasive) of 11 screen-detected cancers in BRCA2 (P < 0.0001). In the model, the preclinical period during which cancer is screen-detectable was 1 to 4 years for BRCA1 and 2 to 7 years for BRCA2. The model predicted breast cancer mortality reductions of 42% to 47% for mammography, 48% to 61% for MRI, and 50% to 62% for combined screening. CONCLUSIONS: Our studies suggest substantial mortality benefits in using MRI to screen BRCA1/2 mutation carriers aged 25 to 60 years but show important clinical differences in natural history. IMPACT: BRCA1 and BRCA2 mutation carriers may benefit from different screening protocols, for example, below the age of 40..
Killick, E.
Bancroft, E.
Kote-Jarai, Z.
Eeles, R.
(2012). Beyond prostate-specific antigen - future biomarkers for the early detection and management of prostate cancer. Clin oncol (r coll radiol),
Vol.24
(8),
pp. 545-555.
show abstract
Prostate-specific antigen is currently commonly used as a screening biomarker for prostate cancer, but it has limitations in both sensitivity and specificity. The development of novel biomarkers for early cancer detection has the potential to improve survival, reduce unnecessary investigations and benefit the health economy. Here we review the use and limitations of prostate-specific antigen and its subtypes, urinary biomarkers including PCA3, alpha-methylacyl-CoA racemase, the TMPRSS2-ERG fusion gene and microseminoprotein-beta, and other novel markers in both serum and urine. Many of these biomarkers are at early stages of development and require evaluation in prospective trials to determine their potential usefulness in clinical practice. Genetic profiling may allow for the targeting of high-risk populations for screening and may offer the opportunity to combine biomarker results with genotype to aid risk assessment..
Cheng, I.
Chen, G.K.
Nakagawa, H.
He, J.
Wan, P.
Laurie, C.C.
Shen, J.
Sheng, X.
Pooler, L.C.
Crenshaw, A.T.
Mirel, D.B.
Takahashi, A.
Kubo, M.
Nakamura, Y.
Al Olama, A.A.
Benlloch, S.
Donovan, J.L.
Guy, M.
Hamdy, F.C.
Kote-Jarai, Z.
Neal, D.E.
Wilkens, L.R.
Monroe, K.R.
Stram, D.O.
Muir, K.
Eeles, R.A.
Easton, D.F.
Kolonel, L.N.
Henderson, B.E.
Le Marchand, L.
Haiman, C.A.
(2012). Evaluating genetic risk for prostate cancer among Japanese and Latinos. Cancer epidemiol biomarkers prev,
Vol.21
(11),
pp. 2048-2058.
show abstract
BACKGROUND: There have been few genome-wide association studies (GWAS) of prostate cancer among diverse populations. To search for novel prostate cancer risk variants, we conducted GWAS of prostate cancer in Japanese and Latinos. In addition, we tested prostate cancer risk variants and developed genetic risk models of prostate cancer for Japanese and Latinos. METHODS: Our first-stage GWAS of prostate cancer included Japanese (cases/controls = 1,033/1,042) and Latino (cases/controls = 1,043/1,057) from the Multiethnic Cohort (MEC). Significant associations from stage I (P < 1.0 × 10(-4)) were examined in silico in GWAS of prostate cancer (stage II) in Japanese (cases/controls = 1,583/3,386) and Europeans (cases/controls = 1,854/1,894). RESULTS: No novel stage I single-nucleotide polymorphism (SNP) outside of known risk regions reached genome-wide significance. For Japanese, in stage I, the most notable putative novel association was seen with 10 SNPs (P ≤ 8.0 × 10(-6)) at chromosome 2q33; however, this was not replicated in stage II. For Latinos, the most significant association was observed with rs17023900 at the known 3p12 risk locus (stage I: OR = 1.45; P = 7.01 × 10(-5) and stage II: OR = 1.58; P = 3.05 × 10(-7)). The majority of the established risk variants for prostate cancer, 79% and 88%, were positively associated with prostate cancer in Japanese and Latinos (stage I), respectively. The cumulative effects of these variants significantly influence prostate cancer risk (OR per allele = 1.10; P = 2.71 × 10(-25) and OR = 1.07; P = 1.02 × 10(-16) for Japanese and Latinos, respectively). CONCLUSION AND IMPACT: Our GWAS of prostate cancer did not identify novel genome-wide significant variants. However, our findings show that established risk variants for prostate cancer significantly contribute to risk among Japanese and Latinos..
Robertson, L.
Hanson, H.
Seal, S.
Warren-Perry, M.
Hughes, D.
Howell, I.
Turnbull, C.
Houlston, R.
Shanley, S.
Butler, S.
Evans, D.G.
Ross, G.
Eccles, D.
Tutt, A.
Rahman, N.
TNT Trial TMG,
BCSC (UK),
(2012). BRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years. Br j cancer,
Vol.106
(6),
pp. 1234-1238.
show abstract
BACKGROUND: Triple-negative (TN) tumours are the predominant breast cancer subtype in BRCA1 mutation carriers. Recently, it was proposed that all individuals below 50 years of age with TN breast cancer should be offered BRCA testing. We have evaluated the BRCA1 mutation frequency and the implications for clinical practice of undertaking genetic testing in women with TN breast cancer. METHODS: We undertook BRCA1 mutation analysis in 308 individuals with TN breast cancer, 159 individuals from unselected series of breast cancer and 149 individuals from series ascertained on the basis of young age and/or family history. RESULTS: BRCA1 mutations were present in 45 out of 308 individuals. Individuals with TN cancer <50 years had >10% likelihood of carrying a BRCA1 mutation in both the unselected (11 out of 58, 19%) and selected (26 out of 111, 23%) series. However, over a third would not have been offered testing using existing criteria. We estimate that testing all individuals with TN breast cancer <50 years would generate an extra 1200 tests annually in England. CONCLUSION: Women with TN breast cancer diagnosed below 50 years have >10% likelihood of carrying a BRCA1 mutation and are therefore eligible for testing in most centres. However, implementation may place short-term logistical and financial burdens on genetic services..
Turnbull, C.
Seal, S.
Renwick, A.
Warren-Perry, M.
Hughes, D.
Elliott, A.
Pernet, D.
Peock, S.
Adlard, J.W.
Barwell, J.
Berg, J.
Brady, A.F.
Brewer, C.
Brice, G.
Chapman, C.
Cook, J.
Davidson, R.
Donaldson, A.
Douglas, F.
Greenhalgh, L.
Henderson, A.
Izatt, L.
Kumar, A.
Lalloo, F.
Miedzybrodzka, Z.
Morrison, P.J.
Paterson, J.
Porteous, M.
Rogers, M.T.
Shanley, S.
Walker, L.
Breast Cancer Susceptibility Collaboration (UK), EMBRACE,
Ahmed, M.
Eccles, D.
Evans, D.G.
Donnelly, P.
Easton, D.F.
Stratton, M.R.
Rahman, N.
(2012). Gene-gene interactions in breast cancer susceptibility. Hum mol genet,
Vol.21
(4),
pp. 958-962.
show abstract
There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10(-4); ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 × 10(-4); CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation..
Bailey-Wilson, J.E.
Childs, E.J.
Cropp, C.D.
Schaid, D.J.
Xu, J.
Camp, N.J.
Cannon-Albright, L.A.
Farnham, J.M.
George, A.
Powell, I.
Carpten, J.D.
Giles, G.G.
Hopper, J.L.
Severi, G.
English, D.R.
Foulkes, W.D.
Maehle, L.
Moller, P.
Eeles, R.
Easton, D.
Guy, M.
Edwards, S.
Badzioch, M.D.
Whittemore, A.S.
Oakley-Girvan, I.
Hsieh, C.-.
Dimitrov, L.
Stanford, J.L.
Karyadi, D.M.
Deutsch, K.
McIntosh, L.
Ostrander, E.A.
Wiley, K.E.
Isaacs, S.D.
Walsh, P.C.
Thibodeau, S.N.
McDonnell, S.K.
Hebbring, S.
Lange, E.M.
Cooney, K.A.
Tammela, T.L.
Schleutker, J.
Maier, C.
Bochum, S.
Hoegel, J.
Gronberg, H.
Wiklund, F.
Emanuelsson, M.
Cancel-Tassin, G.
Valeri, A.
Cussenot, O.
Isaacs, W.B.
Genet, I.C.
(2012). Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families. Bmc medical genetics,
Vol.13.
Finkelman, B.S.
Rubinstein, W.S.
Friedman, S.
Friebel, T.M.
Dubitsky, S.
Schonberger, N.S.
Shoretz, R.
Singer, C.F.
Blum, J.L.
Tung, N.
Olopade, O.I.
Weitzel, J.N.
Lynch, H.T.
Snyder, C.
Garber, J.E.
Schildkraut, J.
Daly, M.B.
Isaacs, C.
Pichert, G.
Neuhausen, S.L.
Couch, F.J.
van't Veer, L.
Eeles, R.
Bancroft, E.
Evans, D.G.
Ganz, P.A.
Tomlinson, G.E.
Narod, S.A.
Matloff, E.
Domchek, S.
Rebbeck, T.R.
(2012). Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. J clin oncol,
Vol.30
(12),
pp. 1321-1328.
show abstract
PURPOSE: Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction. METHODS: Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self-identified Jewish status. RESULTS: Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively; odds ratio, 1.87; 95% CI, 1.44 to 2.42). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers (hazard ratio, 0.35; 95% CI, 0.18 to 0.69). No significant difference was seen in cancer risk reduction after RRSO among subgroups. CONCLUSION: Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care..
Bolton, K.L.
Chenevix-Trench, G.
Goh, C.
Sadetzki, S.
Ramus, S.J.
Karlan, B.Y.
Lambrechts, D.
Despierre, E.
Barrowdale, D.
McGuffog, L.
Healey, S.
Easton, D.F.
Sinilnikova, O.
Benitez, J.
Garcia, M.J.
Neuhausen, S.
Gail, M.H.
Hartge, P.
Peock, S.
Frost, D.
Evans, G.
Eeles, R.
Godwin, A.K.
Daly, M.B.
Kwong, A.
Ma, E.S.
Lazaro, C.
Blanco, I.
Montagna, M.
D'Andrea, E.
Nicoletto, M.O.
Johnatty, S.E.
Krueger, S.
Jensen, A.
Hogdall, E.
Goode, E.L.
Fridley, B.L.
Loud, J.T.
Greene, M.H.
Mai, P.L.
Chetrit, A.
Lubin, F.
Hirsh-Yechezkel, G.
Glendon, G.
Andrulis, I.L.
Toland, A.E.
Senter, L.
Gore, M.E.
Gourley, C.
Michie, C.O.
Song, H.
Tyrer, J.
Whittemore, A.S.
McGuire, V.
Sieh, W.
Kristoffersson, U.
Olsson, H.
Borg, A.
Levine, D.A.
Steele, L.
Beattie, M.S.
Chan, S.
Nussbaum, R.L.
Moysich, K.B.
Gross, J.
Cass, I.
Walsh, C.
Li, A.J.
Leuchter, R.
Gordon, O.
Garcia-Closas, M.
Gayther, S.A.
Chanock, S.J.
Antoniou, A.C.
Pharoah, P.D.
EMBRACE,
Investigators, K.
Network, C.G.
(2012). Association Between BRCA1 and BRCA2 Mutations and Survival in Women With Invasive Epithelial Ovarian Cancer. Jama-journal of the american medical association,
Vol.307
(4),
pp. 382-390.
Kirchhoff, T.
Gaudet, M.M.
Antoniou, A.C.
McGuffog, L.
Humphreys, M.K.
Dunning, A.M.
Bojesen, S.E.
Nordestgaard, B.G.
Flyger, H.
Kang, D.
Yoo, K.-.
Noh, D.-.
Ahn, S.-.
Dork, T.
Schuermann, P.
Karstens, J.H.
Hillemanns, P.
Couch, F.J.
Olson, J.
Vachon, C.
Wang, X.
Cox, A.
Brock, I.
Elliott, G.
Reed, M.W.
Burwinkel, B.
Meindl, A.
Brauch, H.
Hamann, U.
Ko, Y.-.
Broeks, A.
Schmidt, M.K.
Van 't Veer, L.J.
Braaf, L.M.
Johnson, N.
Fletcher, O.
Gibson, L.
Peto, J.
Turnbull, C.
Seal, S.
Renwick, A.
Rahman, N.
Wu, P.-.
Yu, J.-.
Hsiung, C.-.
Shen, C.-.
Southey, M.C.
Hopper, J.L.
Hammet, F.
Van Dorpe, T.
Dieudonne, A.-.
Hatse, S.
Lambrechts, D.
Andrulis, I.L.
Bogdanova, N.
Antonenkova, N.
Rogov, J.I.
Prokofieva, D.
Bermisheva, M.
Khusnutdinova, E.
van Asperen, C.J.
Tollenaar, R.A.
Hooning, M.J.
Devilee, P.
Margolin, S.
Lindblom, A.
Milne, R.L.
Ignacio Arias, J.
Pilar Zamora, M.
Benitez, J.
Severi, G.
Baglietto, L.
Giles, G.G.
Spurdle, A.B.
Beesley, J.
Chen, X.
Holland, H.
Healey, S.
Wang-Gohrke, S.
Chang-Claude, J.
Mannermaa, A.
Kosma, V.-.
Kauppinen, J.
Kataja, V.
Agnarsson, B.A.
Caligo, M.A.
Godwin, A.K.
Nevanlinna, H.
Heikkinen, T.
Fredericksen, Z.
Lindor, N.
Nathanson, K.L.
Domchek, S.M.
Loman, N.
Karlsson, P.
Askmalm, M.S.
Melin, B.
von Wachenfeldt, A.
Hogervorst, F.B.
Verheus, M.
Rookus, M.A.
Seynaeve, C.
Oldenburg, R.A.
Ligtenberg, M.J.
Ausems, M.G.
Aalfs, C.M.
Gille, H.J.
Wijnen, J.T.
Garcia, E.B.
Peock, S.
Cook, M.
Oliver, C.T.
Frost, D.
Luccarini, C.
Pichert, G.
Davidson, R.
Chu, C.
Eccles, D.
Ong, K.-.
Cook, J.
Douglas, F.
Hodgson, S.
Evans, D.G.
Eeles, R.
Gold, B.
Pharoah, P.D.
Offit, K.
Chenevix-Trench, G.
Easton, D.F.
Network, G.E.
kConFab,
Grp, A.O.
SWE-BRCA,
HEBON,
EMBRACE,
BCAC-CIMBA,
(2012). Breast Cancer Risk and 6q22 33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2. Plos one,
Vol.7
(6).
Maia, A.-.
Antoniou, A.C.
O'Reilly, M.
Samarajiwa, S.
Dunning, M.
Kartsonaki, C.
Chin, S.-.
Curtis, C.N.
McGuffog, L.
Domchek, S.M.
Easton, D.F.
Peock, S.
Frost, D.
Evans, D.G.
Eeles, R.
Izatt, L.
Adlard, J.
Eccles, D.
Sinilnikova, O.M.
Mazoyer, S.
Stoppa-Lyonnet, D.
Gauthier-Villars, M.
Faivre, L.
Venat-Bouvet, L.
Delnatte, C.
Nevanlinna, H.
Couch, F.J.
Godwin, A.K.
Caligo, M.A.
Barkardottir, R.B.
Chen, X.
Beesley, J.
Healey, S.
Caldas, C.
Chenevix-Trench, G.
Ponder, B.A.
EMBRACE,
Collaborators, G.E.
SWE-BRCA,
Investigators, K.
(2012). Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers. Breast cancer research,
Vol.14
(2).
Antoniou, A.C.
Kuchenbaecker, K.B.
Soucy, P.
Beesley, J.
Chen, X.
McGuffog, L.
Lee, A.
Barrowdale, D.
Healey, S.
Sinilnikova, O.M.
Caligo, M.A.
Loman, N.
Harbst, K.
Lindblom, A.
Arver, B.
Rosenquist, R.
Karlsson, P.
Nathanson, K.
Domchek, S.
Rebbeck, T.
Jakubowska, A.
Lubinski, J.
Jaworska, K.
Durda, K.
Zlowowcka-Perlowska, E.
Osorio, A.
Duran, M.
Andres, R.
Benitez, J.
Hamann, U.
Hogervorst, F.B.
van Os, T.A.
Verhoef, S.
Meijers-Heijboer, H.E.
Wijnen, J.
Garcia, E.B.
Ligtenberg, M.J.
Kriege, M.
Collee, M.
Ausems, M.G.
Oosterwijk, J.C.
Peock, S.
Frost, D.
Ellis, S.D.
Platte, R.
Fineberg, E.
Evans, D.G.
Lalloo, F.
Jacobs, C.
Eeles, R.
Adlard, J.
Davidson, R.
Cole, T.
Cook, J.
Paterson, J.
Douglas, F.
Brewer, C.
Hodgson, S.
Morrison, P.J.
Walker, L.
Rogers, M.T.
Donaldson, A.
Dorkins, H.
Godwin, A.K.
Bove, B.
Stoppa-Lyonnet, D.
Houdayer, C.
Buecher, B.
de Pauw, A.
Mazoyer, S.
Calender, A.
Leone, M.
Bressac-de Paillerets, B.
Caron, O.
Sobol, H.
Frenay, M.
Prieur, F.
Ferrer, S.F.
Mortemousque, I.
Buys, S.
Daly, M.
Miron, A.
Terry, M.B.
Hopper, J.L.
John, E.M.
Southey, M.
Goldgar, D.
Singer, C.F.
Fink-Retter, A.
Tea, M.-.
Kaulich, D.G.
Hansen, T.V.
Nielsen, F.C.
Barkardottir, R.B.
Gaudet, M.
Kirchhoff, T.
Joseph, V.
Dutra-Clarke, A.
Offit, K.
Piedmonte, M.
Kirk, J.
Cohn, D.
Hurteau, J.
Byron, J.
Fiorica, J.
Toland, A.E.
Montagna, M.
Oliani, C.
Imyanitov, E.
Isaacs, C.
Tihomirova, L.
Blanco, I.
Lazaro, C.
Teule, A.
Del Valle, J.
Gayther, S.A.
Odunsi, K.
Gross, J.
Karlan, B.Y.
Olah, E.
Teo, S.-.
Ganz, P.A.
Beattie, M.S.
Dorfling, C.M.
van Rensburg, E.J.
Diez, O.
Kwong, A.
Schmutzler, R.K.
Wappenschmidt, B.
Engel, C.
Meindl, A.
Ditsch, N.
Arnold, N.
Heidemann, S.
Niederacher, D.
Preisler-Adams, S.
Gadzicki, D.
Varon-Mateeva, R.
Deissler, H.
Gehrig, A.
Sutter, C.
Kast, K.
Fiebig, B.
Schaefer, D.
Caldes, T.
de la Hoya, M.
Nevanlinna, H.
Muranen, T.A.
Lesperance, B.
Spurdle, A.B.
Neuhausen, S.L.
Ding, Y.C.
Wang, X.
Fredericksen, Z.
Pankratz, V.S.
Lindor, N.M.
Peterlongo, P.
Manoukian, S.
Peissel, B.
Zaffaroni, D.
Bonanni, B.
Bernard, L.
Dolcetti, R.
Papi, L.
Ottini, L.
Radice, P.
Greene, M.H.
Loud, J.T.
Andrulis, I.L.
Ozcelik, H.
Mulligan, A.M.
Glendon, G.
Thomassen, M.
Gerdes, A.-.
Jensen, U.B.
Skytte, A.-.
Kruse, T.A.
Chenevix-Trench, G.
Couch, F.J.
Simard, J.
Easton, D.F.
Collaborator, C.I.
Collaborator, S.W.
Collaborator, H.E.
Collaborator, E.M.
Collaborator, G.E.
Investigators, K.
(2012). Common variants at 12p11, 12q24, 9p21, 9q31 2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. Breast cancer research,
Vol.14
(1).
Mitra, A.V.
Bancroft, E.K.
Barbachano, Y.
Page, E.C.
Foster, C.S.
Jameson, C.
Mitchell, G.
Lindeman, G.J.
Stapleton, A.
Suthers, G.
Evans, D.G.
Cruger, D.
Blanco, I.
Mercer, C.
Kirk, J.
Maehle, L.
Hodgson, S.
Walker, L.
Izatt, L.
Douglas, F.
Tucker, K.
Dorkins, H.
Clowes, V.
Male, A.
Donaldson, A.
Brewer, C.
Doherty, R.
Bulman, B.
Osther, P.J.
Salinas, M.
Eccles, D.
Axcrona, K.
Jobson, I.
Newcombe, B.
Cybulski, C.
Rubinstein, W.S.
Buys, S.
Townshend, S.
Friedman, E.
Domchek, S.
Ramon Y Cajal, T.
Spigelman, A.
Teo, S.H.
Nicolai, N.
Aaronson, N.
Ardern-Jones, A.
Bangma, C.
Dearnaley, D.
Eyfjord, J.
Falconer, A.
Grönberg, H.
Hamdy, F.
Johannsson, O.
Khoo, V.
Kote-Jarai, Z.
Lilja, H.
Lubinski, J.
Melia, J.
Moynihan, C.
Peock, S.
Rennert, G.
Schröder, F.
Sibley, P.
Suri, M.
Wilson, P.
Bignon, Y.J.
Strom, S.
Tischkowitz, M.
Liljegren, A.
Ilencikova, D.
Abele, A.
Kyriacou, K.
van Asperen, C.
Kiemeney, L.
IMPACT Study Collaborators,
Easton, D.F.
Eeles, R.A.
(2011). Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study. Bju int,
Vol.107
(1),
pp. 28-39.
show abstract
full text
OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS: Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (± 5 years) who were negative for the familial mutation. RESULTS: In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47·6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS: The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men..
Schumacher, F.R.
Berndt, S.I.
Siddiq, A.
Jacobs, K.B.
Wang, Z.
Lindstrom, S.
Stevens, V.L.
Chen, C.
Mondul, A.M.
Travis, R.C.
Stram, D.O.
Eeles, R.A.
Easton, D.F.
Giles, G.
Hopper, J.L.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Muir, K.
Al Olama, A.A.
Kote-Jarai, Z.
Guy, M.
Severi, G.
Grönberg, H.
Isaacs, W.B.
Karlsson, R.
Wiklund, F.
Xu, J.
Allen, N.E.
Andriole, G.L.
Barricarte, A.
Boeing, H.
Bueno-de-Mesquita, H.B.
Crawford, E.D.
Diver, W.R.
Gonzalez, C.A.
Gaziano, J.M.
Giovannucci, E.L.
Johansson, M.
Le Marchand, L.
Ma, J.
Sieri, S.
Stattin, P.
Stampfer, M.J.
Tjonneland, A.
Vineis, P.
Virtamo, J.
Vogel, U.
Weinstein, S.J.
Yeager, M.
Thun, M.J.
Kolonel, L.N.
Henderson, B.E.
Albanes, D.
Hayes, R.B.
Feigelson, H.S.
Riboli, E.
Hunter, D.J.
Chanock, S.J.
Haiman, C.A.
Kraft, P.
(2011). Genome-wide association study identifies new prostate cancer susceptibility loci. Hum mol genet,
Vol.20
(19),
pp. 3867-3875.
show abstract
Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P= 4.3 × 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P= 8.6 × 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P= 0.72 and P= 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes..
Chang, B.-.
Spangler, E.
Gallagher, S.
Haiman, C.A.
Henderson, B.
Isaacs, W.
Benford, M.L.
Kidd, L.R.
Cooney, K.
Strom, S.
Ingles, S.A.
Stern, M.C.
Corral, R.
Joshi, A.D.
Xu, J.
Giri, V.N.
Rybicki, B.
Neslund-Dudas, C.
Kibel, A.S.
Thompson, I.M.
Leach, R.J.
Ostrander, E.A.
Stanford, J.L.
Witte, J.
Casey, G.
Eeles, R.
Hsing, A.W.
Chanock, S.
Hu, J.J.
John, E.M.
Park, J.
Stefflova, K.
Zeigler-Johnson, C.
Rebbeck, T.R.
(2011). Validation of Genome-Wide Prostate Cancer Associations in Men of African Descent. Cancer epidemiology biomarkers & prevention,
Vol.20
(1),
pp. 23-10.
Cox, D.G.
Simard, J.
Sinnett, D.
Hamdi, Y.
Soucy, P.
Ouimet, M.
Barjhoux, L.
Verny-Pierre, C.
McGuffog, L.
Healey, S.
Szabo, C.
Greene, M.H.
Mai, P.L.
Andrulis, I.L.
Thomassen, M.
Gerdes, A.-.
Caligo, M.A.
Friedman, E.
Laitman, Y.
Kaufman, B.
Paluch, S.S.
Borg, A.
Karlsson, P.
Askmalm, M.S.
Bustinza, G.B.
Nathanson, K.L.
Domchek, S.M.
Rebbeck, T.R.
Benitez, J.
Hamann, U.
Rookus, M.A.
van den Ouweland, A.M.
Ausems, M.G.
Aalfs, C.M.
van Asperen, C.J.
Devilee, P.
Gille, H.J.
Peock, S.
Frost, D.
Evans, D.G.
Eeles, R.
Izatt, L.
Adlard, J.
Paterson, J.
Eason, J.
Godwin, A.K.
Remon, M.-.
Moncoutier, V.
Gauthier-Villars, M.
Lasset, C.
Giraud, S.
Hardouin, A.
Berthet, P.
Sobol, H.
Eisinger, F.
de Paillerets, B.B.
Caron, O.
Delnatte, C.
Goldgar, D.
Miron, A.
Ozcelik, H.
Buys, S.
Southey, M.C.
Terry, M.B.
Singer, C.F.
Dressler, A.-.
Tea, M.-.
Hansen, T.V.
Johannsson, O.
Piedmonte, M.
Rodriguez, G.C.
Basil, J.B.
Blank, S.
Toland, A.E.
Montagna, M.
Isaacs, C.
Blanco, I.
Gayther, S.A.
Moysich, K.B.
Schmutzler, R.K.
Wappenschmidt, B.
Engel, C.
Meindl, A.
Ditsch, N.
Arnold, N.
Niederacher, D.
Sutter, C.
Gadzicki, D.
Fiebig, B.
Caldes, T.
Laframboise, R.
Nevanlinna, H.
Chen, X.
Beesley, J.
Spurdle, A.B.
Neuhausen, S.L.
Ding, Y.C.
Couch, F.J.
Wang, X.
Peterlongo, P.
Manoukian, S.
Bernard, L.
Radice, P.
Easton, D.F.
Chenevix-Trench, G.
Antoniou, A.C.
Stoppa-Lyonnet, D.
Mazoyer, S.
Sinilnikova, O.M.
Network, O.C.
Collaborators, S.W.
HEBON,
EMBRACE,
Collaborators, G.E.
Registry, B.C.
Modifiers, C.I.
(2011). Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers. Human molecular genetics,
Vol.20
(23),
pp. 4732-4747.
Rahman, A.A.
Lophatananon, A.
Stewart-Brown, S.
Harriss, D.
Anderson, J.
Parker, T.
Easton, D.
Kote-Jarai, Z.
Pocock, R.
Dearnaley, D.
Guy, M.
O'Brien, L.
Wilkinson, R.A.
Hall, A.L.
Sawyer, E.
Page, E.
Liu, J.-.
UK Genetic Prostate Cancer Study Collaborators,
British Association of Urological Surgeons' Section of Oncology,
Eeles, R.A.
Muir, K.
(2011). Hand pattern indicates prostate cancer risk. Br j cancer,
Vol.104
(1),
pp. 175-177.
show abstract
BACKGROUND: The ratio of digit lengths is fixed in utero, and may be a proxy indicator for prenatal testosterone levels. METHODS: We analysed the right-hand pattern and prostate cancer risk in 1524 prostate cancer cases and 3044 population-based controls. RESULTS: Compared with index finger shorter than ring finger (low 2D : 4D), men with index finger longer than ring finger (high 2D : 4D) showed a negative association, suggesting a protective effect with a 33% risk reduction (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.57-0.80). Risk reduction was even greater (87%) in age group <60 (OR 0.13, 95% CI 0.09-0.21). CONCLUSION: Pattern of finger lengths may be a simple marker of prostate cancer risk, with length of 2D greater than 4D suggestive of lower risk..
Kenen, R.
Ardern-Jones, A.
Lynch, E.
Eeles, R.
(2011). Ownership of Uncertainty: Healthcare Professionals Counseling and Treating Women from Hereditary Breast and Ovarian Cancer Families Who Receive an Inconclusive BRCA1/2 Genetic Test Result. Genetic testing and molecular biomarkers,
Vol.15
(4),
pp. 243-8.
Spurdle, A.B.
Marquart, L.
McGuffog, L.
Healey, S.
Sinilnikova, O.
Wan, F.
Chen, X.
Beesley, J.
Singer, C.F.
Dressler, A.-.
Gschwantler-Kaulich, D.
Blum, J.L.
Tung, N.
Weitzel, J.
Lynch, H.
Garber, J.
Easton, D.F.
Peock, S.
Cook, M.
Oliver, C.T.
Frost, D.
Conroy, D.
Evans, D.G.
Lalloo, F.
Eeles, R.
Izatt, L.
Davidson, R.
Chu, C.
Eccles, D.
Selkirk, C.G.
Daly, M.
Isaacs, C.
Stoppa-Lyonnet, D.
Buecher, B.
Belotti, M.
Mazoyer, S.
Barjhoux, L.
Verny-Pierre, C.
Lasset, C.
Dreyfus, H.
Pujol, P.
Collonge-Rame, M.-.
Rookus, M.A.
Verhoef, S.
Kriege, M.
Hoogerbrugge, N.
Ausems, M.G.
van Os, T.A.
Wijnen, J.
Devilee, P.
Meijers-Heijboer, H.E.
Blok, M.J.
Heikkinen, T.
Nevanlinna, H.
Jakubowska, A.
Lubinski, J.
Huzarski, T.
Byrski, T.
Durocher, F.
Couch, F.J.
Lindor, N.M.
Wang, X.
Thomassen, M.
Domchek, S.
Nathanson, K.
Caligo, M.A.
Jernstrom, H.
Liljegren, A.
Ehrencrona, H.
Karlsson, P.
Ganz, P.A.
Olopade, O.I.
Tomlinson, G.
Neuhausen, S.
Antoniou, A.C.
Chenevix-Trench, G.
Rebbeck, T.R.
(2011). Common Genetic Variation at BARD1 Is Not Associated with Breast Cancer Risk in BRCA1 or BRCA2 Mutation Carriers. Cancer epidemiology biomarkers & prevention,
Vol.20
(5),
pp. 1032-7.
Kote-Jarai, Z.
Amin Al Olama, A.
Leongamornlert, D.
Tymrakiewicz, M.
Saunders, E.
Guy, M.
Giles, G.G.
Severi, G.
Southey, M.
Hopper, J.L.
Sit, K.C.
Harris, J.M.
Batra, J.
Spurdle, A.B.
Clements, J.A.
Hamdy, F.
Neal, D.
Donovan, J.
Muir, K.
Pharoah, P.D.
Chanock, S.J.
Brown, N.
Benlloch, S.
Castro, E.
Mahmud, N.
O'Brien, L.
Hall, A.
Sawyer, E.
Wilkinson, R.
Easton, D.F.
Eeles, R.A.
(2011). Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript. Hum genet,
Vol.129
(6),
pp. 687-694.
show abstract
Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10(-22)). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10(-34)). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk..
Loveday, C.
Turnbull, C.
Ramsay, E.
Hughes, D.
Ruark, E.
Frankum, J.R.
Bowden, G.
Kalmyrzaev, B.
Warren-Perry, M.
Snape, K.
Adlard, J.W.
Barwell, J.
Berg, J.
Brady, A.F.
Brewer, C.
Brice, G.
Chapman, C.
Cook, J.
Davidson, R.
Donaldson, A.
Douglas, F.
Greenhalgh, L.
Henderson, A.
Izatt, L.
Kumar, A.
Lalloo, F.
Miedzybrodzka, Z.
Morrison, P.J.
Paterson, J.
Porteous, M.
Rogers, M.T.
Shanley, S.
Walker, L.
Breast Cancer Susceptibility Collaboration (UK),
Eccles, D.
Evans, D.G.
Renwick, A.
Seal, S.
Lord, C.J.
Ashworth, A.
Reis-Filho, J.S.
Antoniou, A.C.
Rahman, N.
(2011). Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat genet,
Vol.43
(9),
pp. 879-882.
show abstract
full text
Recently, RAD51C mutations were identified in families with breast and ovarian cancer. This observation prompted us to investigate the role of RAD51D in cancer susceptibility. We identified eight inactivating RAD51D mutations in unrelated individuals from 911 breast-ovarian cancer families compared with one inactivating mutation identified in 1,060 controls (P = 0.01). The association found here was principally with ovarian cancer, with three mutations identified in the 59 pedigrees with three or more individuals with ovarian cancer (P = 0.0005). The relative risk of ovarian cancer for RAD51D mutation carriers was estimated to be 6.30 (95% CI 2.86-13.85, P = 4.8 × 10(-6)). By contrast, we estimated the relative risk of breast cancer to be 1.32 (95% CI 0.59-2.96, P = 0.50). These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. Moreover, we show that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers..
Macinnis, R.J.
Antoniou, A.C.
Eeles, R.A.
Severi, G.
Al Olama, A.A.
McGuffog, L.
Kote-Jarai, Z.
Guy, M.
O'Brien, L.T.
Hall, A.L.
Wilkinson, R.A.
Sawyer, E.
Ardern-Jones, A.T.
Dearnaley, D.P.
Horwich, A.
Khoo, V.S.
Parker, C.C.
Huddart, R.A.
Van As, N.
McCredie, M.R.
English, D.R.
Giles, G.G.
Hopper, J.L.
Easton, D.F.
(2011). A risk prediction algorithm based on family history and common genetic variants: application to prostate cancer with potential clinical impact. Genet epidemiol,
Vol.35
(6),
pp. 549-556.
show abstract
full text
Genome wide association studies have identified several single nucleotide polymorphisms (SNPs) that are independently associated with small increments in risk of prostate cancer, opening up the possibility for using such variants in risk prediction. Using segregation analysis of population-based samples of 4,390 families of prostate cancer patients from the UK and Australia, and assuming all familial aggregation has genetic causes, we previously found that the best model for the genetic susceptibility to prostate cancer was a mixed model of inheritance that included both a recessive major gene component and a polygenic component (P) that represents the effect of a large number of genetic variants each of small effect, where . Based on published studies of 26 SNPs that are currently known to be associated with prostate cancer, we have extended our model to incorporate these SNPs by decomposing the polygenic component into two parts: a polygenic component due to the known susceptibility SNPs, , and the residual polygenic component due to the postulated but as yet unknown genetic variants, . The resulting algorithm can be used for predicting the probability of developing prostate cancer in the future based on both SNP profiles and explicit family history information. This approach can be applied to other diseases for which population-based family data and established risk variants exist..
Kote-Jarai, Z.
Olama, A.A.
Giles, G.G.
Severi, G.
Schleutker, J.
Weischer, M.
Campa, D.
Riboli, E.
Key, T.
Gronberg, H.
Hunter, D.J.
Kraft, P.
Thun, M.J.
Ingles, S.
Chanock, S.
Albanes, D.
Hayes, R.B.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Pharoah, P.
Schumacher, F.
Henderson, B.E.
Stanford, J.L.
Ostrander, E.A.
Sorensen, K.D.
Dörk, T.
Andriole, G.
Dickinson, J.L.
Cybulski, C.
Lubinski, J.
Spurdle, A.
Clements, J.A.
Chambers, S.
Aitken, J.
Gardiner, R.A.
Thibodeau, S.N.
Schaid, D.
John, E.M.
Maier, C.
Vogel, W.
Cooney, K.A.
Park, J.Y.
Cannon-Albright, L.
Brenner, H.
Habuchi, T.
Zhang, H.-.
Lu, Y.-.
Kaneva, R.
Muir, K.
Benlloch, S.
Leongamornlert, D.A.
Saunders, E.J.
Tymrakiewicz, M.
Mahmud, N.
Guy, M.
O'Brien, L.T.
Wilkinson, R.A.
Hall, A.L.
Sawyer, E.J.
Dadaev, T.
Morrison, J.
Dearnaley, D.P.
Horwich, A.
Huddart, R.A.
Khoo, V.S.
Parker, C.C.
Van As, N.
Woodhouse, C.J.
Thompson, A.
Christmas, T.
Ogden, C.
Cooper, C.S.
Lophatonanon, A.
Southey, M.C.
Hopper, J.L.
English, D.R.
Wahlfors, T.
Tammela, T.L.
Klarskov, P.
Nordestgaard, B.G.
Røder, M.A.
Tybjærg-Hansen, A.
Bojesen, S.E.
Travis, R.
Canzian, F.
Kaaks, R.
Wiklund, F.
Aly, M.
Lindstrom, S.
Diver, W.R.
Gapstur, S.
Stern, M.C.
Corral, R.
Virtamo, J.
Cox, A.
Haiman, C.A.
Le Marchand, L.
Fitzgerald, L.
Kolb, S.
Kwon, E.M.
Karyadi, D.M.
Orntoft, T.F.
Borre, M.
Meyer, A.
Serth, J.
Yeager, M.
Berndt, S.I.
Marthick, J.R.
Patterson, B.
Wokolorczyk, D.
Batra, J.
Lose, F.
McDonnell, S.K.
Joshi, A.D.
Shahabi, A.
Rinckleb, A.E.
Ray, A.
Sellers, T.A.
Lin, H.-.
Stephenson, R.A.
Farnham, J.
Muller, H.
Rothenbacher, D.
Tsuchiya, N.
Narita, S.
Cao, G.-.
Slavov, C.
Mitev, V.
Easton, D.F.
Eeles, R.A.
UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology,
UK ProtecT Study Collaborators, The Australian Prostate Cancer BioResource,
PRACTICAL Consortium,
(2011). Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study. Nat genet,
Vol.43
(8),
pp. 785-791.
show abstract
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10(-8) to P = 2.7 × 10(-24)). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ∼25% of the familial risk in this disease, have now been identified..
Eeles, R.
Knee, G.
Jhavar, S.
Mangion, J.
Ebbs, S.
Gui, G.
Thomas, S.
Coppen, M.
A'hern, R.
Gray, S.
Cooper, C.
Bartek, J.
Yarnold, J.
(2011). Multicentric breast cancer: clonality and prognostic studies. Breast cancer res treat,
Vol.129
(3),
pp. 703-716.
show abstract
Clonality of multicentric breast cancer has traditionally been difficult to assess. We aimed to assess this using analysis of TP53 status (expression and mutation status). These results were then incorporated into an analysis of prognostic factors in multicentric tumours in a 10-year follow up study. Clonal status of multicentric breast cancer foci (n = 88 foci) was determined by immunohistochemical and molecular studies of TP53 in a total of 40 patients. Prognostic factors from these patients were also compared with 80 age- and stage-matched controls with unicentric breast cancer from the Royal Marsden NHS Foundation Trust Breast Cancer Database. Our results indicate that multicentric breast cancer foci were polyclonal within an individual patient in at least 10 patients (25%) with respect to immunohistochemical staining and in four patients (10%) with respect to abnormal band shifts on single strand conformational polymorphism (SSCP) molecular analysis. No individual variable was predictive of multicentric or unicentric disease. However, there was a worse overall survival in the multicentric breast cancer patients in whom at least two cancer foci stained positively on TP53 immunohistochemistry compared with the matched control group (P = 0.04). In conclusion, these results suggest that a proportion of multicentric breast cancer foci are polyclonal with respect to TP53 status and that TP53 over-expression predicts for a poorer prognosis in multicentric breast cancer..
Pashayan, N.
Duffy, S.W.
Chowdhury, S.
Dent, T.
Burton, H.
Neal, D.E.
Easton, D.F.
Eeles, R.
Pharoah, P.
(2011). Polygenic susceptibility to prostate and breast cancer: implications for personalised screening. British journal of cancer,
Vol.104
(10),
pp. 1656-8.
Im, K.M.
Kirchhoff, T.
Wang, X.
Green, T.
Chow, C.Y.
Vijai, J.
Korn, J.
Gaudet, M.M.
Fredericksen, Z.
Pankratz, V.S.
Guiducci, C.
Crenshaw, A.
McGuffog, L.
Kartsonaki, C.
Morrison, J.
Healey, S.
Sinilnikova, O.M.
Mai, P.L.
Greene, M.H.
Piedmonte, M.
Rubinstein, W.S.
Hogervorst, F.B.
Rookus, M.A.
Collee, J.M.
Hoogerbrugge, N.
van Asperen, C.J.
Meijers-Heijboer, H.E.
van Roozendaal, C.E.
Caldes, T.
Perez-Segura, P.
Jakubowska, A.
Lubinski, J.
Huzarski, T.
Blecharz, P.
Nevanlinna, H.
Aittomaki, K.
Lazaro, C.
Blanco, I.
Barkardottir, R.B.
Montagna, M.
D'Andrea, E.
Devilee, P.
Olopade, O.I.
Neuhausen, S.L.
Peissel, B.
Bonanni, B.
Peterlongo, P.
Singer, C.F.
Rennert, G.
Lejbkowicz, F.
Andrulis, I.L.
Glendon, G.
Ozcelik, H.
Toland, A.E.
Caligo, M.A.
Beattie, M.S.
Chan, S.
Domchek, S.M.
Nathanson, K.L.
Rebbeck, T.R.
Phelan, C.
Narod, S.
John, E.M.
Hopper, J.L.
Buys, S.S.
Daly, M.B.
Southey, M.C.
Terry, M.-.
Tung, N.
Hansen, T.V.
Osorio, A.
Benitez, J.
Duran, M.
Weitzel, J.N.
Garber, J.
Hamann, U.
Peock, S.
Cook, M.
Oliver, C.T.
Frost, D.
Platte, R.
Evans, D.G.
Eeles, R.
Izatt, L.
Paterson, J.
Brewer, C.
Hodgson, S.
Morrison, P.J.
Porteous, M.
Walker, L.
Rogers, M.T.
Side, L.E.
Godwin, A.K.
Schmutzler, R.K.
Wappenschmidt, B.
Laitman, Y.
Meindl, A.
Deissler, H.
Varon-Mateeva, R.
Preisler-Adams, S.
Kast, K.
Venat-Bouvet, L.
Stoppa-Lyonnet, D.
Chenevix-Trench, G.
Easton, D.F.
Klein, R.J.
Daly, M.J.
Friedman, E.
Dean, M.
Clark, A.G.
Altshuler, D.M.
Antoniou, A.C.
Couch, F.J.
Offit, K.
Gold, B.
(2011). Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers. Human genetics,
Vol.130
(5),
pp. 685-15.
Kote-Jarai, Z.
Leongamornlert, D.
Saunders, E.
Tymrakiewicz, M.
Castro, E.
Mahmud, N.
Guy, M.
Edwards, S.
O'Brien, L.
Sawyer, E.
Hall, A.
Wilkinson, R.
Dadaev, T.
Goh, C.
Easton, D.
Goldgar, D.
Eeles, R.
(2011). BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. British journal of cancer,
Vol.105
(8),
pp. 1230-5.
Maxwell, C.A.
Benitez, J.
Gomez-Baldo, L.
Osorio, A.
Bonifaci, N.
Fernandez-Ramires, R.
Costes, S.V.
Guino, E.
Chen, H.
Evans, G.J.
Mohan, P.
Catala, I.
Petit, A.
Aguilar, H.
Villanueva, A.
Aytes, A.
Serra-Musach, J.
Rennert, G.
Lejbkowicz, F.
Peterlongo, P.
Manoukian, S.
Peissel, B.
Ripamonti, C.B.
Bonanni, B.
Viel, A.
Allavena, A.
Bernard, L.
Radice, P.
Friedman, E.
Kaufman, B.
Laitman, Y.
Dubrovsky, M.
Milgrom, R.
Jakubowska, A.
Cybulski, C.
Gorski, B.
Jaworska, K.
Durda, K.
Sukiennicki, G.
Lubinski, J.
Shugart, Y.Y.
Domchek, S.M.
Letrero, R.
Weber, B.L.
Hogervorst, F.B.
Rookus, M.A.
Collee, J.M.
Devilee, P.
Ligtenberg, M.J.
van der Luijt, R.B.
Aalfs, C.M.
Waisfisz, Q.
Wijnen, J.
van Roozendaal, C.E.
Easton, D.F.
Peock, S.
Cook, M.
Oliver, C.
Frost, D.
Harrington, P.
Evans, D.G.
Lalloo, F.
Eeles, R.
Izatt, L.
Chu, C.
Eccles, D.
Douglas, F.
Brewer, C.
Nevanlinna, H.
Heikkinen, T.
Couch, F.J.
Lindor, N.M.
Wang, X.
Godwin, A.K.
Caligo, M.A.
Lombardi, G.
Loman, N.
Karlsson, P.
Ehrencrona, H.
von Wachenfeldt, A.
Barkardottir, R.B.
Hamann, U.
Rashid, M.U.
Lasa, A.
Caldes, T.
Andres, R.
Schmitt, M.
Assmann, V.
Stevens, K.
Offit, K.
Curado, J.
Tilgner, H.
Guigo, R.
Aiza, G.
Brunet, J.
Castellsague, J.
Martrat, G.
Urruticoechea, A.
Blanco, I.
Tihomirova, L.
Goldgar, D.E.
Buys, S.
John, E.M.
Miron, A.
Southey, M.
Daly, M.B.
Schmutzler, R.K.
Wappenschmidt, B.
Meindl, A.
Arnold, N.
Deissler, H.
Varon-Mateeva, R.
Sutter, C.
Niederacher, D.
Imyamitov, E.
Sinilnikova, O.M.
Stoppa-Lyonne, D.
Mazoyer, S.
Verny-Pierre, C.
Castera, L.
de Pauw, A.
Bignon, Y.-.
Uhrhammer, N.
Peyrat, J.-.
Vennin, P.
Ferrer, S.F.
Collonge-Rame, M.-.
Mortemousque, I.
Spurdle, A.B.
Beesley, J.
Chen, X.
Healey, S.
Barcellos-Hoff, M.H.
Vidal, M.
Gruber, S.B.
Lazaro, C.
Capella, G.
McGuffog, L.
Nathanson, K.L.
Antoniou, A.C.
Chenevix-Trench, G.
Fleisch, M.C.
Moreno, V.
Angel Pujana, M.
HEBON,
EMBRACE,
SWE-BRCA,
BCFR,
Collaborators, G.E.
kConFab,
(2011). Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer. Plos biology,
Vol.9
(11).
Osorio, A.
Milne, R.L.
Alonso, R.
Pita, G.
Peterlongo, P.
Teule, A.
Nathanson, K.L.
Domchek, S.M.
Rebbeck, T.
Lasa, A.
Konstantopoulou, I.
Hogervorst, F.B.
Verhoef, S.
van Dooren, M.F.
Jager, A.
Ausems, M.G.
Aalfs, C.M.
van Asperen, C.J.
Vreeswijk, M.
Waisfisz, Q.
Van Roozendaal, C.E.
Ligtenberg, M.J.
Easton, D.F.
Peock, S.
Cook, M.
Oliver, C.T.
Frost, D.
Curzon, B.
Evans, D.G.
Lalloo, F.
Eeles, R.
Izatt, L.
Davidson, R.
Adlard, J.
Eccles, D.
Ong, K.-.
Douglas, F.
Downing, S.
Brewer, C.
Walker, L.
Nevanlinna, H.
Aittomaki, K.
Couch, F.J.
Fredericksen, Z.
Lindor, N.M.
Godwin, A.
Isaacs, C.
Caligo, M.A.
Loman, N.
Jernstrom, H.
Barbany-Bustinza, G.
Liljegren, A.
Ehrencrona, H.
Stenmark-Askmalm, M.
Feliubadalo, L.
Manoukian, S.
Peissel, B.
Zaffaroni, D.
Bonanni, B.
Fortuzzi, S.
Johannsson, O.T.
Chenevix-Trench, G.
Chen, X.-.
Beesley, J.
Spurdle, A.B.
Sinilnikova, O.M.
Healey, S.
McGuffog, L.
Antoniou, A.C.
Brunet, J.
Radice, P.
Benitez, J.
(2011). Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers Results from the consortium of investigators of modifiers of BRCA1/BRCA2. British journal of cancer,
Vol.104
(8),
pp. 1356-6.
Antoniou, A.C.
Kartsonaki, C.
Sinilnikova, O.M.
Soucy, P.
McGuffog, L.
Healey, S.
Lee, A.
Peterlongo, P.
Manoukian, S.
Peissel, B.
Zaffaroni, D.
Cattaneo, E.
Barile, M.
Pensotti, V.
Pasini, B.
Dolcetti, R.
Giannini, G.
Putignano, A.L.
Varesco, L.
Radice, P.
Mai, P.L.
Greene, M.H.
Andrulis, I.L.
Glendon, G.
Ozcelik, H.
Thomassen, M.
Gerdes, A.-.
Kruse, T.A.
Jensen, U.B.
Crueger, D.G.
Caligo, M.A.
Laitman, Y.
Milgrom, R.
Kaufman, B.
Paluch-Shimon, S.
Friedman, E.
Loman, N.
Harbst, K.
Lindblom, A.
Arver, B.
Ehrencrona, H.
Melin, B.
Nathanson, K.L.
Domchek, S.M.
Rebbeck, T.
Jakubowska, A.
Lubinski, J.
Gronwald, J.
Huzarski, T.
Byrski, T.
Cybulski, C.
Gorski, B.
Osorio, A.
Ramon y Cajal, T.
Fostira, F.
Andres, R.
Benitez, J.
Hamann, U.
Hogervorst, F.B.
Rookus, M.A.
Hooning, M.J.
Nelen, M.R.
van der Luijt, R.B.
van Os, T.A.
van Asperen, C.J.
Devilee, P.
Meijers-Heijboer, H.E.
Garcia, E.B.
Peock, S.
Cook, M.
Frost, D.
Platte, R.
Leyland, J.
Evans, D.G.
Lalloo, F.
Eeles, R.
Izatt, L.
Adlard, J.
Davidson, R.
Eccles, D.
Ong, K.-.
Cook, J.
Douglas, F.
Paterson, J.
Kennedy, M.J.
Miedzybrodzka, Z.
Godwin, A.
Stoppa-Lyonnet, D.
Buecher, B.
Belotti, M.
Tirapo, C.
Mazoyer, S.
Barjhoux, L.
Lasset, C.
Leroux, D.
Faivre, L.
Bronner, M.
Prieur, F.
Nogues, C.
Rouleau, E.
Pujol, P.
Coupier, I.
Frenay, M.
Hopper, J.L.
Daly, M.B.
Terry, M.B.
John, E.M.
Buys, S.S.
Yassin, Y.
Miron, A.
Goldgar, D.
Singer, C.F.
Tea, M.-.
Pfeiler, G.
Dressler, A.C.
Hansen, T.V.
Jonson, L.
Ejlertsen, B.
Barkardottir, R.B.
Kirchhoff, T.
Offit, K.
Piedmonte, M.
Rodriguez, G.
Small, L.
Boggess, J.
Blank, S.
Basil, J.
Azodi, M.
Toland, A.E.
Montagna, M.
Tognazzo, S.
Agata, S.
Imyanitov, E.
Janavicius, R.
Lazaro, C.
Blanco, I.
Pharoah, P.D.
Sucheston, L.
Karlan, B.Y.
Walsh, C.S.
Olah, E.
Bozsik, A.
Teo, S.-.
Seldon, J.L.
Beattie, M.S.
van Rensburg, E.J.
Sluiter, M.D.
Diez, O.
Schmutzler, R.K.
Wappenschmidt, B.
Engel, C.
Meindl, A.
Ruehl, I.
Varon-Mateeva, R.
Kast, K.
Deissler, H.
Niederacher, D.
Arnold, N.
Gadzicki, D.
Schoenbuchner, I.
Caldes, T.
de la Hoya, M.
Nevanlinna, H.
Aittomaki, K.
Dumont, M.
Chiquette, J.
Tischkowitz, M.
Chen, X.
Beesley, J.
Spurdle, A.B.
Neuhausen, S.L.
Ding, Y.C.
Fredericksen, Z.
Wang, X.
Pankratz, V.S.
Couch, F.
Simard, J.
Easton, D.F.
Chenevix-Trench, G.
(2011). Common alleles at 6q25 1 and 1p11 2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers. Human molecular genetics,
Vol.20
(16),
pp. 3304-18.
Hutton, J.
Walker, L.G.
Gilbert, F.J.
Evans, D.G.
Eeles, R.
Kwan-Lim, G.E.
Thompson, D.
Pointon, L.J.
Sharp, D.M.
Leach, M.O.
(2011). Psychological impact and acceptability of magnetic resonance imaging and X-ray mammography: the MARIBS Study. British journal of cancer,
Vol.104
(4),
pp. 578-9.
Warde, P.
Mason, M.
Ding, K.
Kirkbride, P.
Brundage, M.
Cowan, R.
Gospodarowicz, M.
Sanders, K.
Kostashuk, E.
Swanson, G.
Barber, J.
Hiltz, A.
Parmar, M.K.
Sathya, J.
Anderson, J.
Hayter, C.
Hetherington, J.
Sydes, M.R.
Parulekar, W.
NCIC CTG PR.3/MRC UK PR07 investigators,
(2011). Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet,
Vol.378
(9809),
pp. 2104-2111.
show abstract
BACKGROUND: Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer. METHODS: Patients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65-69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at controlledtrials.com as ISRCTN24991896 and Clinicaltrials.gov as NCT00002633. RESULTS: Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4-8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70-78 vs 66%, 60-70; hazard ratio [HR] 0·77, 95% CI 0·61-0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups). INTERPRETATION: The benefits of combined modality treatment--ADT and RT--should be discussed with all patients with locally advanced prostate cancer. FUNDING: Canadian Cancer Society Research Institute, US National Cancer Institute, and UK Medical Research Council..
Ramus, S.J.
Kartsonaki, C.
Gayther, S.A.
Pharoah, P.D.
Sinilnikova, O.M.
Beesley, J.
Chen, X.
McGuffog, L.
Healey, S.
Couch, F.J.
Wang, X.
Fredericksen, Z.
Peterlongo, P.
Manoukian, S.
Peissel, B.
Zaffaroni, D.
Roversi, G.
Barile, M.
Viel, A.
Allavena, A.
Ottini, L.
Papi, L.
Gismondi, V.
Capra, F.
Radice, P.
Greene, M.H.
Mai, P.L.
Andrulis, I.L.
Glendon, G.
Ozcelik, H.
OCGN,
Thomassen, M.
Gerdes, A.-.
Kruse, T.A.
Cruger, D.
Jensen, U.B.
Caligo, M.A.
Olsson, H.
Kristoffersson, U.
Lindblom, A.
Arver, B.
Karlsson, P.
Stenmark Askmalm, M.
Borg, A.
Neuhausen, S.L.
Ding, Y.C.
Nathanson, K.L.
Domchek, S.M.
Jakubowska, A.
Lubiński, J.
Huzarski, T.
Byrski, T.
Gronwald, J.
Górski, B.
Cybulski, C.
Dębniak, T.
Osorio, A.
Durán, M.
Tejada, M.-.
Benítez, J.
Hamann, U.
Rookus, M.A.
Verhoef, S.
Tilanus-Linthorst, M.A.
Vreeswijk, M.P.
Bodmer, D.
Ausems, M.G.
van Os, T.A.
Asperen, C.J.
Blok, M.J.
Meijers-Heijboer, H.E.
HEBON,
EMBRACE,
Peock, S.
Cook, M.
Oliver, C.
Frost, D.
Dunning, A.M.
Evans, D.G.
Eeles, R.
Pichert, G.
Cole, T.
Hodgson, S.
Brewer, C.
Morrison, P.J.
Porteous, M.
Kennedy, M.J.
Rogers, M.T.
Side, L.E.
Donaldson, A.
Gregory, H.
Godwin, A.
Stoppa-Lyonnet, D.
Moncoutier, V.
Castera, L.
Mazoyer, S.
Barjhoux, L.
Bonadona, V.
Leroux, D.
Faivre, L.
Lidereau, R.
Nogues, C.
Bignon, Y.-.
Prieur, F.
Collonge-Rame, M.-.
Venat-Bouvet, L.
Fert-Ferrer, S.
GEMO Study Collaborators,
Miron, A.
Buys, S.S.
Hopper, J.L.
Daly, M.B.
John, E.M.
Terry, M.B.
Goldgar, D.
BCFR,
Hansen, T.V.
Jønson, L.
Ejlertsen, B.
Agnarsson, B.A.
Offit, K.
Kirchhoff, T.
Vijai, J.
Dutra-Clarke, A.V.
Przybylo, J.A.
Montagna, M.
Casella, C.
Imyanitov, E.N.
Janavicius, R.
Blanco, I.
Lázaro, C.
Moysich, K.B.
Karlan, B.Y.
Gross, J.
Beattie, M.S.
Schmutzler, R.
Wappenschmidt, B.
Meindl, A.
Ruehl, I.
Fiebig, B.
Sutter, C.
Arnold, N.
Deissler, H.
Varon-Mateeva, R.
Kast, K.
Niederacher, D.
Gadzicki, D.
Caldes, T.
de la Hoya, M.
Nevanlinna, H.
Aittomäki, K.
Simard, J.
Soucy, P.
kConFab Investigators,
Spurdle, A.B.
Holland, H.
Chenevix-Trench, G.
Easton, D.F.
Antoniou, A.C.
Consortium of Investigators of Modifiers of BRCA1/2,
(2011). Genetic variation at 9p22 2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. J natl cancer inst,
Vol.103
(2),
pp. 105-116.
show abstract
BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. METHODS: We genotyped rs3814113 in 10,029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. RESULTS: The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10(-9)) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10(-4)). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. CONCLUSION: Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation..
Castro, E.
Goh, C.L.
Olmos, D.
Leongamornlert, D.
Saunders, E.
Tymrakiewicz, M.
Mahmud, N.
Dadaev, T.
Govindasami, K.
Guy, M.
OBrien, L.
Sawyer, E.
Hall, A.
Wilkinson, R.
Kote-Jarai, Z.
Eeles, R.A.
UKGPCS collaborators,
(2011). Correlation of germ-line BRCA2 mutations with aggressive prostate cancer and outcome. J clin oncol,
Vol.29
(15_suppl),
p. 1517.
show abstract
1517 Background: Previous studies have linked some BRCA1/2 mutations with increased incidence and poor overall survival (OS) in prostate cancer (PCa). In this study both BRCA genes were screened for germline mutations in a larger cohort of PCa and mutation status was correlated with PCa prognostic factors (PFs). METHODS: 3818 patients (pts) were enrolled in the UK Genetic Prostate Cancer Study (UKGPCS) between1990-2005. Inclusion criteria for our analysis were available genomic DNA and clinical and survival data in our prospectively maintained UKGPCS database. Genomic DNA was screened for BRCA1/2 mutations. The Kaplan-Meier method and Cox Regression models were used to study the association between BRCA mutation carrier status and other PCa PFs with OS, cause specific OS (CSS), and metastasis free survival (MFS). RESULTS: 2181 pts were eligible for analysis. Median age was 57yrs (range 32-89). BRCA1and BRCA2mutations were detected in 5 and 34 patients respectively. BRCA2 tumors were associated with higher histologic grade (Gleason≥8: BRCA2 50%, BRCA120%, Non carriers [NC] 21%; p=0.017), nodal disease (N1: BRCA2 35%, BRCA1 50%, NC 11%; p<0.001), metastasis (M1: BRCA221%, BRCA1 20%, NC9%, p=0.034) and advanced stage (BRCA2 62%, BRCA1 50% NC18%, p<0.001). Median OS for BRCA2 was significantly inferior to NC (10.8 vs 13.3 yrs, respectively, HR 2.5, p<0.001). The later difference was greater when analyzing CSS (8.6 vs 16.3 yrs, HR 2.8, p<0.001). PFs for CSS in the multivariate analysis (MVA) included stage and PSA doubling time but not BRCA2 per se (HR 1.9, CI95% 0.7-6.7). BRCA2 pts had a worse 10 yrs MFS rate than NC (63% vs 86%, HR 3.6, p=0.001). Median OS from M1 was not significantly different between BRCA2 and NC (2.8 vs 3.4 yrs, p=0.7). BRCA1 pts had a shorter median OS and CSS (10.6 yrs) than NC (p=0.14 and p=0.09), but this trend was lost in the MVA. CONCLUSIONS: Our results confirm that PCa pts with BRCA mutations have a poor outcome. Both BRCA1 and BRCA2mutation carriers with PCa are more likely to have nodal involvement and metastasis at diagnosis and earlier disease progression. OS and CSS are significantly lower in men with BRCA2 mutations.These data should be taken into account in the screening and management of BRCA mutation carriers..
Domchek, S.M.
Friebel, T.
Neuhausen, S.L.
Lynch, H.T.
Singer, C.F.
Eeles, R.A.
Isaacs, C.
Tung, N.M.
Ganz, P.A.
Couch, F.J.
Weitzel, J.N.
Olopade, O.I.
Rubinstein, W.S.
Tomlinson, G.E.
Pichert, G.C.
Daly, M.B.
Matloff, E.T.
Evans, D.G.
Garber, J.E.
Rebbeck, T.R.
PROSE Consortium,
(2011). Is hormone replacement therapy (HRT) following risk-reducing salpingo-oophorectomy (RRSO) in BRCA1 (B1)- and BRCA2 (B2)-mutation carriers associated with an increased risk of breast cancer?. J clin oncol,
Vol.29
(15_suppl),
p. 1501.
show abstract
1501 Background: Women with B1 and B2 mutation are at increased risk of breast and ovarian cancer, which is significantly reduced by RRSO. The reduction in breast cancer risk may be greatest prior to age 40; however, such early menopause can lead to significant menopausal symptoms and other health problems. Two small prior studies have suggested that HRT following RRSO does not increase the risk of breast cancer, but further data are needed. METHODS: From the PROSE consortium, 1,299 B1 (n= 795) and B2 (n=504) mutation carriers who underwent RRSO following study ascertainment and in whom HRT status was known were followed prospectively. Data were collected on HRT use and subsequent breast cancer diagnosis. RESULTS: In both B1 and B2 mutation carriers with ever use of HRT following RRSO, no increased risk of breast cancer was observed compared to those with no RRSO. In B1 carriers, HRT use both with (HR 0.52) and without (HR 0.29) RRSO was associated with a decreased risk of breast cancer. No increased risk of breast cancer was seen with either combination HRT or estrogen-only HRT. CONCLUSIONS: In this prospective study of 1,299 B1 and B2 mutation carriers, HRT following RRSO was not associated with an increased risk of breast cancer. [Table: see text]..
Nobbenhuis, M.A.
Bancroft, E.
Moskovic, E.
Lennard, F.
Pharoah, P.
Jacobs, I.
Ward, A.
Barton, D.P.
Ind, T.E.
Shepherd, J.H.
Bridges, J.E.
Gore, M.
Haracopos, C.
Shanley, S.
Ardern-Jones, A.
Thomas, S.
Eeles, R.
(2011). Screening for ovarian cancer in women with varying levels of risk, using annual tests, results in high recall for repeat screening tests. Hered cancer clin pract,
Vol.9
(1),
p. 11.
show abstract
BACKGROUND: We assessed ovarian cancer screening outcomes in women with a positive family history of ovarian cancer divided into a low-, moderate- or high-risk group for development of ovarian cancer. METHODS: 545 women with a positive family history of ovarian cancer referred to the Ovarian Screening Service at the Royal Marsden Hospital, London from January 2000- December 2008 were included. They were stratified into three risk-groups according to family history (high-, moderate- and low-risk) of developing ovarian cancer and offered annual serum CA 125 and transvaginal ultrasound screening. The high-risk group was offered genetic testing. RESULTS: The median age at entry was 44 years. The number of women in the high, moderate and low-risk groups was 397, 112, and 36, respectively. During 2266 women years of follow-up two ovarian cancer cases were found: one advanced stage at her fourth annual screening, and one early stage at prophylactic bilateral salpingo-oophorectomy (BSO). Prophylactic BSO was performed in 138 women (25.3%). Forty-three women had an abnormal CA125, resulting in 59 repeat tests. The re-call rate in the high, moderate and low-risk group was 14%, 3% and 6%. Equivocal transvaginal ultrasound results required 108 recalls in 71 women. The re-call rate in the high, moderate, and low-risk group was 25%, 6% and 17%. CONCLUSION: No early stage ovarian cancer was picked up at annual screening and a significant number of re-calls for repeat screening tests was identified..
Batra, J.
Lose, F.
O'Mara, T.
Marquart, L.
Stephens, C.
Alexander, K.
Srinivasan, S.
Eeles, R.A.
Easton, D.F.
Al Olama, A.A.
Kote-Jarai, Z.
Guy, M.
Muir, K.
Lophatananon, A.
Rahman, A.A.
Neal, D.E.
Hamdy, F.C.
Donovan, J.L.
Chambers, S.
Gardiner, R.A.
Aitken, J.
Yaxley, J.
Kedda, M.-.
Clements, J.A.
Spurdle, A.B.
(2011). Association between Prostinogen (KLK15) Genetic Variants and Prostate Cancer Risk and Aggressiveness in Australia and a Meta-Analysis of GWAS Data. Plos one,
Vol.6
(11).
Martrat, G.
Maxwell, C.A.
Tominaga, E.
Porta-de-la-Riva, M.
Bonifaci, N.
Gomez-Baldo, L.
Bogliolo, M.
Lazaro, C.
Blanco, I.
Brunet, J.
Aguilar, H.
Fernandez-Rodriguez, J.
Seal, S.
Renwick, A.
Rahman, N.
Kuehl, J.
Neveling, K.
Schindler, D.
Ramirez, M.J.
Castella, M.
Hernandez, G.
Easton, D.F.
Peock, S.
Cook, M.
Oliver, C.T.
Frost, D.
Platte, R.
Evans, D.G.
Lalloo, F.
Eeles, R.
Izatt, L.
Chu, C.
Davidson, R.
Ong, K.-.
Cook, J.
Douglas, F.
Hodgson, S.
Brewer, C.
Morrison, P.J.
Porteous, M.
Peterlongo, P.
Manoukian, S.
Peissel, B.
Zaffaroni, D.
Roversi, G.
Barile, M.
Viel, A.
Pasini, B.
Ottini, L.
Putignano, A.L.
Savarese, A.
Bernard, L.
Radice, P.
Healey, S.
Spurdle, A.
Chen, X.
Beesley, J.
Rookus, M.A.
Verhoef, S.
Tilanus-Linthorst, M.A.
Vreeswijk, M.P.
Asperen, C.J.
Bodmer, D.
Ausems, M.G.
van Os, T.A.
Blok, M.J.
Meijers-Heijboer, H.E.
Hogervorst, F.B.
Goldgar, D.E.
Buys, S.
John, E.M.
Miron, A.
Southey, M.
Daly, M.B.
Harbst, K.
Borg, A.
Rantala, J.
Barbany-Bustinza, G.
Ehrencrona, H.
Stenmark-Askmalm, M.
Kaufman, B.
Laitman, Y.
Milgrom, R.
Friedman, E.
Domchek, S.M.
Nathanson, K.L.
Rebbeck, T.R.
Johannsson, O.T.
Couch, F.J.
Wang, X.
Fredericksen, Z.
Cuadras, D.
Moreno, V.
Pientka, F.K.
Depping, R.
Caldes, T.
Osorio, A.
Benitez, J.
Bueren, J.
Heikkinen, T.
Nevanlinna, H.
Hamann, U.
Torres, D.
Caligo, M.A.
Godwin, A.K.
Imyanitov, E.N.
Janavicius, R.
Sinilnikova, O.M.
Stoppa-Lyonnet, D.
Mazoyer, S.
Verny-Pierre, C.
Castera, L.
de Pauw, A.
Bignon, Y.-.
Uhrhammer, N.
Peyrat, J.-.
Vennin, P.
Ferrer, S.F.
Collonge-Rame, M.-.
Mortemousque, I.
McGuffog, L.
Chenevix-Trench, G.
Pereira-Smith, O.M.
Antoniou, A.C.
Ceron, J.
Tominaga, K.
Surralles, J.
Angel Pujana, M.
(2011). Exploring the link between MORF4L1 and risk of breast cancer. Breast cancer research,
Vol.13
(2),
p. 14.
Mulligan, A.M.
Couch, F.J.
Barrowdale, D.
Domchek, S.M.
Eccles, D.
Nevanlinna, H.
Ramus, S.J.
Robson, M.
Sherman, M.
Spurdle, A.B.
Wappenschmidt, B.
Lee, A.
McGuffog, L.
Healey, S.
Sinilnikova, O.M.
Janavicius, R.
Hansen, T.V.
Nielsen, F.C.
Ejlertsen, B.
Osorio, A.
Munoz-Repeto, I.
Duran, M.
Godino, J.
Pertesi, M.
Benitez, J.
Peterlongo, P.
Manoukian, S.
Peissel, B.
Zaffaroni, D.
Cattaneo, E.
Bonanni, B.
Viel, A.
Pasini, B.
Papi, L.
Ottini, L.
Savarese, A.
Bernard, L.
Radice, P.
Hamann, U.
Verheus, M.
Meijers-Heijboer, H.E.
Wijnen, J.
Garcia, E.B.
Nelen, M.R.
Kets, C.M.
Seynaeve, C.
Tilanus-Linthorst, M.M.
van der Luijt, R.B.
van Os, T.
Rookus, M.
Frost, D.
Jones, J.L.
Evans, D.G.
Lalloo, F.
Eeles, R.
Izatt, L.
Adlard, J.
Davidson, R.
Cook, J.
Donaldson, A.
Dorkins, H.
Gregory, H.
Eason, J.
Houghton, C.
Barwell, J.
Side, L.E.
McCann, E.
Murray, A.
Peock, S.
Godwin, A.K.
Schmutzler, R.K.
Rhiem, K.
Engel, C.
Meindl, A.
Ruehl, I.
Arnold, N.
Niederacher, D.
Sutter, C.
Deissler, H.
Gadzicki, D.
Kast, K.
Preisler-Adams, S.
Varon-Mateeva, R.
Schoenbuchner, I.
Fiebig, B.
Heinritz, W.
Schaefer, D.
Gevensleben, H.
Caux-Moncoutier, V.
Fassy-Colcombet, M.
Cornelis, F.
Mazoyer, S.
Leone, M.
Boutry-Kryza, N.
Hardouin, A.
Berthet, P.
Muller, D.
Fricker, J.-.
Mortemousque, I.
Pujol, P.
Coupier, I.
Lebrun, M.
Kientz, C.
Longy, M.
Sevenet, N.
Stoppa-Lyonnet, D.
Isaacs, C.
Caldes, T.
de la Hoya, M.
Heikkinen, T.
Aittomaki, K.
Blanco, I.
Lazaro, C.
Barkardottir, R.B.
Soucy, P.
Dumont, M.
Simard, J.
Montagna, M.
Tognazzo, S.
D'Andrea, E.
Fox, S.
Yan, M.
Rebbeck, T.
Olopade, O.I.
Weitzel, J.N.
Lynch, H.T.
Ganz, P.A.
Tomlinson, G.E.
Wang, X.
Fredericksen, Z.
Pankratz, V.S.
Lindor, N.M.
Szabo, C.
Offit, K.
Sakr, R.
Gaudet, M.
Bhatia, J.
Kauff, N.
Singer, C.F.
Tea, M.-.
Gschwantler-Kaulich, D.
Fink-Retter, A.
Mai, P.L.
Greene, M.H.
Imyanitov, E.
O'Malley, F.P.
Ozcelik, H.
Glendon, G.
Toland, A.E.
Gerdes, A.-.
Thomassen, M.
Kruse, T.A.
Jensen, U.B.
Skytte, A.-.
Caligo, M.A.
Soller, M.
Henriksson, K.
Wachenfeldt, V.A.
Arver, B.
Stenmark-Askmalm, M.
Karlsson, P.
Ding, Y.C.
Neuhausen, S.L.
Beattie, M.
Pharoah, P.D.
Moysich, K.B.
Nathanson, K.L.
Karlan, B.Y.
Gross, J.
John, E.M.
Daly, M.B.
Buys, S.M.
Southey, M.C.
Hopper, J.L.
Terry, M.B.
Chung, W.
Miron, A.F.
Goldgar, D.
Chenevix-Trench, G.
Easton, D.F.
Andrulis, I.L.
Antoniou, A.C.
Registry, B.C.
EMBRACE,
Collaborators, G.E.
HEBON,
Investigators, K.
Network, O.C.
SWE-BRCA,
CIMBA,
(2011). Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2. Breast cancer research,
Vol.13
(6).
MacInnis, R.J.
Antoniou, A.C.
Eeles, R.A.
Severi, G.
Guy, M.
McGuffog, L.
Hall, A.L.
O'Brien, L.T.
Wilkinson, R.A.
Dearnaley, D.P.
Ardern-Jones, A.T.
Horwich, A.
Khoo, V.S.
Parker, C.C.
Huddart, R.A.
McCredie, M.R.
Smith, C.
Southey, M.C.
Staples, M.P.
English, D.R.
Hopper, J.L.
Giles, G.G.
Easton, D.F.
(2010). Prostate cancer segregation analyses using 4390 families from UK and Australian population-based studies. Genet epidemiol,
Vol.34
(1),
pp. 42-50.
show abstract
Familial aggregation of prostate cancer is likely to be due to multiple susceptibility loci, perhaps acting in conjunction with shared lifestyle risk factors. Models that assume a single mode of inheritance may be unrealistic. We analyzed genetic models of susceptibility to prostate cancer using segregation analysis of occurrence in families ascertained through population-based series totaling 4390 incident cases. We investigated major gene models (dominant, recessive, general, X-linked), polygenic models, and mixed models of susceptibility using the pedigree analysis software MENDEL. The hypergeometric model was used to approximate polygenic inheritance. The best-fitting model for the familial aggregation of prostate cancer was the mixed recessive model. The frequency of the susceptibility allele in the population was estimated to be 0.15 (95% confidence interval (CI) 0.11-0.20), with a relative risk for homozygote carriers of 94 (95% CI 46-192), and a polygenic standard deviation of 2.01 (95% CI 1.72-2.34). These analyses suggest that one or more genes having a strong recessively inherited effect on risk, as well as a number of genes with variants having small multiplicative effects on risk, may account for the genetic susceptibility to prostate cancer. The recessive component would predict the observed higher familial risk for siblings of cases than for fathers, but this could also be due to other factors such as shared lifestyle by siblings, targeted screening effects, and/or non-additive effects of one or more genes..
Vergis, R.
Corbishley, C.M.
Thomas, K.
Horwich, A.
Huddart, R.
Khoo, V.
Eeles, R.
Sydes, M.R.
Cooper, C.S.
Dearnaley, D.
Parker, C.
(2010). Expression of Bcl-2, p53, and MDM2 in localized prostate cancer with respect to the outcome of radical radiotherapy dose escalation. Int j radiat oncol biol phys,
Vol.78
(1),
pp. 35-41.
show abstract
PURPOSE: Established prognostic factors in localized prostate cancer explain only a moderate proportion of variation in outcome. We analyzed tumor expression of apoptotic markers with respect to outcome in men with localized prostate cancer in two randomized controlled trials of radiotherapy dose escalation. METHODS AND MATERIALS: Between 1995 and 2001, 308 patients with localized prostate cancer received neoadjuvant androgen deprivation and radical radiotherapy at our institution in one of two dose-escalation trials. The biopsy specimens in 201 cases were used to make a biopsy tissue microarray. We evaluated tumor expression of Bcl-2, p53, and MDM2 by immunohistochemistry with respect to outcome. RESULTS: Median follow-up was 7 years, and 5-year freedom from biochemical failure (FFBF) was 70.4% (95% CI, 63.5-76.3%). On univariate analysis, expression of Bcl-2 (p < 0.001) and p53 (p = 0.017), but not MDM2 (p = 0.224), was significantly associated with FFBF. Expression of Bcl-2 remained significantly associated with FFBF (p = 0.001) on multivariate analysis, independently of T stage, Gleason score, initial prostate-specific antigen level, and radiotherapy dose. Seven-year biochemical control was 61% vs. 41% (p = 0.0122) for 74 Gy vs. 64 Gy, respectively, among patients with Bcl-2-positive tumors and 87% vs. 81% (p = 0.423) for 74 Gy vs. 64 Gy, respectively, among patients with Bcl-2-negative tumors. There was no statistically significant interaction between dose and Bcl-2 expression. CONCLUSIONS: Bcl-2 expression was a significant, independent determinant of biochemical control after neoadjuvant androgen deprivation and radical radiotherapy for prostate cancer. These data generate the hypothesis that Bcl-2 expression could be used to inform the choice of radiotherapy dose in individual patients..
Gaudet, M.M.
Kirchhoff, T.
Green, T.
Vijai, J.
Korn, J.M.
Guiducci, C.
Segre, A.V.
McGee, K.
McGuffog, L.
Kartsonaki, C.
Morrison, J.
Healey, S.
Sinilnikova, O.M.
Stoppa-Lyonnet, D.
Mazoyer, S.
Gauthier-Villars, M.
Sobol, H.
Longy, M.
Frenay, M.
Hogervorst, F.B.
Rookus, M.A.
Collee, J.M.
Hoogerbrugge, N.
van Roozendaal, K.E.
Piedmonte, M.
Rubinstein, W.
Nerenstone, S.
Van Le, L.
Blank, S.V.
Caldes, T.
de la Hoya, M.
Nevanlinna, H.
Aittomaki, K.
Lazaro, C.
Blanco, I.
Arason, A.
Johannsson, O.T.
Barkardottir, R.B.
Devilee, P.
Olopade, O.I.
Neuhausen, S.L.
Wang, X.
Fredericksen, Z.S.
Peterlongo, P.
Manoukian, S.
Barile, M.
Viel, A.
Radice, P.
Phelan, C.M.
Narod, S.
Rennert, G.
Lejbkowicz, F.
Flugelman, A.
Andrulis, I.L.
Glendon, G.
Ozcelik, H.
Toland, A.E.
Montagna, M.
D'Andrea, E.
Friedman, E.
Laitman, Y.
Borg, A.
Beattie, M.
Ramus, S.J.
Domchek, S.M.
Nathanson, K.L.
Rebbeck, T.
Spurdle, A.B.
Chen, X.
Holland, H.
John, E.M.
Hopper, J.L.
Buys, S.S.
Daly, M.B.
Southey, M.C.
Terry, M.B.
Tung, N.
Hansen, T.V.
Nielsen, F.C.
Greene, M.I.
Mai, P.L.
Osorio, A.
Duran, M.
Andres, R.
Benitez, J.
Weitzel, J.N.
Garber, J.
Hamann, U.
Peock, S.
Cook, M.
Oliver, C.
Frost, D.
Platte, R.
Evans, D.G.
Lalloo, F.
Eeles, R.
Izatt, L.
Walker, L.
Eason, J.
Barwell, J.
Godwin, A.K.
Schmutzler, R.K.
Wappenschmidt, B.
Engert, S.
Arnold, N.
Gadzicki, D.
Dean, M.
Gold, B.
Klein, R.J.
Couch, F.J.
Chenevix-Trench, G.
Easton, D.F.
Daly, M.J.
Antoniou, A.C.
Altshuler, D.M.
Offit, K.
(2010). Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer. Plos genetics,
Vol.6
(10),
p. 12.
Domchek, S.M.
Friebel, T.M.
Singer, C.F.
Evans, D.G.
Lynch, H.T.
Isaacs, C.
Garber, J.E.
Neuhausen, S.L.
Matloff, E.
Eeles, R.
Pichert, G.
Van T'veer, L.
Tung, N.
Weitzel, J.N.
Couch, F.J.
Rubinstein, W.S.
Ganz, P.A.
Daly, M.B.
Olopade, O.I.
Tomlinson, G.
Schildkraut, J.
Blum, J.L.
Rebbeck, T.R.
(2010). Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers With Cancer Risk and Mortality. Jama-journal of the american medical association,
Vol.304
(9),
pp. 967-9.
Evans, D.G.
Lunt, P.
Clancy, T.
Eeles, R.
(2010). Childhood predictive genetic testing for Li-Fraumeni syndrome. Familial cancer,
Vol.9
(1),
pp. 65-5.
Antoniou, A.C.
Beesley, J.
McGuffog, L.
Sinilnikova, O.M.
Healey, S.
Neuhausen, S.L.
Ding, Y.C.
Rebbeck, T.R.
Weitzel, J.N.
Lynch, H.T.
Isaacs, C.
Ganz, P.A.
Tomlinson, G.
Olopade, O.I.
Couch, F.J.
Wang, X.
Lindor, N.M.
Pankratz, V.S.
Radice, P.
Manoukian, S.
Peissel, B.
Zaffaroni, D.
Barile, M.
Viel, A.
Allavena, A.
Dall'Olio, V.
Peterlongo, P.
Szabo, C.I.
Zikan, M.
Claes, K.
Poppe, B.
Foretova, L.
Mai, P.L.
Greene, M.H.
Rennert, G.
Lejbkowicz, F.
Glendon, G.
Ozcelik, H.
Andrulis, I.L.
Ontario Cancer Genetics Network,
Thomassen, M.
Gerdes, A.-.
Sunde, L.
Cruger, D.
Birk Jensen, U.
Caligo, M.
Friedman, E.
Kaufman, B.
Laitman, Y.
Milgrom, R.
Dubrovsky, M.
Cohen, S.
Borg, A.
Jernström, H.
Lindblom, A.
Rantala, J.
Stenmark-Askmalm, M.
Melin, B.
SWE-BRCA,
Nathanson, K.
Domchek, S.
Jakubowska, A.
Lubinski, J.
Huzarski, T.
Osorio, A.
Lasa, A.
Durán, M.
Tejada, M.-.
Godino, J.
Benitez, J.
Hamann, U.
Kriege, M.
Hoogerbrugge, N.
van der Luijt, R.B.
van Asperen, C.J.
Devilee, P.
Meijers-Heijboer, E.J.
Blok, M.J.
Aalfs, C.M.
Hogervorst, F.
Rookus, M.
HEBON,
Cook, M.
Oliver, C.
Frost, D.
Conroy, D.
Evans, D.G.
Lalloo, F.
Pichert, G.
Davidson, R.
Cole, T.
Cook, J.
Paterson, J.
Hodgson, S.
Morrison, P.J.
Porteous, M.E.
Walker, L.
Kennedy, M.J.
Dorkins, H.
Peock, S.
EMBRACE,
Godwin, A.K.
Stoppa-Lyonnet, D.
de Pauw, A.
Mazoyer, S.
Bonadona, V.
Lasset, C.
Dreyfus, H.
Leroux, D.
Hardouin, A.
Berthet, P.
Faivre, L.
GEMO,
Loustalot, C.
Noguchi, T.
Sobol, H.
Rouleau, E.
Nogues, C.
Frénay, M.
Vénat-Bouvet, L.
GEMO,
Hopper, J.L.
Daly, M.B.
Terry, M.B.
John, E.M.
Buys, S.S.
Yassin, Y.
Miron, A.
Goldgar, D.
Breast Cancer Family Registry,
Singer, C.F.
Dressler, A.C.
Gschwantler-Kaulich, D.
Pfeiler, G.
Hansen, T.V.
Jønson, L.
Agnarsson, B.A.
Kirchhoff, T.
Offit, K.
Devlin, V.
Dutra-Clarke, A.
Piedmonte, M.
Rodriguez, G.C.
Wakeley, K.
Boggess, J.F.
Basil, J.
Schwartz, P.E.
Blank, S.V.
Toland, A.E.
Montagna, M.
Casella, C.
Imyanitov, E.
Tihomirova, L.
Blanco, I.
Lazaro, C.
Ramus, S.J.
Sucheston, L.
Karlan, B.Y.
Gross, J.
Schmutzler, R.
Wappenschmidt, B.
Engel, C.
Meindl, A.
Lochmann, M.
Arnold, N.
Heidemann, S.
Varon-Mateeva, R.
Niederacher, D.
Sutter, C.
Deissler, H.
Gadzicki, D.
Preisler-Adams, S.
Kast, K.
Schönbuchner, I.
Caldes, T.
de la Hoya, M.
Aittomäki, K.
Nevanlinna, H.
Simard, J.
Spurdle, A.B.
Holland, H.
Chen, X.
kConFab,
Platte, R.
Chenevix-Trench, G.
Easton, D.F.
CIMBA,
(2010). Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer res,
Vol.70
(23),
pp. 9742-9754.
show abstract
The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers..
Kirby, R.S.
Eeles, R.A.
Kote-Jarai, Z.
Guy, M.
Easton, D.
Fitzpatrick, J.M.
(2010). Screening for prostate cancer: the way ahead. Bju int,
Vol.105
(3),
pp. 295-297.
Mitra, A.V.
Jameson, C.
Barbachano, Y.
Sodha, N.
Kote-Jarai, Z.
Javed, A.
Bancroft, E.
Fletcher, A.
Cooper, C.
Peock, S.
IMPACT and EMBRACE Collaborators,
Easton, D.
Eeles, R.
Foster, C.S.
(2010). Elevated expression of Ki-67 identifies aggressive prostate cancers but does not distinguish BRCA1 or BRCA2 mutation carriers. Oncol rep,
Vol.23
(2),
pp. 299-305.
show abstract
Prostate cancers in men with germline BRCA1 and BRCA2 mutations are more aggressive than morphologically similar cancers in men without these mutations. This study was performed to test the hypothesis that enhanced expression of Ki-67, as a surrogate of cell proliferation, is a characteristic feature of prostate cancers occurring in BRCA1 or BRCA2 mutation carriers. The study cohort comprised 20 cases of prostate cancer in mutation carriers and 126 control sporadic prostate cancers. Of the combined sample cohort, 65.7% stained only within malignant tissues while 0.7% stained in both malignant and benign tissues (p<0.001). Significantly increased expression of Ki-67 occurred in prostate cancers with higher Gleason score (p<0.001). Elevated Ki-67 expression was identified in 71% of prostate cancers in BRCA1 or BRCA2 mutation carriers and in 67% of the sporadic controls (p>0.5). Similar results were obtained when the data were analysed using a threshold set at 3.5 and 7.1%. This study shows that elevated expression of Ki-67 is associated both with aggressive prostate cancers and with high Gleason score irrespective of whether their occurrence is against a background of BRCA1 or BRCA2 mutations or as sporadic disease. The data suggest that, since elevated Ki-67 does not distinguish prostate cancers occurring in BRCA1 or BRCA2 mutation carriers from sporadic prostatic malignancies, the effects of these genetic mutations are probably independent. While all prostate cancers occurring in the presence of BRCA germline mutations are clinically aggressive, their potentially different phenotypes consistently involve maximal rates of cell proliferation..
Guerrero Urbano, T.
Khoo, V.
Staffurth, J.
Norman, A.
Buffa, F.
Jackson, A.
Adams, E.
Hansen, V.
Clark, C.
Miles, E.
McNair, H.
Nutting, C.
Parker, C.
Eeles, R.
Huddart, R.
Horwich, A.
Dearnaley, D.P.
(2010). Intensity-modulated radiotherapy allows escalation of the radiation dose to the pelvic lymph nodes in patients with locally advanced prostate cancer: preliminary results of a phase I dose escalation study. Clin oncol (r coll radiol),
Vol.22
(3),
pp. 236-244.
show abstract
AIM: Pelvic irradiation in addition to prostate irradiation may improve outcome in locally advanced prostate cancer, but is associated with dose-limiting bowel toxicity. We report the preliminary results of a dose escalation study using intensity-modulated radiotherapy. MATERIALS AND METHODS: Eligible patients had high-risk (T3, Gleason > or =8 or prostate-specific antigen > or =20 ng/ml) or lymph node-positive disease. Intensity-modulated radiotherapy was inverse planned giving 70 Gy/35 fractions to the prostate and 50 Gy/55 Gy/60 Gy in sequential cohorts to the pelvis with a 5 Gy boost to positive lymph nodes. Acute and late toxicity were recorded with Radiation Therapy Oncology Group (RTOG) and Late Effects Normal Tissue - Subjective Objective Management LENT-SOM scales. Neoadjuvant androgen suppression was given for 3 years. This report concerns the 50 and 55 Gy cohorts. RESULTS: Seventy-nine men were recruited (25 to 50 Gy/54 to 55 Gy) with a median follow-up of 2 years. Patients were divided into two groups according to the total bowel volume outlined (median 450 cm(3)). Acute RTOG (> or =2) bowel toxicity was 40 and 50% for the 50 and 55 Gy groups and 38 and 51% for bowel volume <450 cm(3) and > or =450 cm(3), respectively, suggesting both volume and dose relationships for acute effects. Late RTOG diarrhoea > or =grade 2 was only seen with bowel volume > or =450 cm(3), but no dose effect was apparent (12%/50 Gy and 10%/55 Gy). LENT-SOM bowel > or =grade 2 toxicity occurred in 22%/50 Gy and 15%/55 Gy. Only one patient had grade 3 toxicity. A dose volume histogram analysis showed increased late RTOG diarrhoea > or =grade 2 with larger bowel volume irradiated, significant for BV40 >124 cm(3) (P=0.04), BV45 >71 cm(3) (P=0.03) and BV60 >2 cm(3) (P=0.01). CONCLUSIONS: Acute and late bowel toxicity was acceptably low using a pelvic dose of up to 55 Gy over 7 weeks. Both relate to total pelvic bowel volume and dose volume constraints have been defined..
Lophatananon, A.
Archer, J.
Easton, D.
Pocock, R.
Dearnaley, D.
Guy, M.
Kote-Jarai, Z.
O'Brien, L.
Wilkinson, R.A.
Hall, A.L.
Sawyer, E.
Page, E.
Liu, J.-.
Barratt, S.
Rahman, A.A.
UK Genetic Prostate Cancer Study Collaborators,
British Association of Urological Surgeons' Section of Oncology,
Eeles, R.
Muir, K.
(2010). Dietary fat and early-onset prostate cancer risk. Br j nutr,
Vol.103
(9),
pp. 1375-1380.
show abstract
The UK incidence of prostate cancer has been increasing in men aged < 60 years. Migrant studies and global and secular variation in incidence suggest that modifiable factors, including a high-fat diet, may contribute to prostate cancer risk. The aim of the present study was to investigate the role of dietary fat intake and its derivatives on early-onset prostate cancer risk. During 1999-2004, a population-based case-control study with 512 cases and 838 controls was conducted. Cases were diagnosed with prostate cancer when < or = 60 years. Controls were sourced from UK GP practice registers. A self-administered FFQ collected data on typical past diet. A nutritional database was used to calculate daily fat intake. A positive, statistically significant risk estimate for the highest v. lowest quintile of intake of total fat, SFA, MUFA and PUFA was observed when adjusted for confounding variables: OR 2.53 (95 % CI 1.72, 3.74), OR 2.49 (95 % CI 1.69, 3.66), OR 2.69 (95 % CI 1.82, 3.96) and OR 2.34 (95 % CI 1.59, 3.46), respectively, with all P for trend < 0.001. In conclusion, there was a positive statistically significant association between prostate cancer risk and energy-adjusted intake of total fat and fat subtypes. These results potentially identify a modifiable risk factor for early-onset prostate cancer..
Bancroft, E.K.
Locke, I.
Ardern-Jones, A.
D'Mello, L.
McReynolds, K.
Lennard, F.
Barbachano, Y.
Barwell, J.
Walker, L.
Mitchell, G.
Dorkins, H.
Cummings, C.
Paterson, J.
Kote-Jarai, Z.
Mitra, A.
Jhavar, S.
Thomas, S.
Houlston, R.
Shanley, S.
Eeles, R.A.
(2010). The carrier clinic: an evaluation of a novel clinic dedicated to the follow-up of BRCA1 and BRCA2 carriers--implications for oncogenetics practice. J med genet,
Vol.47
(7),
pp. 486-491.
show abstract
BACKGROUND: A novel oncogenetic clinic was established in 2002 at the Royal Marsden NHS Foundation Trust offering advice and specialist follow-up for families with a germline mutation in BRCA1 or BRCA2. The remit of this multidisciplinary clinic, staffed by individuals in both oncology and genetics, is to provide individualised screening recommendations, support in decision making, risk reducing strategies, cascade testing, and an extensive research portfolio. METHODS: A retrospective analysis was performed to evaluate uptake of genetic testing, risk reducing surgery and cancer prevalence in 346 BRCA1/BRCA2 families seen between January 1996 and December 2006. RESULTS: 661 individuals attended the clinic and 406 mutation carriers were identified; 85.8% mutation carriers have chosen to attend for annual follow-up. 70% of mutation carriers elected for risk reducing bilateral salpingo-oophorectomy (RRBSO). 32% of unaffected women chose risk reducing bilateral mastectomy. 32% of women with breast cancer chose contralateral risk reducing mastectomy at time of diagnosis. Some women took over 8 years to decide to have surgery. 91% of individuals approached agreed to participate in research programmes. INTERPRETATION: A novel specialist clinic for BRCA1/2 mutation carriers has been successfully established. The number of mutation positive families is increasing. This, and the high demand for RRBSO in women over 40, is inevitably going to place an increasing demand on existing health resources. Our clinic model has subsequently been adopted in other centres and this will greatly facilitate translational studies and provide a healthcare structure for management and follow-up of such people who are at a high cancer risk..
Edwards, S.M.
Evans, D.G.
Hope, Q.
Norman, A.R.
Barbachano, Y.
Bullock, S.
Kote-Jarai, Z.
Meitz, J.
Falconer, A.
Osin, P.
Fisher, C.
Guy, M.
Jhavar, S.G.
Hall, A.L.
O'Brien, L.T.
Gehr-Swain, B.N.
Wilkinson, R.A.
Forrest, M.S.
Dearnaley, D.P.
Ardern-Jones, A.T.
Page, E.C.
Easton, D.F.
Eeles, R.A.
UK Genetic Prostate Cancer Study Collaborators and BAUS Section of Oncology,
(2010). Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br j cancer,
Vol.103
(6),
pp. 918-924.
show abstract
BACKGROUND: The germline BRCA2 mutation is associated with increased prostate cancer (PrCa) risk. We have assessed survival in young PrCa cases with a germline mutation in BRCA2 and investigated loss of heterozygosity at BRCA2 in their tumours. METHODS: Two cohorts were compared: one was a group with young-onset PrCa, tested for germline BRCA2 mutations (6 of 263 cases had a germline BRAC2 mutation), and the second was a validation set consisting of a clinical set from Manchester of known BRCA2 mutuation carriers (15 cases) with PrCa. Survival data were compared with a control series of patients in a single clinic as determined by Kaplan-Meier estimates. Loss of heterozygosity was tested for in the DNA of tumour tissue of the young-onset group by typing four microsatellite markers that flanked the BRCA2 gene, followed by sequencing. RESULTS: Median survival of all PrCa cases with a germline BRCA2 mutation was shorter at 4.8 years than was survival in controls at 8.5 years (P=0.002). Loss of heterozygosity was found in the majority of tumours of BRCA2 mutation carriers. Multivariate analysis confirmed that the poorer survival of PrCa in BRCA2 mutation carriers is associated with the germline BRCA2 mutation per se. CONCLUSION: BRCA2 germline mutation is an independent prognostic factor for survival in PrCa. Such patients should not be managed with active surveillance as they have more aggressive disease..
Spurdle, A.B.
Fahey, P.
Chen, X.
McGuffog, L.
kConFab,
Easton, D.
Peock, S.
Cook, M.
EMBRACE,
Simard, J.
INHERIT,
Rebbeck, T.R.
MAGIC,
Antoniou, A.C.
Chenevix-Trench, G.
(2010). Pooled analysis indicates that the GSTT1 deletion, GSTM1 deletion, and GSTP1 Ile105Val polymorphisms do not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Breast cancer res treat,
Vol.122
(1),
pp. 281-285.
show abstract
The GSTP1, GSTM1, and GSTT1 detoxification genes all have functional polymorphisms that are common in the general population. A single study of 320 BRCA1/2 carriers previously assessed their effect in BRCA1 or BRCA2 mutation carriers. This study showed no evidence for altered risk of breast cancer for individuals with the GSTT1 and GSTM1 deletion variants, but did report that the GSTP1 Ile105Val (rs1695) variant was associated with increased breast cancer risk in carriers. We investigated the association between these three GST polymorphisms and breast cancer risk using existing data from 718 women BRCA1 and BRCA2 mutation carriers from Australia, the UK, Canada, and the USA. Data were analyzed within a proportional hazards framework using Cox regression. There was no evidence to show that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, and there was no evidence for heterogeneity between sites. These results support the need for replication studies to confirm or refute hypothesis-generating studies..
Antoniou, A.C.
Wang, X.
Fredericksen, Z.S.
McGuffog, L.
Tarrell, R.
Sinilnikova, O.M.
Healey, S.
Morrison, J.
Kartsonaki, C.
Lesnick, T.
Ghoussaini, M.
Barrowdale, D.
Peock, S.
Cook, M.
Oliver, C.
Frost, D.
Eccles, D.
Evans, D.G.
Eeles, R.
Izatt, L.
Chu, C.
Douglas, F.
Paterson, J.
Stoppa-Lyonnet, D.
Houdayer, C.
Mazoyer, S.
Giraud, S.
Lasset, C.
Remenieras, A.
Caron, O.
Hardouin, A.
Berthet, P.
Hogervorst, F.B.
Rookus, M.A.
Jager, A.
van den Ouweland, A.
Hoogerbrugge, N.
van der Luijt, R.B.
Meijers-Heijboer, H.
Garcia, E.B.
Devilee, P.
Vreeswijk, M.P.
Lubinski, J.
Jakubowska, A.
Gronwald, J.
Huzarski, T.
Byrski, T.
Gorski, B.
Cybulski, C.
Spurdle, A.B.
Holland, H.
Goldgar, D.E.
John, E.M.
Hopper, J.L.
Southey, M.
Buys, S.S.
Daly, M.B.
Terry, M.-.
Schmutzler, R.K.
Wappenschmidt, B.
Engel, C.
Meindl, A.
Preisler-Adams, S.
Arnold, N.
Niederacher, D.
Sutter, C.
Domchek, S.M.
Nathanson, K.L.
Rebbeck, T.
Blum, J.L.
Piedmonte, M.
Rodriguez, G.C.
Wakeley, K.
Boggess, J.F.
Basil, J.
Blank, S.V.
Friedman, E.
Kaufman, B.
Laitman, Y.
Milgrom, R.
Andrulis, I.L.
Glendon, G.
Ozcelik, H.
Kirchhoff, T.
Vijai, J.
Gaudet, M.M.
Altshuler, D.
Guiducci, C.
Loman, N.
Harbst, K.
Rantala, J.
Ehrencrona, H.
Gerdes, A.-.
Thomassen, M.
Sunde, L.
Peterlongo, P.
Manoukian, S.
Bonanni, B.
Viel, A.
Radice, P.
Caldes, T.
de la Hoya, M.
Singer, C.F.
Fink-Retter, A.
Greene, M.H.
Mai, P.L.
Loud, J.T.
Guidugli, L.
Lindor, N.M.
Hansen, T.V.
Nielsen, F.C.
Blanco, I.
Lazaro, C.
Garber, J.
Ramus, S.J.
Gayther, S.A.
Phelan, C.
Narod, S.
Szabo, C.I.
Benitez, J.
Osorio, A.
Nevanlinna, H.
Heikkinen, T.
Caligo, M.A.
Beattie, M.S.
Hamann, U.
Godwin, A.K.
Montagna, M.
Casella, C.
Neuhausen, S.L.
Karlan, B.Y.
Tung, N.
Toland, A.E.
Weitzel, J.
Olopade, O.
Simard, J.
Soucy, P.
Rubinstein, W.S.
Arason, A.
Rennert, G.
Martin, N.G.
Montgomery, G.W.
Chang-Claude, J.
Flesch-Janys, D.
Brauch, H.
Severi, G.
Baglietto, L.
Cox, A.
Cross, S.S.
Miron, P.
Gerty, S.M.
Tapper, W.
Yannoukakos, D.
Fountzilas, G.
Fasching, P.A.
Beckmann, M.W.
Silva, I.D.
Peto, J.
Lambrechts, D.
Paridaens, R.
Ruediger, T.
Foersti, A.
Winqvist, R.
Pylkaes, K.
Diasio, R.B.
Lee, A.M.
Eckel-Passow, J.
Vachon, C.
Blows, F.
Driver, K.
Dunning, A.
Pharoah, P.P.
Offit, K.
Pankratz, V.S.
Hakonarson, H.
Chenevix-Trench, G.
Easton, D.F.
Couch, F.J.
(2010). A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nature genetics,
Vol.42
(10),
pp. 885-11.
Turnbull, C.
Hines, S.
Renwick, A.
Hughes, D.
Pernet, D.
Elliott, A.
Seal, S.
Warren-Perry, M.
Gareth Evans, D.
Eccles, D.
Breast Cancer Susceptibility Collaboration UK,
Stratton, M.R.
Rahman, N.
(2010). Mutation and association analysis of GEN1 in breast cancer susceptibility. Breast cancer res treat,
Vol.124
(1),
pp. 283-288.
show abstract
GEN1 was recently identified as a key Holliday junction resolvase involved in homologous recombination. Somatic truncating GEN1 mutations have been reported in two breast cancers. Together these data led to the proposition that GEN1 is a breast cancer predisposition gene. In this article we have formally investigated this hypothesis. We performed full-gene mutational analysis of GEN1 in 176 BRCA1/2-negative familial breast cancer samples and 159 controls. We genotyped six SNPs tagging the 30 common variants in the transcribed region of GEN1 in 3,750 breast cancer cases and 4,907 controls. Mutation analysis revealed one truncating variant, c.2515_2519delAAGTT, which was present in 4% of cases and 4% of controls. We identified control individuals homozygous for the deletion, demonstrating that the last 69 amino acids of GEN1 are dispensable for its function. We identified 17 other variants, but their frequency did not significantly differ between cases and controls. Analysis of 3,750 breast cancer cases and 4,907 controls demonstrated no evidence of significant association with breast cancer for six SNPs tagging the 30 common GEN1 variants. These data indicate that although it also plays a key role in double-strand DNA break repair, GEN1 does not make an appreciable contribution to breast cancer susceptibility by acting as a high- or intermediate-penetrance breast cancer predisposition gene like BRCA1, BRCA2, CHEK2, ATM, BRIP1 and PALB2 and that common GEN1 variants do not act as low-penetrance susceptibility alleles analogous to SNPs in FGFR2. Furthermore, our analyses demonstrate the importance of undertaking appropriate genetic investigations, typically full gene screening in cases and controls together with large-scale case-control association analyses, to evaluate the contribution of genes to cancer susceptibility..
Engel, C.
Versmold, B.
Wappenschmidt, B.
Simard, J.
Easton, D.F.
Peock, S.
Cook, M.
Oliver, C.
Frost, D.
Mayes, R.
Evans, D.G.
Eeles, R.
Paterson, J.
Brewer, C.
McGuffog, L.
Antoniou, A.C.
Stoppa-Lyonnet, D.
Sinilnikova, O.M.
Barjhoux, L.
Frenay, M.
Michel, C.
Leroux, D.
Dreyfus, H.
Toulas, C.
Gladieff, L.
Uhrhammer, N.
Bignon, Y.-.
Meindl, A.
Arnold, N.
Varon-Mateeva, R.
Niederacher, D.
Preisler-Adams, S.
Kast, K.
Deissler, H.
Sutter, C.
Gadzicki, D.
Chenevix-Trench, G.
Spurdle, A.B.
Chen, X.
Beesley, J.
Olsson, H.
Kristoffersson, U.
Ehrencrona, H.
Liljegren, A.
van der Luijt, R.B.
van Os, T.A.
van Leeuwen, F.E.
Domchek, S.M.
Rebbeck, T.R.
Nathanson, K.L.
Osorio, A.
Ramon y Cajal, T.
Konstantopoulou, I.
Benitez, J.
Friedman, E.
Kaufman, B.
Laitman, Y.
Mai, P.L.
Greene, M.H.
Nevanlinna, H.
Aittomaki, K.
Szabo, C.I.
Caldes, T.
Couch, F.J.
Andrulis, I.L.
Godwin, A.K.
Hamann, U.
Schmutzler, R.K.
(2010). Association of the Variants CASP8 D302H and CASP10 V410I with Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. Cancer epidemiology biomarkers & prevention,
Vol.19
(11),
pp. 2859-10.
Domchek, S.M.
Friebel, T.M.
Garber, J.E.
Isaacs, C.
Matloff, E.
Eeles, R.
Evans, D.G.
Rubinstein, W.
Singer, C.F.
Rubin, S.
Lynch, H.T.
Daly, M.B.
Weitzel, J.
Ganz, P.A.
Pichert, G.
Olopade, O.I.
Tomlinson, G.
Tung, N.
Blum, J.L.
Couch, F.
Rebbeck, T.R.
(2010). Occult ovarian cancers identified at risk-reducing salpingo-oophorectomy in a prospective cohort of BRCA1/2 mutation carriers. Breast cancer research and treatment,
Vol.124
(1),
pp. 195-9.
Ardern-Jones, A.
Kenen, R.
Lynch, E.
Doherty, R.
Eeles, R.
(2010). Is no news good news? Inconclusive genetic test results in BRCA1 and BRCA2 from patients and professionals' perspectives. Hered cancer clin pract,
Vol.8
(1),
p. 1.
show abstract
BACKGROUND: Women from families with a high risk of breast or ovarian cancer in which genetic testing for mutations in the BRCA1/2 genes is inconclusive are a vulnerable and understudied group. Furthermore, there are no studies of the professional specialists who treat them - geneticists, genetic counsellors/nurses, oncologists, gynaecologists and breast surgeons. METHODS: We conducted a small qualitative study that investigated women who had developed breast cancer under the age of 45 and who had an inconclusive BRCA1/2 genetic diagnostic test (where no mutations or unclassified variants were identified). We arranged three focus groups for affected women and their close female relatives - 13 women took part. We also interviewed 12 health professionals who were involved in the care of these women. RESULTS: The majority of the women had a good grasp of the meaning of their own or a family member's inconclusive result, but a few indicated some misunderstanding. Most of the women in this study underwent the test for the benefit of others in the family and none mentioned that they were having the test purely for themselves. A difficult issue for sisters of affected women was whether or not to undertake prophylactic breast surgery. The professionals were sensitive to the difficulties in explaining an inconclusive result. Some felt frustrated that technology had not as yet provided them with a better tool for prediction of risk. CONCLUSIONS: Some of the women were left with the dilemma of what decision to make regarding medical management of their cancer risk. For the most part, the professionals believed that the women should be supported in whatever management decisions they considered best, provided these decisions were based on a complete and accurate understanding of the genetic test that had taken place in the family..
Whitaker, H.C.
Kote-Jarai, Z.
Ross-Adams, H.
Warren, A.Y.
Burge, J.
George, A.
Bancroft, E.
Jhavar, S.
Leongamornlert, D.
Tymrakiewicz, M.
Saunders, E.
Page, E.
Mitra, A.
Mitchell, G.
Lindeman, G.J.
Evans, D.G.
Blanco, I.
Mercer, C.
Rubinstein, W.S.
Clowes, V.
Douglas, F.
Hodgson, S.
Walker, L.
Donaldson, A.
Izatt, L.
Dorkins, H.
Male, A.
Tucker, K.
Stapleton, A.
Lam, J.
Kirk, J.
Lilja, H.
Easton, D.
IMPACT Study Steering Committee,
IMPACT Study Collaborators,
UK GPCS Collaborators,
Cooper, C.
Eeles, R.
Neal, D.E.
(2010). The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine. Plos one,
Vol.5
(10),
p. e13363.
show abstract
BACKGROUND: Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk. METHODOLOGY/PRINCIPAL FINDINGS: MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate. CONCLUSIONS: These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring..
Christensen, G.B.
Baffoe-Bonnie, A.B.
George, A.
Powell, I.
Bailey-Wilson, J.E.
Carpten, J.D.
Giles, G.G.
Hopper, J.L.
Seven, G.
English, D.R.
Foulkes, W.D.
Maehle, L.
Moller, P.
Eeles, R.
Easton, D.
Badzioch, M.D.
Whittemore, A.S.
Oakley-Girvan, I.
Hsieh, C.-.
Dimitrov, L.
Xu, J.
Stanford, J.L.
Johanneson, B.
Deutsch, K.
McIntosh, L.
Ostrander, E.A.
Wiley, K.E.
Isaacs, S.D.
Walsh, P.C.
Isaacs, W.B.
Thibodeau, S.N.
McDonnell, S.K.
Hebbring, S.
Schaid, D.J.
Lange, E.M.
Cooney, K.A.
Tammela, T.L.
Schleutker, J.
Paiss, T.
Maier, C.
Gronberg, H.
Wiklund, F.
Emanuelsson, M.
Farnham, J.M.
Cannon-Albright, L.A.
Camp, N.J.
(2010). Genome-Wide Linkage Analysis of 1,233 Prostate Cancer Pedigrees From the International Consortium for Prostate Cancer Genetics Using Novel sum LINK and sum LOD Analyses. Prostate,
Vol.70
(7),
pp. 735-10.
Wang, X.
Pankratz, V.S.
Fredericksen, Z.
Tarrell, R.
Karaus, M.
McGuffog, L.
Pharaoh, P.D.
Ponder, B.A.
Dunning, A.M.
Peock, S.
Cook, M.
Oliver, C.
Frost, D.
EMBRACE,
Sinilnikova, O.M.
Stoppa-Lyonnet, D.
Mazoyer, S.
Houdayer, C.
GEMO,
Hogervorst, F.B.
Hooning, M.J.
Ligtenberg, M.J.
HEBON,
Spurdle, A.
Chenevix-Trench, G.
kConFab,
Schmutzler, R.K.
Wappenschmidt, B.
Engel, C.
Meindl, A.
Domchek, S.M.
Nathanson, K.L.
Rebbeck, T.R.
Singer, C.F.
Gschwantler-Kaulich, D.
Dressler, C.
Fink, A.
Szabo, C.I.
Zikan, M.
Foretova, L.
Claes, K.
Thomas, G.
Hoover, R.N.
Hunter, D.J.
Chanock, S.J.
Easton, D.F.
Antoniou, A.C.
Couch, F.J.
(2010). Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Hum mol genet,
Vol.19
(14),
pp. 2886-2897.
show abstract
full text
Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 x 10(-3)) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (P(trend) < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69-0.90, P(trend) = 3.6 x 10(-4) and HR = 1.25, 95% CI: 1.10-1.41, P(trend) = 4.2 x 10(-4)), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25-1.92, P(trend) = 6 x 10(-5) and HR = 1.37, 95% CI: 1.16-1.62, P(trend) = 1.7 x 10(-4)). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations..
Eeles, R.A.
(2010). Germline and somatic studies in the TP53 gene in breast and other cancers. ,
.
Kote-Jarai, Z.
Leongamornlert, D.
Tymrakiewicz, M.
Field, H.
Guy, M.
Al Olama, A.A.
Morrison, J.
O'Brien, L.
Wilkinson, R.
Hall, A.
Sawyer, E.
Muir, K.
Hamdy, F.
Donovan, J.
Neal, D.
Easton, D.
Eeles, R.
(2010). Mutation analysis of the MSMB gene in familial prostate cancer. Br j cancer,
Vol.102
(2),
pp. 414-418.
show abstract
BACKGROUND: MSMB, a gene coding for beta-microseminoprotein, has been identified as a candidate susceptibility gene for prostate cancer (PrCa) in two genome-wide association studies (GWAS). SNP rs10993994 is 2 bp upstream of the transcription initiation site of MSMB and was identified as an associated PrCa risk variant. The MSMB protein is underexpressed in PrCa and it was previously proposed to be an independent marker for the recurrence of cancer after radical prostatectomy. METHODS: In this study, the coding region of this gene and 1500 bp upstream of the 5'UTR has been sequenced in germline DNA in 192 PrCa patients with family history. To evaluate the possible effects of these variants we used in silico analysis. RESULTS: No deleterious mutations were identified, however, nine new sequence variants were found, most of these in the promoter and 5'UTR region. In silico analysis suggests that four of these SNPs are likely to have some effect on gene expression either by affecting ubiquitous or prostate-specific transcription factor (TF)-binding sites or modifying splicing efficiency. INTERPRETATION: We conclude that MSMB is unlikely to be a familial PrCa gene and propose that the high-risk alleles of the SNPs in the 5'UTR effect PrCa risk by modifying MSMB gene expression in response to hormones in a tissue-specific manner..
Elliott, K.S.
Zeggini, E.
McCarthy, M.I.
Gudmundsson, J.
Sulem, P.
Stacey, S.N.
Thorlacius, S.
Amundadottir, L.
Grönberg, H.
Xu, J.
Gaborieau, V.
Eeles, R.A.
Neal, D.E.
Donovan, J.L.
Hamdy, F.C.
Muir, K.
Hwang, S.-.
Spitz, M.R.
Zanke, B.
Carvajal-Carmona, L.
Brown, K.M.
Australian Melanoma Family Study Investigators,
Hayward, N.K.
Macgregor, S.
Tomlinson, I.P.
Lemire, M.
Amos, C.I.
Murabito, J.M.
Isaacs, W.B.
Easton, D.F.
Brennan, P.
PanScan Consortium,
Barkardottir, R.B.
Gudbjartsson, D.F.
Rafnar, T.
Hunter, D.J.
Chanock, S.J.
Stefansson, K.
Ioannidis, J.P.
(2010). Evaluation of association of HNF1B variants with diverse cancers: collaborative analysis of data from 19 genome-wide association studies. Plos one,
Vol.5
(5),
p. e10858.
show abstract
BACKGROUND: Genome-wide association studies have found type 2 diabetes-associated variants in the HNF1B gene to exhibit reciprocal associations with prostate cancer risk. We aimed to identify whether these variants may have an effect on cancer risk in general versus a specific effect on prostate cancer only. METHODOLOGY/PRINCIPAL FINDINGS: In a collaborative analysis, we collected data from GWAS of cancer phenotypes for the frequently reported variants of HNF1B, rs4430796 and rs7501939, which are in linkage disequilibrium (r(2) = 0.76, HapMap CEU). Overall, the analysis included 16 datasets on rs4430796 with 19,640 cancer cases and 21,929 controls; and 21 datasets on rs7501939 with 26,923 cases and 49,085 controls. Malignancies other than prostate cancer included colorectal, breast, lung and pancreatic cancers, and melanoma. Meta-analysis showed large between-dataset heterogeneity that was driven by different effects in prostate cancer and other cancers. The per-T2D-risk-allele odds ratios (95% confidence intervals) for rs4430796 were 0.79 (0.76, 0.83)] per G allele for prostate cancer (p<10(-15) for both); and 1.03 (0.99, 1.07) for all other cancers. Similarly for rs7501939 the per-T2D-risk-allele odds ratios (95% confidence intervals) were 0.80 (0.77, 0.83) per T allele for prostate cancer (p<10(-15) for both); and 1.00 (0.97, 1.04) for all other cancers. No malignancy other than prostate cancer had a nominally statistically significant association. CONCLUSIONS/SIGNIFICANCE: The examined HNF1B variants have a highly specific effect on prostate cancer risk with no apparent association with any of the other studied cancer types..
Walker, L.C.
Fredericksen, Z.S.
Wang, X.
Tarrell, R.
Pankratz, V.S.
Lindor, N.M.
Beesley, J.
Healey, S.
Chen, X.
Fab, K.C.
Stoppa-Lyonnet, D.
Tirapo, C.
Giraud, S.
Mazoyer, S.
Muller, D.
Fricker, J.-.
Delnatte, C.
Schmutzler, R.K.
Wappenschmidt, B.
Engel, C.
Schoenbuchner, I.
Deissler, H.
Meindl, A.
Hogervorst, F.B.
Verheus, M.
Hooning, M.J.
van den Ouweland, A.M.
Nelen, M.R.
Ausems, M.G.
Aalfs, C.M.
van Asperen, C.J.
Devilee, P.
Gerrits, M.M.
Waisfisz, Q.
Szabo, C.I.
Quad, M.S.
Easton, D.F.
Peock, S.
Cook, M.
Oliver, C.T.
Frost, D.
Harrington, P.
Evans, D.G.
Lalloo, F.
Eeles, R.
Izatt, L.
Chu, C.
Davidson, R.
Eccles, D.
Ong, K.-.
Cook, J.
Rebbeck, T.
Nathanson, K.L.
Domchek, S.M.
Singer, C.F.
Gschwantler-Kaulich, D.
Dressler, A.-.
Pfeiler, G.
Godwin, A.K.
Heikkinen, T.
Nevanlinna, H.
Agnarsson, B.A.
Caligo, M.A.
Olsson, H.
Kristoffersson, U.
Liljegren, A.
Arver, B.
Karlsson, P.
Melin, B.
Sinilnikova, O.M.
McGuffog, L.
Antoniou, A.C.
Chenevix-Trench, G.
Spurdle, A.B.
Couch, F.J.
(2010). Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers. Breast cancer research,
Vol.12
(6),
p. 10.
Hall, J.
Gray, S.
A'Hern, R.
Shanley, S.
Watson, M.
Kash, K.
Croyle, R.
Eeles, R.
(2009). Genetic testing for BRCA1: effects of a randomised study of knowledge provision on interest in testing and long term test uptake; implications for the NICE guidelines. Familial cancer,
Vol.8
(1),
pp. 5-9.
Dimitropoulou, P.
Lophatananon, A.
Easton, D.
Pocock, R.
Dearnaley, D.P.
Guy, M.
Edwards, S.
O'Brien, L.
Hall, A.
Wilkinson, R.
Eeles, R.
Muir, K.R.
UK Genetic Prostate Cancer Study Collaborators,
British Association of Urological Surgeons Section of Oncology,
(2009). Sexual activity and prostate cancer risk in men diagnosed at a younger age. Bju int,
Vol.103
(2),
pp. 178-185.
show abstract
OBJECTIVE: To examine, in a case-control study, the association between the frequency of sexual activity (intercourse, masturbation, overall) and prostate cancer risk in younger men diagnosed at < or = 60 years old. PATIENTS, SUBJECTS AND METHODS: In all, 431 prostate cancer cases and 409 controls participated and provided information on their sexual activity. In particular, the frequencies of intercourse and masturbation during the participants' different age decades (20s, 30s, 40s, 50s) were collected. RESULTS: Whereas frequent overall sexual activity in younger life (20s) increased the disease risk, it appeared to be protective against the disease when older (50s). Alone, frequent masturbation activity was a marker for increased risk in the 20s and 30s but appeared to be associated with a decreased risk in the 50s, while intercourse activity alone was not associated with the disease. CONCLUSION: These findings could imply different mechanisms by which sexual activity is involved in the aetiology of prostate cancer at different ages. Alternatively, there is a possibility of reverse causation in explaining part of the protective effect seen for men in their 50s..
Venkitaraman, R.
Cook, G.J.
Dearnaley, D.P.
Parker, C.C.
Huddart, R.A.
Khoo, V.
Eeles, R.
Horwich, A.
Sohaib, S.A.
(2009). Does magnetic resonance imaging of the spine have a role in the staging of prostate cancer?. Clin oncol (r coll radiol),
Vol.21
(1),
pp. 39-42.
show abstract
AIMS: Magnetic resonance imaging (MRI) is an effective method for evaluating the spine in patients with a high risk of metastatic disease. The aim of this study was to compare MRI spine with radionuclide bone scan in detecting spinal metastases for staging prostate cancer patients. MATERIALS AND METHODS: A cohort of 99 patients with locally advanced prostate cancer at high risk of skeletal metastasis (prostate-specific antigen>10 ng/ml, composite Gleason score>or=8) or equivocal findings on bone scan were included in the retrospective study, and their MRI spine and bone scans were analysed. RESULTS: Ten patients were detected to have definite spinal metastasis by bone scan, whereas 12 patients had definite skeletal metastasis by MRI spine. Compared with the 'gold standard', derived from clinical and radiological follow-up, the sensitivities for radionuclide bone scan and that for MRI spine for detecting skeletal metastasis were 71.4 and 85.7%, respectively (P=0.023), whereas the specificities were 96.5 and 97.7%, respectively (P=0.95). Of the 34 individual metastatic lesions in the spine, 15 were concordantly positive on both scans, whereas five lesions were positive only by bone scan and 11 positive only by MRI. The addition of MRI spine in the staging for prostate cancer resulted in a change of stage and management plan in seven (7%) patients. CONCLUSION: MRI spine has comparable specificity and slightly better sensitivity than bone scan to detect spinal metastasis from prostate cancer..
Antoniou, A.C.
Rookus, M.
Andrieu, N.
Brohet, R.
Chang-Claude, J.
Peock, S.
Cook, M.
Evans, D.G.
Eeles, R.
Nogues, C.
Faivre, L.
Gesta, P.
van Leeuwen, F.E.
Ausems, M.G.
Sorio, A.
Caldes, T.
Simard, J.
Lubinski, J.
Gerdes, A.-.
Olah, E.
Fuerhauser, C.
Olsson, H.
Arver, B.
Radice, P.
Easton, D.F.
Goldgarl, D.E.
(2009). Reproductive and Hormonal Factors, and Ovarian Cancer Risk for BRCA1 and BRCA2 Mutation Carriers: Results from the International BRCA1/2 Carrier Cohort Study. Cancer epidemiology biomarkers & prevention,
Vol.18
(2),
pp. 601-10.
Yu, V.P.
Novelli, M.
Payne, S.J.
Fisher, S.
Barnetson, R.A.
Frayling, I.M.
Barrett, A.
Goudie, D.
Ardern-Jones, A.
Eeles, R.
Shanley, S.
(2009). Unusual presentation of Lynch Syndrome. Hered cancer clin pract,
Vol.7
(1),
p. 12.
show abstract
Lynch Syndrome/HNPCC is a syndrome of cancer predisposition linked to inherited mutations of genes participating in post-replicative DNA mismatch repair (MMR). The spectrum of cancer associated with Lynch Syndrome includes tumours of the colorectum, endometrium, ovary, upper gastrointestinal tract and the urothelium although other cancers are rarely described. We describe a family of Lynch Syndrome with an hMLH1 mutation, that harbours an unusual tumour spectrum and its diagnostic and management challenges..
Jhavar, S.
Brewer, D.
Edwards, S.
Kote-Jarai, Z.
Attard, G.
Clark, J.
Flohr, P.
Christmas, T.
Thompson, A.
Parker, M.
Shepherd, C.
Stenman, U.-.
Marchbank, T.
Playford, R.J.
Woodhouse, C.
Ogden, C.
Fisher, C.
Kovacs, G.
Corbishley, C.
Jameson, C.
Norman, A.
De-Bono, J.
Bjartell, A.
Eeles, R.
Cooper, C.S.
(2009). Integration of ERG gene mapping and gene-expression profiling identifies distinct categories of human prostate cancer. Bju int,
Vol.103
(9),
pp. 1256-1269.
show abstract
OBJECTIVE: To integrate the mapping of ERG alterations with the collection of expression microarray (EMA) data, as previous EMA analyses have failed to consider the genetic heterogeneity and complex patterns of ERG alteration frequently found in cancerous prostates. MATERIALS AND METHODS: We determined genome-wide expression levels with GeneChip Human Exon 1.0 ST arrays (Affymetrix, Santa Clara, CA, USA) using RNA prepared from 35 specimens of prostate cancer from 28 prostates. RESULTS: The expression profiles showed clustering, in unsupervised hierarchical analyses, into two distinct prostate cancer categories, with one group strongly associated with indicators of poor clinical outcome. The two categories are not tightly linked to ERG status. By analysis of the data we identified a subgroup of cancers lacking ERG rearrangements that showed an outlier pattern of SPINK1 mRNA expression. There was a major distinction between ERG rearranged and non-rearranged cancers that involves the levels of expression of genes linked to exposure to beta-oestradiol, and to retinoic acid. CONCLUSIONS: Expression profiling of prostate cancer samples containing single patterns of ERG alterations can provide novel insights into the mechanism of prostate cancer development, and support the view that factors other than ERG status are the major determinants of poor clinical outcome..
Rebbeck, T.R.
Antoniou, A.C.
Llopis, T.C.
Nevanlinna, H.
Aittomäki, K.
Simard, J.
Spurdle, A.B.
KConFab,
Couch, F.J.
Pereira, L.H.
Greene, M.H.
Andrulis, I.L.
Ontario Cancer Genetics Network,
Pasche, B.
Kaklamani, V.
Breast Cancer Family Registry,
Hamann, U.
Szabo, C.
Peock, S.
Cook, M.
Harrington, P.A.
Donaldson, A.
Male, A.M.
Gardiner, C.A.
Gregory, H.
Side, L.E.
Robinson, A.C.
Emmerson, L.
Ellis, I.
EMBRACE,
Peyrat, J.-.
Fournier, J.
Vennin, P.
Adenis, C.
Muller, D.
Fricker, J.-.
Longy, M.
Sinilnikova, O.M.
Stoppa-Lyonnet, D.
GEMO,
Schmutzler, R.K.
Versmold, B.
Engel, C.
Meindl, A.
Kast, K.
Schaefer, D.
Froster, U.G.
Chenevix-Trench, G.
Easton, D.F.
(2009). No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study. Breast cancer res treat,
Vol.115
(1),
pp. 185-192.
show abstract
BACKGROUND: The transforming growth factor beta-1 gene (TGFB1) is a plausible candidate for breast cancer susceptibility. The L10P variant of TGFB1 is associated with higher circulating levels and secretion of TGF-beta, and recent large-scale studies suggest strongly that this variant is associated with breast cancer risk in the general population. METHODS: To evaluate whether TGFB1 L10P also modifies the risk of breast cancer in BRCA1 or BRCA2 mutation carriers, we undertook a multi-center study of 3,442 BRCA1 and 2,095 BRCA2 mutation carriers. RESULTS: We found no evidence of association between TGFB1 L10P and breast cancer risk in either BRCA1 or BRCA2 mutation carriers. The per-allele HR for the L10P variant was 1.01 (95%CI: 0.92-1.11) in BRCA1 carriers and 0.92 (95%CI: 0.81-1.04) in BRCA2 mutation carriers. CONCLUSIONS: These results do not support the hypothesis that TGFB1 L10P genotypes modify the risk of breast cancer in BRCA1 or BRCA2 mutation carriers..
Spurdle, A.B.
Deans, A.J.
Duffy, D.
Goldgar, D.E.
Chen, X.
Beesley, J.
kConFaB,
Easton, D.F.
Antoniou, A.C.
Peock, S.
Cook, M.
EMBRACE Study Collaborators,
Nathanson, K.L.
Domchek, S.M.
MacArthur, G.A.
Chenevix-Trench, G.
(2009). No evidence that CDKN1B (p27) polymorphisms modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Breast cancer res treat,
Vol.115
(2),
pp. 307-313.
show abstract
The p27(kip1) protein functions as an inhibitor of cyclin dependent kinase-2, and shows loss of expression in a large percentage of BRCA1 and BRCA2 breast cancer cases. We investigated the association between CDKN1B gene variants and breast cancer risk in 2359 female BRCA1 and BRCA2 mutation carriers from Australia, the UK, and the USA. Samples were genotyped for five single nucleotide polymorphisms, including coding variant rs2066827 (V109G). Cox regression provided no convincing evidence that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, either alone or as a haplotype. Borderline associations were observed for homozygote carriers of the rs3759216 rare allele, but were opposite in effect for BRCA1 and BRCA2 carriers (adjusted hazard ratio (HR) 0.72 (95% CI = 0.53-0.99; P = 0.04 for BRCA1, HR 1.47 (95% CI = 0.99-2.18; P = 0.06 for BRCA2). The 95% confidence intervals for per allele risk estimates excluded a twofold risk, indicating that common CDKN1B polymorphisms do not markedly modify breast cancer risk among BRCA1 or BRCA2 carriers..
Venkitaraman, R.
Cook, G.J.
Dearnaley, D.P.
Parker, C.C.
Khoo, V.
Eeles, R.
Huddart, R.A.
Horwich, A.
Sohaib, S.A.
(2009). Whole-body magnetic resonance imaging in the detection of skeletal metastases in patients with prostate cancer. J med imaging radiat oncol,
Vol.53
(3),
pp. 241-247.
show abstract
Whole-body MRI is an effective method for evaluating the entire skeletal system in patients with metastatic disease. This study aimed to compare whole-body MRI and radionuclide bone scintigraph in the detection of skeletal metastases in patients with prostate cancer. Patients with prostate cancer at high risk of skeletal metastasis with (i) prostate-specific antigen of > or =50 ng/mL; (ii) composite Gleason score of > or =8 with prostate-specific antigen of >20 ng/mL; or (iii) node-positive disease were enrolled in this prospective study before systemic treatment was initiated. Whole-body MR images and bone scans of 39 patients were analysed. Seven patients had bone metastases on bone scans, while seven patients had skeletal metastases by whole-body MRI, with concordant findings only in four patients. Compared with the 'gold standard', derived from clinical and radiological follow-up, the sensitivity for both bone scans and MRI was 70%, and the specificity for both was 100%. Magnetic resonance imaging detected 26 individual lesions compared with 18 lesions on bone scans. Only eight lesions were positive on both. Bone scans detected more rib metastases, while MRI identified more metastatic lesions in the spine. Whole-body MRI and radionuclide bone scintigraphy have similar specificity and sensitivity and may be used as complementary investigations to detect skeletal metastases from prostate cancer..
Evans, D.G.
Lennard, F.
Pointon, L.J.
Ramus, S.J.
Gayther, S.A.
Sodha, N.
Kwan-Lim, G.E.
Leach, M.O.
Warren, R.
Thompson, D.
Easton, D.F.
Eeles, R.
(2009). Eligibility for Magnetic Resonance Imaging Screening in the United Kingdom: Effect of Strict Selection Criteria and Anonymous DNA Testing on Breast Cancer Incidence in the MARIBS Study. Cancer epidemiology biomarkers & prevention,
Vol.18
(7),
pp. 2123-9.
Gilbert, F.J.
Warren, R.M.
Kwan-Lim, G.
Thompson, D.J.
Eeles, R.A.
Evans, D.G.
Leach, M.O.
United Kingdom Magnetic Resonance Imaging in Breast Screening (MARIBS) Study Group,
(2009). Cancers in BRCA1 and BRCA2 carriers and in women at high risk for breast cancer: MR imaging and mammographic features. Radiology,
Vol.252
(2),
pp. 358-368.
show abstract
PURPOSE: To review imaging features of screening-detected cancers on images from diagnostic and prior examinations to identify specific abnormalities to aid earlier detection of or facilitate differentiation of cancers in BRCA1 and BRCA2 carriers and in women with a high risk for breast cancer. MATERIALS AND METHODS: Informed consent and multicenter and local research ethics committee approval were obtained. Women (mean age, 40.1 years; range, 27-55 years) who had at least a 50% risk of being a BRCA1, BRCA2, or TP53 gene mutation carrier were recruited from August 1997 to March 2003 into the United Kingdom Magnetic Resonance Imaging in Breast Screening Study Group trial and were offered annual magnetic resonance (MR) imaging and two-view mammography (total number of screenings, 2065 and 1973; mean, 2.38 and 2.36, respectively). Images in all 39 cancer cases were reread in consensus to document the morphologic and enhancement imaging features on MR and mammographic images in screening and prior examinations. Cases were grouped into genetic subtypes. RESULTS: With MR imaging, there was no difference in morphologic or enhancement characteristics between the genetic subgroups. Cancers on images from prior examinations were of smaller size, showed less enhancement, and were more likely to have a type 1 enhancement curve compared with those cancers in the subsequent diagnostic screening examinations. The tumor sizes detected by using MR imaging and mammography were not significantly different (P = .46). The cancers in BRCA1 carriers found by using MR imaging tended to be smaller than those detected by using mammography (median, 17 mm vs 30 mm; P = .37), whereas the opposite was true for cancers found in BRCA2 carriers (MR imaging median size = 12.5 mm vs mammographic median size = 6 mm; P = .067); the difference was not significant. Tumors with prior MR imaging abnormalities grew at an average of 5.1 mm/y. CONCLUSION: When undertaking MR imaging surveillance in high-risk women, small enhancing lesions should be regarded with suspicion and biopsied or patients should be followed up at 6 months..
Osorio, A.
Milne, R.L.
Pita, G.
Peterlongo, P.
Heikkinen, T.
Simard, J.
Chenevix-Trench, G.
Spurdle, A.B.
Beesley, J.
Chen, X.
Healey, S.
Neuhausen, S.L.
Ding, Y.C.
Couch, F.J.
Wang, X.
Lindor, N.
Manoukian, S.
Barile, M.
Viel, A.
Tizzoni, L.
Szabo, C.I.
Foretova, L.
Zikan, M.
Claes, K.
Greene, M.H.
Mai, P.
Rennert, G.
Lejbkowicz, F.
Barnett-Griness, O.
Andrulis, I.L.
Ozcelik, H.
Weerasooriya, N.
Gerdes, A.-.
Thomassen, M.
Cruger, D.G.
Caligo, M.A.
Friedman, E.
Kaufman, B.
Laitman, Y.
Cohen, S.
Kontorovich, T.
Gershoni-Baruch, R.
Dagan, E.
Jernstrom, H.
Askmalm, M.S.
Arver, B.
Malmer, B.
Domchek, S.M.
Nathanson, K.L.
Brunet, J.
Ramon y Cajal, T.
Yannoukakos, D.
Hamann, U.
Hogervorst, F.B.
Verhoef, S.
Gomez Garcia, E.B.
Wijnen, J.T.
van den Ouweland, A.
Easton, D.F.
Peock, S.
Cook, M.
Oliver, C.T.
Frost, D.
Luccarini, C.
Evans, D.G.
Lalloo, F.
Eeles, R.
Pichert, G.
Cook, J.
Hodgson, S.
Morrison, P.J.
Douglas, F.
Godwin, A.K.
Sinilnikova, O.M.
Barjhoux, L.
Stoppa-Lyonnet, D.
Moncoutier, V.
Giraud, S.
Cassini, C.
Olivier-Faivre, L.
Revillion, F.
Peyrat, J.-.
Muller, D.
Fricker, J.-.
Lynch, H.T.
John, E.M.
Buys, S.
Daly, M.
Hopper, J.L.
Terry, M.B.
Miron, A.
Yassin, Y.
Goldgar, D.
Singer, C.F.
Gschwantler-Kaulich, D.
Pfeiler, G.
Spiess, A.-.
Hansen, T.V.
Johannsson, O.T.
Kirchhoff, T.
Offit, K.
Kosarin, K.
Piedmonte, M.
Rodriguez, G.C.
Wakeley, K.
Boggess, J.F.
Basil, J.
Schwartz, P.E.
Blank, S.V.
Toland, A.E.
Montagna, M.
Casella, C.
Imyanitov, E.N.
Allavena, A.
Schmutzler, R.K.
Versmold, B.
Engel, C.
Meindl, A.
Ditsch, N.
Arnold, N.
Niederacher, D.
Deissler, H.
Fiebig, B.
Varon-Mateeva, R.
Schaefer, D.
Froster, U.G.
Caldes, T.
de la Hoya, M.
McGuffog, L.
Antoniou, A.C.
Nevanlinna, H.
Radice, P.
Benitez, J.
(2009). Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA). British journal of cancer,
Vol.101
(12),
pp. 2048-7.
Moule, R.
Sohaib, A.
Eeles, R.
(2009). Dramatic Response to Platinum in a Patient with Cancer with a Germline BRCA2 Mutation. Clinical oncology,
Vol.21
(6),
pp. 444-4.
Collin, S.M.
Metcalfe, C.
Zuccolo, L.
Lewis, S.J.
Chen, L.
Cox, A.
Davis, M.
Lane, J.A.
Donovan, J.
Smith, G.D.
Neal, D.E.
Hamdy, F.C.
Gudmundsson, J.
Sulem, P.
Rafnar, T.
Benediktsdottir, K.R.
Eeles, R.A.
Guy, M.
Kote-Jarai, Z.
UK Genetic Prostate Cancer Study Group,
Morrison, J.
Al Olama, A.A.
Stefansson, K.
Easton, D.F.
Martin, R.M.
(2009). Association of folate-pathway gene polymorphisms with the risk of prostate cancer: a population-based nested case-control study, systematic review, and meta-analysis. Cancer epidemiol biomarkers prev,
Vol.18
(9),
pp. 2528-2539.
show abstract
Folate-pathway gene polymorphisms have been implicated in several cancers and investigated inconclusively in relation to prostate cancer. We conducted a systematic review, which identified nine case-control studies (eight included, one excluded). We also included data from four genome-wide association studies and from a case-control study nested within the UK population-based Prostate Testing for Cancer and Treatment study. We investigated by meta-analysis the effects of eight polymorphisms: MTHFR C677T (rs1801133; 12 studies; 10,745 cases; 40,158 controls), MTHFR A1298C (rs1801131; 5 studies; 3,176 cases; 4,829 controls), MTR A2756G (rs1805087; 8 studies; 7,810 cases; 37,543 controls), MTRR A66G (rs1801394; 4 studies; 3,032 cases; 4,515 controls), MTHFD1 G1958A (rs2236225; 6 studies; 7,493 cases; 36,941 controls), SLC19A1/RFC1 G80A (rs1051266; 4 studies; 6,222 cases; 35,821 controls), SHMT1 C1420T (rs1979277; 2 studies; 2,689 cases; 4,110 controls), and FOLH1 T1561C (rs202676; 5 studies; 6,314 cases; 35,190 controls). The majority (10 of 13) of eligible studies had 100% Caucasian subjects; only one study had <90% Caucasian subjects. We found weak evidence of dominant effects of two alleles: MTR 2756A>G [random effects pooled odds ratio, 1.06 (1.00-1.12); P = 0.06 (P = 0.59 for heterogeneity across studies)] and SHMT1 1420C>T [random effects pooled odds ratio, 1.11 (1.00-1.22); P = 0.05 (P = 0.38 for heterogeneity across studies)]. We found no effect of MTHFR 677C>T or any of the other alleles in dominant, recessive or additive models, or in comparing a/a versus A/A homozygous. Neither did we find any difference in effects on advanced or localized cancers. Our meta-analysis suggests that known common folate-pathway single nucleotide polymorphisms do not have significant effects on susceptibility to prostate cancer..
Johnatty, S.E.
Couch, F.J.
Fredericksen, Z.
Tarrell, R.
Spurdle, A.B.
Beesley, J.
Chen, X.
Gschwantler-Kaulich, D.
Singer, C.F.
Fuerhauser, C.
Fink-Retter, A.
Domchek, S.M.
Nathanson, K.L.
Pankratz, V.S.
Lindor, N.M.
Godwin, A.K.
Caligo, M.A.
Hopper, J.
Southey, M.C.
Giles, G.G.
Justenhoven, C.
Brauch, H.
Hamann, U.
Ko, Y.-.
Heikkinen, T.
Aaltonen, K.
Aittomaki, K.
Blomqvist, C.
Nevanlinna, H.
Hall, P.
Czene, K.
Liu, J.
Peock, S.
Cook, M.
Platte, R.
Evans, D.G.
Lalloo, F.
Eeles, R.
Pichert, G.
Eccles, D.
Davidson, R.
Cole, T.
Cook, J.
Douglas, F.
Chu, C.
Hodgson, S.
Paterson, J.
Hogervorst, F.B.
Rookus, M.A.
Seynaeve, C.
Wijnen, J.
Vreeswijk, M.
Ligtenberg, M.
van der Luijt, R.B.
van Os, T.A.
Gille, H.J.
Blok, M.J.
Issacs, C.
Humphreys, M.K.
McGuffog, L.
Healey, S.
Sinilnikova, O.
Antoniou, A.C.
Easton, D.F.
Chenevix-Trench, G.
(2009). No evidence that GATA3 rs570613 SNP modifies breast cancer risk. Breast cancer research and treatment,
Vol.117
(2),
pp. 371-9.
Grindedal, E.M.
Moller, P.
Eeles, R.
Stormorken, A.T.
Bowitz-Lothe, I.M.
Landro, S.M.
Clark, N.
Kvale, R.
Shanley, S.
Maehle, L.
(2009). Germ-Line Mutations in Mismatch Repair Genes Associated with Prostate Cancer. Cancer epidemiology biomarkers & prevention,
Vol.18
(9),
pp. 2460-8.
Al Olama, A.A.
Kote-Jarai, Z.
Giles, G.G.
Guy, M.
Morrison, J.
Severi, G.
Leongamornlert, D.A.
Tymrakiewicz, M.
Jhavar, S.
Saunders, E.
Hopper, J.L.
Southey, M.C.
Muir, K.R.
English, D.R.
Dearnaley, D.P.
Ardern-Jones, A.T.
Hall, A.L.
O'Brien, L.T.
Wilkinson, R.A.
Sawyer, E.
Lophatananon, A.
UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology,
UK Prostate testing for cancer and Treatment study (ProtecT Study) Collaborators,
Horwich, A.
Huddart, R.A.
Khoo, V.S.
Parker, C.C.
Woodhouse, C.J.
Thompson, A.
Christmas, T.
Ogden, C.
Cooper, C.
Donovan, J.L.
Hamdy, F.C.
Neal, D.E.
Eeles, R.A.
Easton, D.F.
(2009). Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat genet,
Vol.41
(10),
pp. 1058-1060.
show abstract
Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility..
Eeles, R.A.
Kote-Jarai, Z.
Al Olama, A.A.
Giles, G.G.
Guy, M.
Severi, G.
Muir, K.
Hopper, J.L.
Henderson, B.E.
Haiman, C.A.
Schleutker, J.
Hamdy, F.C.
Neal, D.E.
Donovan, J.L.
Stanford, J.L.
Ostrander, E.A.
Ingles, S.A.
John, E.M.
Thibodeau, S.N.
Schaid, D.
Park, J.Y.
Spurdle, A.
Clements, J.
Dickinson, J.L.
Maier, C.
Vogel, W.
Dörk, T.
Rebbeck, T.R.
Cooney, K.A.
Cannon-Albright, L.
Chappuis, P.O.
Hutter, P.
Zeegers, M.
Kaneva, R.
Zhang, H.-.
Lu, Y.-.
Foulkes, W.D.
English, D.R.
Leongamornlert, D.A.
Tymrakiewicz, M.
Morrison, J.
Ardern-Jones, A.T.
Hall, A.L.
O'Brien, L.T.
Wilkinson, R.A.
Saunders, E.J.
Page, E.C.
Sawyer, E.J.
Edwards, S.M.
Dearnaley, D.P.
Horwich, A.
Huddart, R.A.
Khoo, V.S.
Parker, C.C.
Van As, N.
Woodhouse, C.J.
Thompson, A.
Christmas, T.
Ogden, C.
Cooper, C.S.
Southey, M.C.
Lophatananon, A.
Liu, J.-.
Kolonel, L.N.
Le Marchand, L.
Wahlfors, T.
Tammela, T.L.
Auvinen, A.
Lewis, S.J.
Cox, A.
FitzGerald, L.M.
Koopmeiners, J.S.
Karyadi, D.M.
Kwon, E.M.
Stern, M.C.
Corral, R.
Joshi, A.D.
Shahabi, A.
McDonnell, S.K.
Sellers, T.A.
Pow-Sang, J.
Chambers, S.
Aitken, J.
Gardiner, R.A.
Batra, J.
Kedda, M.A.
Lose, F.
Polanowski, A.
Patterson, B.
Serth, J.
Meyer, A.
Luedeke, M.
Stefflova, K.
Ray, A.M.
Lange, E.M.
Farnham, J.
Khan, H.
Slavov, C.
Mitkova, A.
Cao, G.
UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology,
UK ProtecT Study Collaborators,
PRACTICAL Consortium,
Easton, D.F.
(2009). Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat genet,
Vol.41
(10),
pp. 1116-1121.
show abstract
Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in developed countries. To identify common PrCa susceptibility alleles, we previously conducted a genome-wide association study in which 541,129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and in 1,894 controls. We have now extended the study to evaluate promising associations in a second stage in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, we identified seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11 and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33))..
Mitra, A.
Jameson, C.
Barbachano, Y.
Sanchez, L.
Kote-Jarai, Z.
Peock, S.
Sodha, N.
Bancroft, E.
Fletcher, A.
Cooper, C.
Easton, D.
IMPACT Steering Committee and IMPACT and EMBRACE Collaborators,
Eeles, R.
Foster, C.S.
(2009). Overexpression of RAD51 occurs in aggressive prostatic cancer. Histopathology,
Vol.55
(6),
pp. 696-704.
show abstract
AIMS: To test the hypothesis that, in a matched series of prostatic cancers, either with or without BRCA1 or BRCA2 mutations, RAD51 protein expression is enhanced in association with BRCA mutation genotypes. METHODS AND RESULTS: RAD51 expression identified immunohistochemically was compared between prostatic cancers occurring in BRCA1 or BRCA2 mutation carriers and controls. RAD51 protein expression in the cytoplasm and nuclei of the benign tissues was significantly less than in the malignant tissues (P < 0.001). In all cancers, cytoplasmic expression of RAD51 was more prevalent and associated with higher Gleason score (P < 0.05) irrespective of BRCA mutational status, than its expression in benign tissues (P < 0.001). Although nuclear immunoreactivity was not observed in BRCA-associated cancers with Gleason score < or =7, it was significantly increased in all other groups of prostatic cancers when compared with benign tissues (P < 0.001). CONCLUSIONS: RAD51 protein is strongly expressed in high-grade prostatic cancers, whether sporadic or associated with BRCA germ-line mutations. Distinct localization of RAD51 between cytoplasm and nucleus, particularly in cancers of Gleason score < or =7, reflects distinct levels of RAD51 regulatory activity, from transcription to DNA repair. This biomarker may be of value in identifying patients requiring urgent treatment at diagnosis as well as in analysing biological mechanisms underlying aggressive phenotype of human prostatic cancer..
Sinilnikova, O.M.
Antoniou, A.C.
Simard, J.
Healey, S.
Leone, M.
Sinnett, D.
Spurdle, A.B.
Beesley, J.
Chen, X.
Greene, M.H.
Loud, J.T.
Lejbkowicz, F.
Rennert, G.
Dishon, S.
Andrulis, I.L.
Domchek, S.M.
Nathanson, K.L.
Manoukian, S.
Radice, P.
Konstantopoulou, I.
Blanco, I.
Laborde, A.L.
Duran, M.
Osorio, A.
Benitez, J.
Hamann, U.
Hogervorst, F.B.
van Os, T.A.
Gille, H.J.
Peock, S.
Cook, M.
Luccarini, C.
Evans, D.G.
Lalloo, F.
Eeles, R.
Pichert, G.
Davidson, R.
Cole, T.
Cook, J.
Paterson, J.
Brewer, C.
Hughes, D.J.
Coupier, I.
Giraud, S.
Coulet, F.
Colas, C.
Soubrier, F.
Rouleau, E.
Bieche, I.
Lidereau, R.
Demange, L.
Nogues, C.
Lynch, H.T.
Schmutzler, R.K.
Versmold, B.
Engel, C.
Meindl, A.
Arnold, N.
Sutter, C.
Deissler, H.
Schaefer, D.
Froster, U.G.
Aittomaki, K.
Nevanlinna, H.
McGuffog, L.
Easton, D.F.
Chenevix-Trench, G.
Stoppa-Lyonnet, D.
(2009). The TP53 Arg72Pro and MDM2 309G > T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. British journal of cancer,
Vol.101
(8),
pp. 1456-5.
Antoniou, A.C.
Sinilnikova, O.M.
McGuffog, L.
Healey, S.
Nevanlinna, H.
Heikkinen, T.
Simard, J.
Spurdle, A.B.
Beesley, J.
Chen, X.
Neuhausen, S.L.
Ding, Y.C.
Couch, F.J.
Wang, X.
Fredericksen, Z.
Peterlongo, P.
Peissel, B.
Bonanni, B.
Viel, A.
Bernard, L.
Radice, P.
Szabo, C.I.
Foretova, L.
Zikan, M.
Claes, K.
Greene, M.H.
Mai, P.L.
Rennert, G.
Lejbkowicz, F.
Andrulis, I.L.
Ozcelik, H.
Glendon, G.
Gerdes, A.-.
Thomassen, M.
Sunde, L.
Caligo, M.A.
Laitman, Y.
Kontorovich, T.
Cohen, S.
Kaufman, B.
Dagan, E.
Baruch, R.G.
Friedman, E.
Harbst, K.
Barbany-Bustinza, G.
Rantala, J.
Ehrencrona, H.
Karlsson, P.
Domchek, S.M.
Nathanson, K.L.
Osorio, A.
Blanco, I.
Lasa, A.
Benitez, J.
Hamann, U.
Hogervorst, F.B.
Rookus, M.A.
Collee, J.M.
Devilee, P.
Ligtenberg, M.J.
van der Luijt, R.B.
Aalfs, C.M.
Waisfisz, Q.
Wijnen, J.
van Roozendaal, C.E.
Peock, S.
Cook, M.
Frost, D.
Oliver, C.
Platte, R.
Evans, D.G.
Lalloo, F.
Eeles, R.
Izatt, L.
Davidson, R.
Chu, C.
Eccles, D.
Cole, T.
Hodgson, S.
Godwin, A.K.
Stoppa-Lyonnet, D.
Buecher, B.
Leone, M.
Bressac-de Paillerets, B.
Remenieras, A.
Caron, O.
Lenoir, G.M.
Sevenet, N.
Longy, M.
Ferrer, S.F.
Prieur, F.
Goldgar, D.
Miron, A.
John, E.M.
Buys, S.S.
Daly, M.B.
Hopper, J.L.
Terry, M.B.
Yassin, Y.
Singer, C.
Gschwantler-Kaulich, D.
Staudigl, C.
Hansen, T.V.
Barkardottir, R.B.
Kirchhoff, T.
Pal, P.
Kosarin, K.
Offit, K.
Piedmonte, M.
Rodriguez, G.C.
Wakeley, K.
Boggess, J.F.
Basil, J.
Schwartz, P.E.
Blank, S.V.
Toland, A.E.
Montagna, M.
Casella, C.
Imyanitov, E.N.
Allavena, A.
Schmutzler, R.K.
Versmold, B.
Engel, C.
Meindl, A.
Ditsch, N.
Arnold, N.
Niederacher, D.
Deissler, H.
Fiebig, B.
Suttner, C.
Schoenbuchner, I.
Gadzicki, D.
Caldes, T.
de la Hoya, M.
Pooley, K.A.
Easton, D.F.
Chenevix-Trench, G.
(2009). Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. Human molecular genetics,
Vol.18
(22),
pp. 4442-15.
Clyne, M.
Offman, J.
Shanley, S.
Virgo, J.D.
Radulovic, M.
Wang, Y.
Ardern-Jones, A.
Eeles, R.
Hoffmann, E.
Yu, V.P.
(2009). The G67E mutation in hMLH1 is associated with an unusual presentation of Lynch syndrome. British journal of cancer,
Vol.100
(2),
pp. 376-5.
Kote-Jarai, Z.
Jugurnauth, S.
Mulholland, S.
Leongamornlert, D.A.
Guy, M.
Edwards, S.
Tymrakiewitcz, M.
O'Brien, L.
Hall, A.
Wilkinson, R.
Al Olama, A.A.
Morrison, J.
Muir, K.
Neal, D.
Donovan, J.
Hamdy, F.
Easton, D.F.
Eeles, R.
UKGPCS Collaborators,
British Association of Urological Surgeons' Section of Oncology,
(2009). A recurrent truncating germline mutation in the BRIP1/FANCJ gene and susceptibility to prostate cancer. Br j cancer,
Vol.100
(2),
pp. 426-430.
show abstract
Although prostate cancer (PrCa) is one of the most common cancers in men in Western countries, little is known about the inherited factors that influence PrCa risk. On the basis of the fact that BRIP1/FANCJ interacts with BRCA1 and functions as a regulator of DNA double-strand break repair pathways, and that germline mutations within the BRIP1/FANCJ gene predispose to breast cancer, we chose this gene as a candidate for mutation screening in familial and young-onset PrCa cases. We identified a truncating mutation, R798X, in the BRIP1/FANCJ gene in 4 out of 2714 UK PrCa cases enriched for familial (2 out of 641; 0.3%) and young-onset cases (2 out of 2073; 0.1%). On screening 2045 controls from the UK population, we found one R798X sequence alteration (0.05%; odds ratio 2.4 (95% CI 0.25-23.4)). In addition, using our data from a genome-wide association study, we analysed 25 SNPs in the genomic region of the BRIP1/FANCJ gene. Two SNPs showed evidence of association with familial and young-onset PrCa (rs6504074; P(trend)=0.04 and rs8076727; P(trend)=0.01). These results suggest that truncating mutations in BRIP1/FANCJ might confer an increased risk of PrCa and common SNPs might also contribute to the alteration of risk, but larger case-control series will be required to confirm or refute this association..
Thompson, D.J.
Leach, M.O.
Kwan-Lim, G.
Gayther, S.A.
Ramus, S.J.
Warsi, I.
Lennard, F.
Khazen, M.
Bryant, E.
Reed, S.
Boggis, C.R.
Evans, D.G.
Eeles, R.A.
Easton, D.F.
Warren, R.M.
UK study of MRI screening for breast cancer in women at high risk (MARIBS),
(2009). Assessing the usefulness of a novel MRI-based breast density estimation algorithm in a cohort of women at high genetic risk of breast cancer: the UK MARIBS study. Breast cancer res,
Vol.11
(6),
p. R80.
show abstract
INTRODUCTION: Mammographic breast density is one of the strongest known risk factors for breast cancer. We present a novel technique for estimating breast density based on 3D T1-weighted Magnetic Resonance Imaging (MRI) and evaluate its performance, including for breast cancer risk prediction, relative to two standard mammographic density-estimation methods. METHODS: The analyses were based on MRI (n = 655) and mammography (n = 607) images obtained in the course of the UK multicentre magnetic resonance imaging breast screening (MARIBS) study of asymptomatic women aged 31 to 49 years who were at high genetic risk of breast cancer. The MRI percent and absolute dense volumes were estimated using our novel algorithm (MRIBview) while mammographic percent and absolute dense area were estimated using the Cumulus thresholding algorithm and also using a 21-point Visual Assessment scale for one medio-lateral oblique image per woman. We assessed the relationships of the MRI and mammographic measures to one another, to standard anthropometric and hormonal factors, to BRCA1/2 genetic status, and to breast cancer risk (60 cases) using linear and Poisson regression. RESULTS: MRI percent dense volume is well correlated with mammographic percent dense area (R = 0.76) but overall gives estimates 8.1 percentage points lower (P < 0.0001). Both show strong associations with established anthropometric and hormonal factors. Mammographic percent dense area, and to a lesser extent MRI percent dense volume were lower in BRCA1 carriers (P = 0.001, P = 0.010 respectively) but there was no association with BRCA2 carrier status. The study was underpowered to detect expected associations between percent density and breast cancer, but women with absolute MRI dense volume in the upper half of the distribution had double the risk of those in the lower half (P = 0.009). CONCLUSIONS: The MRIBview estimates of volumetric breast density are highly correlated with mammographic dense area but are not equivalent measures; the MRI absolute dense volume shows potential as a predictor of breast cancer risk that merits further investigation..
Jhavar, S.
Bartlett, J.
Kovacs, G.
Corbishley, C.
Dearnaley, D.
Eeles, R.
Khoo, V.
Huddart, R.
Horwich, A.
Thompson, A.
Norman, A.
Brewer, D.
Cooper, C.S.
Parker, C.
(2009). Biopsy tissue microarray study of Ki-67 expression in untreated, localized prostate cancer managed by active surveillance. Prostate cancer prostatic dis,
Vol.12
(2),
pp. 143-147.
show abstract
Active surveillance provides a unique opportunity to study biomarkers of prostate cancer behaviour, although only small volumes of tumor tissue are typically available. We have evaluated a technique for constructing tissue microarrays (TMAs) from needle biopsies for assessing immunohistochemical markers in localized prostate cancer managed by active surveillance. TMAs were constructed from diagnostic prostate biopsies for 60 patients with localized prostatic adenocarcinoma in a prospective cohort study of active surveillance. Radical treatment was recommended for a prostate-specific antigen (PSA) velocity greater than 1 ng ml(-1) per year or adverse histology in repeat biopsies, defined as Gleason score > or =4+3 or >50% of cores involved. Sections from the TMAs were stained with H&E, P63/AMACR and Ki-67. Time to radical treatment was analysed with respect to clinical characteristics and Ki-67 LI. At a median follow up of 36 months, 25/60 (42%) patients had received radical treatment. On univariate analysis, PSA density (P=0.001), Gleason score (P=0.001), clinical T stage (P=0.01), Ki-67 LI (P=0.02) and initial PSA (P=0.04) were associated with time to radical treatment. On multivariate analysis, PSA density (P=0.01), Ki-67 LI (P=0.03) and Gleason score (P=0.04) were independent determinants of progression to radical treatment. TMAs constructed from prostate needle biopsies can be used to assess immunohistochemical markers in localized prostate cancer managed by active surveillance. Ki-67 LI merits further study as a possible biomarker of early prostate cancer behaviour..
Song, H.
Koessler, T.
Ahmed, S.
Ramus, S.J.
Kjaer, S.K.
Dicioccio, R.A.
Wozniak, E.
Hogdall, E.
Whittemore, A.S.
McGuire, V.
Ponder, B.A.
Turnbull, C.
Hines, S.
Rahman, N.
Breast Cancer Susceptibility Collaboration UK,
Eeles, R.A.
Easton, D.F.
Gayther, S.A.
Dunning, A.M.
Pharoah, P.D.
(2008). Association study of prostate cancer susceptibility variants with risks of invasive ovarian, breast, and colorectal cancer. Cancer res,
Vol.68
(21),
pp. 8837-8842.
show abstract
Several prostate cancer susceptibility loci have recently been identified by genome-wide association studies. These loci are candidates for susceptibility to other epithelial cancers. The aim of this study was to test these tag single nucleotide polymorphisms (SNP) for association with invasive ovarian, colorectal, and breast cancer. Twelve prostate cancer-associated tag SNPs were genotyped in ovarian (2,087 cases/3,491 controls), colorectal (2,148 cases/2,265 controls) and breast (first set, 4,339 cases/4,552 controls; second set, 3,800 cases/3,995 controls) case-control studies. The primary test of association was a comparison of genotype frequencies between cases and controls, and a test for trend stratified by study where appropriate. Genotype-specific odds ratios (OR) were estimated by logistic regression. SNP rs2660753 (chromosome 3p12) showed evidence of association with ovarian cancer [per minor allele OR, 1.19; 95% confidence interval (95% CI), 1.04-1.37; P(trend) = 0.012]. This association was stronger for the serous histologic subtype (OR, 1.29; 95% CI, 1.09-1.53; P = 0.003). SNP rs7931342 (chromosome 11q13) showed some evidence of association with breast cancer (per minor allele OR, 0.95; 95% CI, 0.91-0.99; P(trend) = 0.028). This association was somewhat stronger for estrogen receptor-positive tumors (OR, 0.92; 95% CI, 0.87-0.98; P = 0.011). None of these tag SNPs were associated with risk of colorectal cancer. In conclusion, loci associated with risk of prostate cancer may also be associated with ovarian and breast cancer susceptibility. However, the effects are modest and warrant replication in larger studies..
Tan, D.S.
Rothermundt, C.
Thomas, K.
Bancroft, E.
Eeles, R.
Shanley, S.
Ardern-Jones, A.
Norman, A.
Kaye, S.B.
Gore, M.E.
(2008). "BRCAness" Syndrome in Ovarian Cancer: A Case-Control Study Describing the Clinical Features and Outcome of Patients With Epithelial Ovarian Cancer Associated With BRCA1 and BRCA2 Mutations. Journal of clinical oncology,
Vol.26
(34),
pp. 5530-7.
Jhavar, S.
Reid, A.
Clark, J.
Kote-Jarai, Z.
Christmas, T.
Thompson, A.
Woodhouse, C.
Ogden, C.
Fisher, C.
Corbishley, C.
De-Bono, J.
Eeles, R.
Brewer, D.
Cooper, C.
(2008). Detection of TMPRSS2-ERG translocations in human prostate cancer by expression profiling using GeneChip Human Exon 1 0 ST arrays. J mol diagn,
Vol.10
(1),
pp. 50-57.
show abstract
full text
Translocation of TMPRSS2 to the ERG gene, found in a high proportion of human prostate cancer, results in overexpression of the 3'-ERG sequences joined to the 5'-TMPRSS2 promoter. The studies presented here were designed to test the ability of expression analysis on GeneChip Human Exon 1.0 ST arrays to detect 5'-TMPRSS2-ERG-3' hybrid transcripts encoded by this translocation. Monitoring the relative expression of each ERG exon revealed altered transcription of the ERG gene in 15 of a series of 27 prostate cancer samples. In all cases, exons 4 to 11 exhibited enhanced expression compared with exons 2 and 3. This pattern of expression indicated that the most abundant hybrid transcripts involve fusions to ERG exon 4, and RT-PCR analyses confirmed the joining of TMPRSS2 exon 1 to ERG exon 4 in all 15 cases. The exon expression patterns also indicated that TMPRSS2-ERG fusion transcripts commonly contain deletion of ERG exon 8. Analysis of gene-level data from the arrays allowed the identification of genes whose expression levels significantly correlated with the presence of the translocation. These studies demonstrate that expression analyses using exon arrays represent a valuable approach for detecting ETS gene translocation in prostate cancer, in parallel with analyses of gene expression profiles..
Geary, J.
Sasieni, P.
Houlston, R.
Izatt, L.
Eeles, R.
Payne, S.J.
Fisher, S.
Hodgson, S.V.
(2008). Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC). Familial cancer,
Vol.7
(2),
pp. 163-10.
Thomas, E.R.
Shanley, S.
Walker, L.
Eeles, R.
(2008). Surveillance and treatment of malignancy in Bloom syndrome. Clinical oncology,
Vol.20
(5),
pp. 375-5.
Jefferies, S.
Goldgar, D.
Eeles, R.
(2008). The accuracy of cancer diagnoses as reported in families with head and neck cancer: a case-control study. Clinical oncology,
Vol.20
(4),
pp. 309-6.
Ghoussaini, M.
Song, H.
Koessler, T.
Al Olama, A.A.
Kote-Jarai, Z.
Driver, K.E.
Pooley, K.A.
Ramus, S.J.
Kjaer, S.K.
Hogdall, E.
DiCioccio, R.A.
Whittemore, A.S.
Gayther, S.A.
Giles, G.G.
Guy, M.
Edwards, S.M.
Morrison, J.
Donovan, J.L.
Hamdy, F.C.
Dearnaley, D.P.
Ardern-Jones, A.T.
Hall, A.L.
O'Brien, L.T.
Gehr-Swain, B.N.
Wilkinson, R.A.
Brown, P.M.
Hopper, J.L.
Neal, D.E.
Pharoah, P.D.
Ponder, B.A.
Eeles, R.A.
Easton, D.F.
Dunning, A.M.
UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology,
UK ProtecT Study Collaborators,
(2008). Multiple loci with different cancer specificities within the 8q24 gene desert. J natl cancer inst,
Vol.100
(13),
pp. 962-966.
show abstract
Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported associations of various genetic variants in 8q24 with susceptibility to breast, prostate, and colorectal cancer. This locus lies within a 1.18-Mb region that contains no known genes but is bounded at its centromeric end by FAM84B and at its telomeric end by c-MYC, two candidate cancer susceptibility genes. To investigate the associations of specific loci within 8q24 with specific cancers, we genotyped the nine previously reported cancer-associated single-nucleotide polymorphisms across the region in four case-control sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case subjects and 2280 control subjects), colorectal (2299 case subjects and 2284 control subjects), and ovarian (1975 case subjects and 3411 control subjects) cancer. Five different haplotype blocks within this gene desert were specifically associated with risks of different cancers. One block was solely associated with risk of breast cancer, three others were associated solely with the risk of prostate cancer, and a fifth was associated with the risk of prostate, colorectal, and ovarian cancer, but not breast cancer. We conclude that there are at least five separate functional variants in this region..
Knight, J.F.
Shepherd, C.J.
Rizzo, S.
Brewer, D.
Jhavar, S.
Dodson, A.R.
Cooper, C.S.
Eeles, R.
Falconer, A.
Kovacs, G.
Garrett, M.D.
Norman, A.R.
Shipley, J.
Hudson, D.L.
(2008). TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancer. Br j cancer,
Vol.99
(11),
pp. 1849-1858.
show abstract
Prostate cancer is the most frequently diagnosed male cancer, and its clinical outcome is difficult to predict. The disease may involve the inappropriate expression of genes that normally control the proliferation of epithelial cells in the basal layer and their differentiation into luminal cells. Our aim was to identify novel basal cell markers and assess their prognostic and functional significance in prostate cancer. RNA from basal and luminal cells isolated from benign tissue by immunoguided laser-capture microdissection was subjected to expression profiling. We identified 112 and 267 genes defining basal and luminal populations, respectively. The transcription factor TEAD1 and the ubiquitin ligase c-Cbl were identified as novel basal cell markers. Knockdown of either marker using siRNA in prostate cell lines led to decreased cell growth in PC3 and disrupted acinar formation in a 3D culture system of RWPE1. Analyses of prostate cancer tissue microarray staining established that increased protein levels of either marker were associated with decreased patient survival independent of other clinicopathological metrics. These data are consistent with basal features impacting on the development and clinical course of prostate cancers..
Eeles, R.A.
Kote-Jarai, Z.
Giles, G.G.
Olama, A.A.
Guy, M.
Jugurnauth, S.K.
Mulholland, S.
Leongamornlert, D.A.
Edwards, S.M.
Morrison, J.
Field, H.I.
Southey, M.C.
Severi, G.
Donovan, J.L.
Hamdy, F.C.
Dearnaley, D.P.
Muir, K.R.
Smith, C.
Bagnato, M.
Ardern-Jones, A.T.
Hall, A.L.
O'Brien, L.T.
Gehr-Swain, B.N.
Wilkinson, R.A.
Cox, A.
Lewis, S.
Brown, P.M.
Jhavar, S.G.
Tymrakiewicz, M.
Lophatananon, A.
Bryant, S.L.
UK Genetic Prostate Cancer Study Collaborators,
British Association of Urological Surgeons' Section of Oncology,
UK ProtecT Study Collaborators,
Horwich, A.
Huddart, R.A.
Khoo, V.S.
Parker, C.C.
Woodhouse, C.J.
Thompson, A.
Christmas, T.
Ogden, C.
Fisher, C.
Jamieson, C.
Cooper, C.S.
English, D.R.
Hopper, J.L.
Neal, D.E.
Easton, D.F.
(2008). Multiple newly identified loci associated with prostate cancer susceptibility. Nat genet,
Vol.40
(3),
pp. 316-321.
show abstract
Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at
Myles, P.
Evans, S.
Lophatananon, A.
Dimitropoulou, P.
Easton, D.
Key, T.
Pocock, R.
Dearnaley, D.
Guy, M.
Edwards, S.
O'Brien, L.
Gehr-Swain, B.
Hall, A.
Wilkinson, R.
Eeles, R.
Muir, K.
(2008). Diagnostic radiation procedures and risk of prostate cancer. Br j cancer,
Vol.98
(11),
pp. 1852-1856.
show abstract
Exposure to ionising radiation is an established risk factor for many cancers. We conducted a case-control study to investigate whether exposure to low dose ionisation radiation from diagnostic x-ray procedures could be established as a risk factor for prostate cancer. In all 431 young-onset prostate cancer cases and 409 controls frequency matched by age were included. Exposures to barium meal, barium enema, hip x-rays, leg x-rays and intravenous pyelogram (IVP) were considered. Exposures to barium enema (adjusted odds ratio (OR) 2.06, 95% confidence interval (CI) 1.01-4.20) and hip x-rays (adjusted OR 2.23, 95% CI 1.42-3.49) at least 5 years before diagnosis were significantly associated with increased prostate cancer. For those with a family history of cancer, exposures to hip x-rays dating 10 or 20 years before diagnosis were associated with a significantly increased risk of prostate cancer: adjusted OR 5.01, 95% CI 1.64-15.31 and adjusted OR 14.23, 95% CI 1.83-110.74, respectively. Our findings show that exposure of the prostate gland to diagnostic radiological procedures may be associated with increased cancer risk. This effect seems to be modified by a positive family history of cancer suggesting that genetic factors may play a role in this risk association..
Vergis, R.
Corbishley, C.M.
Norman, A.R.
Bartlett, J.
Jhavar, S.
Borre, M.
Heeboll, S.
Horwich, A.
Huddart, R.
Khoo, V.
Eeles, R.
Cooper, C.
Sydes, M.
Dearnaley, D.
Parker, C.
(2008). Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study. Lancet oncol,
Vol.9
(4),
pp. 342-351.
show abstract
BACKGROUND: Expression of intrinsic markers of tumour hypoxia and angiogenesis are important predictors of radiotherapeutic, and possibly surgical, outcome in several cancers. Extent of tumour hypoxia in localised prostate cancer is comparable to that in other cancers, but few data exist on the association of extent of tumour hypoxia with treatment outcome. We aimed to study the predictive value of intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer, both in patients treated with radiotherapy and in those treated surgically. METHODS: We applied a new, needle biopsy tissue microarray (TMA) technique to study diagnostic samples from men with localised, previously untreated prostate cancer treated in two randomised controlled trials of radiotherapy-dose escalation. Multivariate analysis by Cox proportional hazards was done to assess the association between clinical outcome, in terms of biochemical control, and immunohistochemical staining of hypoxia inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF), and osteopontin expression. The analysis was repeated on an independent series of men with localised, previously untreated prostate cancer treated by radical prostatectomy. The main outcome was time to biochemical (ie, prostate-specific antigen [PSA]) failure. FINDINGS: Between Oct 12, 1995, and Feb 5, 2002, 308 patients were identified from two prospective, randomised trials at the Royal Marsden Hospital, London and Sutton, UK, for the radiotherapy cohort and diagnostic biopsies were available for 201 of these patients. Between June 6, 1995, and Nov 4, 2005, 329 patients were identified from the Aarhus University Hospital, Skejby, Denmark, for the prostatectomy cohort; of these, 40 patients were excluded because the tumour was too small to sample (19 patients), because the paraffin block was too thin (19 patients), or because the blocks were missing (two patients), leaving 289 patients for analysis. For patients treated with radiotherapy, increased staining for VEGF (p=0.008) and HIF-1 alpha (p=0.02) expression, but not increased osteopontin expression (p=0.978), were significant predictors of a shorter time to biochemical failure on multivariate analysis, independent of clinical tumour stage, Gleason score, serum PSA concentration, and dose of radiotherapy. For patients treated with surgery, increased staining for VEGF (p<0.0001) and HIF-1 alpha (p<0.0001) expression, and increased osteopontin expression (p=0.0005) were each significantly associated with a shorter time to biochemical failure on multivariate analysis, independent of pathological tumour stage, Gleason score, serum PSA concentration, and margin status. INTERPRETATION: To our knowledge, this is the largest study of intrinsic markers of hypoxia and angiogenesis in relation to the outcome of radical treatment of localised prostate cancer. Increased expression of VEGF, HIF-1 alpha, and, for patients treated with surgery, osteopontin, identifies patients at high risk of biochemical failure who would be suitable for enrolment into trials of treatment intensification..
Antoniou, A.C.
Spurdle, A.B.
Sinilnikova, O.M.
Healey, S.
Pooley, K.A.
Schmutzler, R.K.
Versmold, B.
Engel, C.
Meindl, A.
Arnold, N.
Hofmann, W.
Sutter, C.
Niederacher, D.
Deissler, H.
Caldes, T.
Kampjarvi, K.
Nevanlinna, H.
Simard, J.
Beesley, J.
Chen, X.
Neuhausen, S.L.
Rebbeck, T.R.
Wagner, T.
Lynch, H.T.
Isaacs, C.
Weitzel, J.
Ganz, P.A.
Daly, M.B.
Tomlinson, G.
Olopade, O.I.
Bium, J.L.
Couch, F.J.
Peterlongo, P.
Manoukian, S.
Barile, M.
Radice, P.
Szabo, C.I.
Pereira, L.H.
Greene, M.H.
Rennert, G.
Leibkowicz, F.
Barnett-Griness, O.
Andrulis, I.L.
Ozcelik, H.
Gerdes, A.-.
Caligo, M.A.
Laitman, Y.
Kaufman, B.
Milgrom, R.
Friedman, E.
Domchek, S.M.
Nathanson, K.L.
Osorio, A.
Llort, G.
Milne, R.L.
Benitez, J.
Hamann, U.
Hogervorst, F.B.
Manders, P.
Ligtenberg, M.J.
van den Ouweland, A.M.
Peock, S.
Cook, M.
Platte, R.
Evans, D.G.
Eeles, R.
Pichert, G.
Chu, C.
Eccles, D.
Davidson, R.
Douglas, F.
Godwin, A.K.
Barjhoux, L.
Mazoyer, S.
Sobol, H.
Bourdon, V.
Eisinger, F.
Chompret, A.
Capoulade, C.
Paillerets, B.B.
Lenoir, G.M.
Gauthier-Villars, M.
Houdayer, C.
Stoppa-Lyonnet, D.
Easton, D.F.
(2008). Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. American journal of human genetics,
Vol.82
(4),
pp. 937-12.
Antoniou, A.C.
Hardy, R.
Walker, L.
Evans, D.G.
Shenton, A.
Eeles, R.
Shanley, S.
Pichert, G.
Izatt, L.
Rose, S.
Douglas, F.
Eccles, D.
Morrison, P.J.
Scott, J.
Zimmern, R.L.
Easton, D.F.
Pharoah, P.D.
(2008). Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics. J med genet,
Vol.45
(7),
pp. 425-431.
show abstract
OBJECTIVES: Genetic testing for the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has important implications for the clinical management of people found to carry a mutation. However, genetic testing is expensive and may be associated with adverse psychosocial effects. To provide a cost-efficient and clinically appropriate genetic counselling service, genetic testing should be targeted at those individuals most likely to carry pathogenic mutations. Several algorithms that predict the likelihood of carrying a BRCA1 or a BRCA2 mutation are currently used in clinical practice to identify such individuals. DESIGN: We evaluated the performance of the carrier prediction algorithms BOADICEA, BRCAPRO, IBIS, the Manchester scoring system and Myriad tables, using 1934 families seen in cancer genetics clinics in the UK in whom an index patient had been screened for BRCA1 and/or BRCA2 mutations. The models were evaluated for calibration, discrimination and accuracy of the predictions. RESULTS: Of the five algorithms, only BOADICEA predicted the overall observed number of mutations detected accurately (ie, was well calibrated). BOADICEA also provided the best discrimination, being significantly better (p<0.05) than all models except BRCAPRO (area under the receiver operating characteristic curve statistics: BOADICEA = 0.77, BRCAPRO = 0.76, IBIS = 0.74, Manchester = 0.75, Myriad = 0.72). All models underpredicted the number of BRCA1 and BRCA2 mutations in the low estimated risk category. CONCLUSIONS: Carrier prediction algorithms provide a rational basis for counselling individuals likely to carry BRCA1 or BRCA2 mutations. Their widespread use would improve equity of access and the cost-effectiveness of genetic testing..
Kote-Jarai, Z.
Easton, D.F.
Stanford, J.L.
Ostrander, E.A.
Schleutker, J.
Ingles, S.A.
Schaid, D.
Thibodeau, S.
Dörk, T.
Neal, D.
Donovan, J.
Hamdy, F.
Cox, A.
Maier, C.
Vogel, W.
Guy, M.
Muir, K.
Lophatananon, A.
Kedda, M.-.
Spurdle, A.
Steginga, S.
John, E.M.
Giles, G.
Hopper, J.
Chappuis, P.O.
Hutter, P.
Foulkes, W.D.
Hamel, N.
Salinas, C.A.
Koopmeiners, J.S.
Karyadi, D.M.
Johanneson, B.
Wahlfors, T.
Tammela, T.L.
Stern, M.C.
Corral, R.
McDonnell, S.K.
Schürmann, P.
Meyer, A.
Kuefer, R.
Leongamornlert, D.A.
Tymrakiewicz, M.
Liu, J.-.
O'Mara, T.
Gardiner, R.A.
Aitken, J.
Joshi, A.D.
Severi, G.
English, D.R.
Southey, M.
Edwards, S.M.
Al Olama, A.A.
PRACTICAL Consortium,
Eeles, R.A.
(2008). Multiple novel prostate cancer predisposition loci confirmed by an international study: the PRACTICAL Consortium. Cancer epidemiol biomarkers prev,
Vol.17
(8),
pp. 2052-2061.
show abstract
A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10(-17)). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction..
Ormondroyd, E.
Moynihan, C.
Ardern-Jones, A.
Eeles, R.
Foster, C.
Davolls, S.
Watson, M.
(2008). Communicating genetics research results to families: problems arising when the patient participant is deceased. Psycho-oncology,
Vol.17
(8),
pp. 804-8.
Khazen, M.
Warren, R.M.
Boggis, C.R.
Bryant, E.C.
Reed, S.
Warsi, I.
Pointon, L.J.
Kwan-Lim, G.E.
Thompson, D.
Eeles, R.
Easton, D.
Evans, D.G.
Leach, M.O.
(2008). A pilot study of compositional analysis of the breast and estimation of breast mammographic density using three-dimensional T1-weighted magnetic resonance imaging. Cancer epidemiology biomarkers & prevention,
Vol.17
(9),
pp. 2268-7.
Kauff, N.D.
Domchek, S.M.
Friebel, T.M.
Robson, M.E.
Lee, J.
Garber, J.E.
Isaacs, C.
Evans, D.G.
Lynch, H.
Eeles, R.A.
Neuhausen, S.L.
Daly, M.B.
Matloff, E.
Blum, J.L.
Sabbatini, P.
Barakat, R.R.
Hudis, C.
Norton, L.
Offit, K.
Rebbeck, T.R.
(2008). Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J clin oncol,
Vol.26
(8),
pp. 1331-1337.
show abstract
PURPOSE: Risk-reducing salpingo-oophorectomy (RRSO) has been widely adopted as a key component of breast and gynecologic cancer risk-reduction for women with BRCA1 and BRCA2 mutations. Despite 17% to 39% of all BRCA mutation carriers having a mutation in BRCA2, no prospective study to date has evaluated the efficacy of RRSO for the prevention of breast and BRCA-associated gynecologic (ovarian, fallopian tube or primary peritoneal) cancer when BRCA2 mutation carriers are analyzed separately from BRCA1 mutation carriers. PATIENTS AND METHODS: A total of 1,079 women 30 years of age and older with ovaries in situ and a deleterious BRCA1 or BRCA2 mutation were enrolled onto prospective follow-up studies at one of 11 centers from November 1, 1994 to December 1, 2004. Women self-selected RRSO or observation. Follow-up information through November 30, 2005, was collected by questionnaire and medical record review. The effect of RRSO on time to diagnosis of breast or BRCA-associated gynecologic cancer was analyzed using a Cox proportional-hazards model. RESULTS: During 3-year follow-up, RRSO was associated with an 85% reduction in BRCA1-associated gynecologic cancer risk (hazard ratio [HR] = 0.15; 95% CI, 0.04 to 0.56) and a 72% reduction in BRCA2-associated breast cancer risk (HR = 0.28; 95% CI, 0.08 to 0.92). While protection against BRCA1-associated breast cancer (HR = 0.61; 95% CI, 0.30 to 1.22) and BRCA2-associated gynecologic cancer (HR = 0.00; 95% CI, not estimable) was suggested, neither effect reached statistical significance. CONCLUSION: The protection conferred by RRSO against breast and gynecologic cancers may differ between carriers of BRCA1 and BRCA2 mutations. Further studies evaluating the efficacy of risk-reduction strategies in BRCA mutation carriers should stratify by the specific gene mutated..
Kadouri, L.
Kote-Jarai, Z.
Hubert, A.
Baras, M.
Abeliovich, D.
Hamburger, T.
Peretz, T.
Eeles, R.A.
(2008). Glutathione-S-transferase M1, T1 and P1 polymorphisms, and breast cancer risk, in BRCA1/2 mutation carriers. Br j cancer,
Vol.98
(12),
pp. 2006-2010.
show abstract
Variation in penetrance estimates for BRCA1/2 carriers suggests that other environmental and genetic factors may modify cancer risk in carriers. The GSTM1, T1 and P1 isoenzymes are involved in metabolism of environmental carcinogens. The GSTM1 and GSTT1 gene is absent in a substantial proportion of the population. In GSTP1, a single-nucleotide polymorphism that translates to Ile112Val was associated with lower activity. We studied the effect of these polymorphisms on breast cancer (BC) risk in BRCA1/2 carriers. A population of 320 BRCA1/2 carriers were genotyped; of them 262 were carriers of one of the three Ashkenazi founder mutations. Two hundred and eleven were affected with BC (20 also with ovarian cancer (OC)) and 109 were unaffected with BC (39 of them had OC). Risk analyses were conducted using Cox proportional hazard models adjusted for origin (Ashkenazi vs non-Ashkenazi). We found an estimated BC HR of 0.89 (95% CI 0.65-1.12, P=0.25) and 1.11 (95% CI 0.81-1.52, P=0.53) for the null alleles of GSTM1 and GSTT1, respectively. For GSTP1, HR for BC was 1.36 (95% CI 1.02-1.81, P=0.04) for individuals with Ile/Val, and 2.00 (95% CI 1.18-3.38) for carriers of the Val/Val genotype (P=0.01). An HR of 3.20 (95% CI 1.26-8.09, P=0.01), and younger age at BC onset (P=0.2), were found among Val/Val, BRCA2 carriers, but not among BRCA1 carriers. In conclusion, our results indicate significantly elevated risk for BC in carriers of BRCA2 mutations with GSTP1-Val allele with dosage effect, as implicated by higher risk in homozygous Val carriers. The GSTM1- and GSTT1-null allele did not seem to have a major effect..
Tan, D.S.
Rothermundt, C.
Thomas, K.
Bancroft, E.
Eeles, R.
Shanley, S.
Ardern-Jones, A.
Norman, A.
Kaye, S.B.
Gore, M.E.
(2008). The "BRCAness" syndrome in ovarian cancer: A case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA 1/2 mutations. Journal of clinical oncology,
Vol.26
(15).
Clark, J.
Attard, G.
Jhavar, S.
Flohr, P.
Reid, A.
De-Bono, J.
Eeles, R.
Scardino, P.
Cuzick, J.
Fisher, G.
Parker, M.D.
Foster, C.S.
Berney, D.
Kovacs, G.
Cooper, C.S.
(2008). Complex patterns of ETS gene alteration arise during cancer development in the human prostate. Oncogene,
Vol.27
(14),
pp. 1993-2003.
show abstract
An ERG gene 'break-apart' fluorescence in situ hybridization (FISH) assay has been used to screen whole-mount prostatectomy specimens for rearrangements at the ERG locus. In cancers containing ERG alterations the observed pattern of changes was often complex. Different categories of ERG gene alteration were found either together in a single cancerous region or within separate foci of cancer in the same prostate slice. In some cases the juxtaposition of particular patterns of ERG alterations suggested possible mechanisms of tumour progression. Prostates harbouring ERG alterations commonly also contained cancer that lacked rearrangements of the ERG gene. A single trans-urethral resection of the prostate specimen examined harboured both ERG and ETV1 gene rearrangements demonstrating that the observed complexity may, at least in part, be explained by multiple ETS gene alterations arising independently in a single prostate. In a search for possible precursor lesions clonal ERG rearrangements were found both in high grade prostatic intraepithelial neoplasia (PIN) and in atypical in situ epithelial lesions consistent with the diagnosis of low grade PIN. Our observations support the view that ERG gene alterations represent an initiating event that promotes clonal expansion initially to form regions of epithelial atypia. The complex patterns of ERG alteration found in prostatectomy specimens have important implications for the design of experiments investigating the clinical significance and mechanism of development of individual prostate cancers..
Mitra, A.
Fisher, C.
Foster, C.S.
Jameson, C.
Barbachanno, Y.
Bartlett, J.
Bancroft, E.
Doherty, R.
Kote-Jarai, Z.
Peock, S.
Easton, D.
IMPACT and EMBRACE Collaborators,
Eeles, R.
(2008). Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype. Br j cancer,
Vol.98
(2),
pp. 502-507.
show abstract
There is a high and rising prevalence of prostate cancer (PRCA) within the male population of the United Kingdom. Although the relative risk of PRCA is higher in male BRCA2 and BRCA1 mutation carriers, the histological characteristics of this malignancy in these groups have not been clearly defined. We present the histopathological findings in the first UK series of BRCA1 and BRCA2 mutation carriers with PRCA. The archived histopathological tissue sections of 20 BRCA1/2 mutation carriers with PRCA were collected from histopathology laboratories in England, Ireland and Scotland. The cases were matched to a control group by age, stage and serum PSA level of PRCA cases diagnosed in the general population. Following histopathological evaluation and re-grading according to current conventional criteria, Gleason scores of PRCA developed by BRCA1/2 mutation carriers were identified to be significantly higher (Gleason scores 8, 9 or 10, P=0.012) than those in the control group. Since BRCA1/2 mutation carrier status is associated with more aggressive disease, it is a prognostic factor for PRCA outcome. Targeting screening to this population may detect disease at an earlier clinical stage which may therefore be beneficial..
Tapper, W.
Hammond, V.
Gerty, S.
Ennis, S.
Simmonds, P.
Collins, A.
Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) Steering Group,
Eccles, D.
(2008). The influence of genetic variation in 30 selected genes on the clinical characteristics of early onset breast cancer. Breast cancer res,
Vol.10
(6),
p. R108.
show abstract
INTRODUCTION: Common variants that alter breast cancer risk are being discovered. Here, we determine how these variants influence breast cancer prognosis, risk and tumour characteristics. METHODS: We selected 1,001 women with early onset nonfamilial invasive breast cancer from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort and genotyped 206 single nucleotide polymorphisms (SNPs) across 30 candidate genes. After quality control, 899 cases and 133 SNPs remained. Survival analyses were used to identify SNPs associated with prognosis and determine their interdependency with recognized prognostic factors. To identify SNPs that alter breast cancer risk, association tests were used to compare cases with controls from the Wellcome Trust Case Control Consortium. To search for SNPs affecting tumour biology, cases were stratified into subgroups according to oestrogen receptor (ER) status and grade and tested for association. RESULTS: We confirmed previous associations between increased breast cancer risk and SNPs in CASP8, TOX3 (previously known as TNRC9) and ESR1. Analysis of prognosis identified eight SNPs in six genes (MAP3K1, DAPK1, LSP1, MMP7, TOX3 and ESR1) and one region without genes on 8q24 that are associated with survival. For MMP7, TOX3 and MAP3K1 the effects on survival are independent of the main recognized clinical prognostic factors. The SNP in 8q24 is more weakly associated with independent effects on survival. Once grade and pathological nodal status (pN stage) were taken into account, SNPs in ESR1 and LSP1 showed no independent survival difference, whereas the effects of the DAPK1 SNP were removed when correcting for ER status. Interestingly, effects on survival for SNPs in ESR1 were most significant when only ER-positive tumours were examined. Stratifying POSH cases by tumour characteristics identified SNPs in FGFR2 and TOX3 associated with ER-positive disease and SNPs in ATM associated with ER-negative disease. CONCLUSIONS: We have demonstrated that several SNPs are associated with survival. In some cases this appears to be due to an effect on tumour characteristics known to have a bearing on prognosis; in other cases the effect appears to be independent of these prognostic factors. These findings require validation by further studies in similar patient groups..
Brohet, R.M.
Goldgar, D.E.
Easton, D.F.
Antoniou, A.C.
Andrieu, N.
Chang-Claude, J.
Peock, S.
Eeles, R.A.
Cook, M.
Chu, C.
Noguès, C.
Lasset, C.
Berthet, P.
Meijers-Heijboer, H.
Gerdes, A.-.
Olsson, H.
Caldes, T.
van Leeuwen, F.E.
Rookus, M.A.
(2007). Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. J clin oncol,
Vol.25
(25),
pp. 3831-3836.
show abstract
PURPOSE Earlier studies have shown that endogenous gonadal hormones play an important role in the etiology of breast cancer among BRCA1/2 mutation carriers. So far, little is known about the safety of exogenous hormonal use in mutation carriers. In this study, we examined the association between oral contraceptive use and risk of breast cancer among BRCA1/2 carriers. PATIENTS AND METHODS In the International BRCA1/2 Carrier Cohort study (IBCCS), a retrospective cohort of 1,593 BRCA1/2 mutation carriers was analyzed with a weighted Cox regression analysis. Results We found an increased risk of breast cancer for BRCA1/2 mutation carriers who ever used oral contraceptives (adjusted hazard ratio [HR] = 1.47; 95% CI, 1.16 to 1.87). HRs did not vary according to time since stopping use, age at start, or calendar year at start. However, a longer duration of use, especially before first full-term pregnancy, was associated with an increased risk of breast cancer for both BRCA1 and BRCA2 mutation carriers (4 or more years of use before first full-term pregnancy: HR = 1.49 [95% CI, 1.05 to 2.11] for BRCA1 carriers and HR = 2.58 [95% CI, 1.21 to 5.49] for BRCA2 carriers). CONCLUSION No evidence was found among BRCA1/2 mutation carriers that current use of oral contraceptives is associated with risk of breast cancer more strongly than is past use, as is found in the general population. However, duration of use, especially before first full-term pregnancy, may be associated with an increasing risk of breast cancer among both BRCA1 and BRCA2 mutation carriers..
Barwell, J.
Pangon, L.
Georgiou, A.
Kesterton, I.
Langman, C.
Arden-Jones, A.
Bancroft, E.
Salmon, A.
Locke, I.
Kote-Jarai, Z.
MorriS, J.R.
Solomon, E.
Berg, J.
DochertY, Z.
Camplejohn, R.
Eeles, R.
Hodgson, S.V.
(2007). Lymphocyte radiosensitivity in BRCA1 and BRCA2 mutation carriers and implications for breast cancer susceptibility. International journal of cancer,
Vol.121
(7),
pp. 1631-6.
Camp, N.J.
Cannon-Albright, L.A.
Farnham, J.M.
Baffoe-Bonnie, A.B.
George, A.
Powell, I.
Bailey-Wilson, J.E.
Carpten, J.D.
Giles, G.G.
Hopper, J.L.
Severi, G.
English, D.R.
Foulkes, W.D.
Maehle, L.
Moller, P.
Eeles, R.
Easton, D.
Badzioch, M.D.
Whittemore, A.S.
Oakley-Girvan, I.
Hsieh, C.-.
Dimitrov, L.
Xu, J.
Stanford, J.L.
Johanneson, B.
Deutsch, K.
Mcintosh, L.
Ostrander, E.A.
Wiley, K.E.
Isaacs, S.D.
Walsh, P.C.
Thibodeau, S.N.
McDonnell, S.K.
Hebbring, S.
Schaid, D.J.
Lange, E.M.
Cooney, K.A.
Tammela, T.L.
Schleutker, J.
Paiss, T.
Maier, C.
Gronberg, H.
Wiklund, F.
Emanuelsson, M.
Isaacs, W.B.
(2007). Compelling evidence for a prostate cancer gene at 22q12 3 by the International Consortium for Prostate Cancer Genetics. Human molecular genetics,
Vol.16
(11),
pp. 1271-8.
full text
Rahman, N.
Seal, S.
Thompson, D.
Kelly, P.
Renwick, A.
Elliott, A.
Reid, S.
Spanova, K.
Barfoot, R.
Chagtai, T.
Jayatilake, H.
McGuffog, L.
Hanks, S.
Evans, D.G.
Eccles, D.
Breast Cancer Susceptibility Collaboration (UK),
Easton, D.F.
Stratton, M.R.
(2007). PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat genet,
Vol.39
(2),
pp. 165-167.
show abstract
full text
PALB2 interacts with BRCA2, and biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia. We identified monoallelic truncating PALB2 mutations in 10/923 individuals with familial breast cancer compared with 0/1,084 controls (P = 0.0004) and show that such mutations confer a 2.3-fold higher risk of breast cancer (95% confidence interval (c.i.) = 1.4-3.9, P = 0.0025). The results show that PALB2 is a breast cancer susceptibility gene and further demonstrate the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition..
Chang-Claude, J.
Andrieu, N.
Rookus, M.
Brohet, R.
Antoniou, A.C.
Peock, S.
Davidson, R.
Izatt, L.
Cole, T.
Noguès, C.
Luporsi, E.
Huiart, L.
Hoogerbrugge, N.
Van Leeuwen, F.E.
Osorio, A.
Eyfjord, J.
Radice, P.
Goldgar, D.E.
Easton, D.F.
Epidemiological Study of Familial Breast Cancer (EMBRACE),
Gene Etude Prospective Sein Ovaire (GENEPSO),
Genen Omgeving studie van de werkgroep Hereditiair Borstkanker Onderzoek Nederland (GEO-HEBON),
International BRCA1/2 Carrier Cohort Study (IBCCS) collaborators group,
(2007). Age at menarche and menopause and breast cancer risk in the International BRCA1/2 Carrier Cohort Study. Cancer epidemiol biomarkers prev,
Vol.16
(4),
pp. 740-746.
show abstract
BACKGROUND: Early menarche and late menopause are important risk factors for breast cancer, but their effects on breast cancer risk in BRCA1 and BRCA2 carriers are unknown. METHODS: We assessed breast cancer risk in a large series of 1,187 BRCA1 and 414 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study. Rate ratios were estimated using a weighted Cox-regression approach. RESULTS: Breast cancer risk was not significantly related to age at menopause [hazard ratio [HR] for menopause below age 35 years, 0.60 [95% confidence interval (95% CI), 0.25-1.44]; 35 to 40 years, 1.15 [0.65-2.04]; 45 to 54 years, 1.02 [0.65-1.60]; >or=55 years, 1.12 [0.12-5.02], as compared with premenopausal women]. However, there was some suggestion of a reduction in risk after menopause in BRCA2 carriers. There was some evidence of a protective effect of oophorectomy (HR, 0.56; 95% CI, 0.29-1.09) and a significant trend of decreasing risk with increasing time since oophorectomy, but no apparent effect of natural menopause. There was no association between age at menarche and breast cancer risk, nor any apparent association with the estimated total duration of breast mitotic activity. CONCLUSIONS: These results are consistent with other observations suggesting a protective effect of oophorectomy, similar in relative effect to that in the general population. The absence of an effect of age at natural menopause is, however, not consistent with findings in the general population and may reflect the different natural history of the disease in carriers..
Senzer, N.
Nemunaitis, J.
Nemunaitis, M.
Lamont, J.
Gore, M.
Gabra, H.
Eeles, R.
Sodha, N.
Lynch, F.J.
Zumstein, L.A.
Menander, K.B.
Sobol, R.E.
Chada, S.
(2007). p53 therapy in a patient with Li-Fraumeni syndrome. Molecular cancer therapeutics,
Vol.6
(5),
pp. 1478-5.
Ramus, S.J.
Harrington, P.A.
Pye, C.
Peock, S.
Cook, M.R.
Cox, M.J.
Jacobs, I.J.
DiCioccio, R.A.
Whittemore, A.S.
Piver, M.S.
EMBRACE,
Easton, D.F.
Ponder, B.A.
Pharoah, P.D.
Gayther, S.A.
(2007). Screening for the BRCA1-ins6kbEx13 mutation: potential for misdiagnosis Mutation in brief #964 Online. Hum mutat,
Vol.28
(5),
pp. 525-526.
show abstract
Misdiagnosis of a germline mutation associated with an inherited disease syndrome can have serious implications for the clinical management of patients. A false negative diagnosis (mutation missed by genetic screening) limits decision making about intervention strategies within families. More serious is the consequence of a false positive diagnosis (genetic test suggesting a mutation is present when it is not). This could lead to an individual, falsely diagnosed as a mutation carrier, undergoing unnecessary clinical intervention, possibly involving risk-reducing surgery. As part of screening 283 ovarian cancer families for BRCA1 mutations, we used two different methods (mutation specific PCR and multiplex ligation-dependent probe amplification) to screen for a known rearrangement mutation L78833.1:g.44369_50449dup (ins6kbEx13). We found false positive and false negative results in several families. We then tested 61 known carriers or non-carriers from an epidemiological study of BRCA1 and BRCA2 mutation carriers (the EMBRACE study). These data highlight the need for caution when interpreting analyses of the ins6kbEx13 mutation and similar mutations, where characterising the exact sequence alteration for a deleterious mutation is not a part of the routine genetic test..
Dearnaley, D.P.
Sydes, M.R.
Graham, J.D.
Aird, E.G.
Bottomley, D.
Cowan, R.A.
Huddart, R.A.
Jose, C.C.
Matthews, J.H.
Millar, J.
Moore, A.R.
Morgan, R.C.
Russell, J.M.
Scrase, C.D.
Stephens, R.J.
Syndikus, I.
Parmar, M.K.
RT01 collaborators,
(2007). Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet oncol,
Vol.8
(6),
pp. 475-487.
show abstract
BACKGROUND: In men with localised prostate cancer, conformal radiotherapy (CFRT) could deliver higher doses of radiation than does standard-dose conventional radical external-beam radiotherapy, and could improve long-term efficacy, potentially at the cost of increased toxicity. We aimed to present the first analyses of effectiveness from the MRC RT01 randomised controlled trial. METHODS: The MRC RT01 trial included 843 men with localised prostate cancer who were randomly assigned to standard-dose CFRT or escalated-dose CFRT, both administered with neoadjuvant androgen suppression. Primary endpoints were biochemical-progression-free survival (bPFS), freedom from local progression, metastases-free survival, overall survival, and late toxicity scores. The toxicity scores were measured with questionnaires for physicians and patients that included the Radiation Therapy Oncology Group (RTOG), the Late Effects on Normal Tissue: Subjective/Objective/Management (LENT/SOM) scales, and the University of California, Los Angeles Prostate Cancer Index (UCLA PCI) scales. Analysis was done by intention to treat. This trial is registered at the Current Controlled Trials website http://www.controlled-trials.com/ISRCTN47772397. FINDINGS: Between January, 1998, and December, 2002, 843 men were randomly assigned to escalated-dose CFRT (n=422) or standard-dose CFRT (n=421). In the escalated group, the hazard ratio (HR) for bPFS was 0.67 (95% CI 0.53-0.85, p=0.0007). We noted 71% bPFS (108 cumulative events) and 60% bPFS (149 cumulative events) by 5 years in the escalated and standard groups, respectively. HR for clinical progression-free survival was 0.69 (0.47-1.02; p=0.064); local control was 0.65 (0.36-1.18; p=0.16); freedom from salvage androgen suppression was 0.78 (0.57-1.07; p=0.12); and metastases-free survival was 0.74 (0.47-1.18; p=0.21). HR for late bowel toxicity in the escalated group was 1.47 (1.12-1.92) according to the RTOG (grade >/=2) scale; 1.44 (1.16-1.80) according to the LENT/SOM (grade >/=2) scales; and 1.28 (1.03-1.60) according to the UCLA PCI (score >/=30) scale. 33% of the escalated and 24% of the standard group reported late bowel toxicity within 5 years of starting treatment. HR for late bladder toxicity according to the RTOG (grade >/=2) scale was 1.36 (0.90-2.06), but this finding was not supported by the LENT/SOM (grade >/=2) scales (HR 1.07 [0.90-1.29]), nor the UCLA PCI (score >/=30) scale (HR 1.05 [0.81-1.36]). INTERPRETATION: Escalated-dose CFRT with neoadjuvant androgen suppression seems clinically worthwhile in terms of bPFS, progression-free survival, and decreased use of salvage androgen suppression. This additional efficacy is offset by an increased incidence of longer term adverse events..
Couch, F.J.
Sinilnikova, O.
Vierkant, R.A.
Pankratz, V.S.
Fredericksen, Z.S.
Stoppa-Lyonnet, D.
Coupier, I.
Hughes, D.
Hardouin, A.
Berthet, P.
Peock, S.
Cook, M.
Baynes, C.
Hodgson, S.
Morrison, P.J.
Porteous, M.E.
Jakubowska, A.
Lubinski, J.
Gronwald, J.
Spurdle, A.B.
kConFab,
Schmutzler, R.
Versmold, B.
Engel, C.
Meindl, A.
Sutter, C.
Horst, J.
Schaefer, D.
Offit, K.
Kirchhoff, T.
Andrulis, I.L.
Ilyushik, E.
Glendon, G.
Devilee, P.
Vreeswijk, M.P.
Vasen, H.F.
Borg, A.
Backenhorn, K.
Struewing, J.P.
Greene, M.H.
Neuhausen, S.L.
Rebbeck, T.R.
Nathanson, K.
Domchek, S.
Wagner, T.
Garber, J.E.
Szabo, C.
Zikan, M.
Foretova, L.
Olson, J.E.
Sellers, T.A.
Lindor, N.
Nevanlinna, H.
Tommiska, J.
Aittomaki, K.
Hamann, U.
Rashid, M.U.
Torres, D.
Simard, J.
Durocher, F.
Guenard, F.
Lynch, H.T.
Isaacs, C.
Weitzel, J.
Olopade, O.I.
Narod, S.
Daly, M.B.
Godwin, A.K.
Tomlinson, G.
Easton, D.F.
Chenevix-Trench, G.
Antoniou, A.C.
Consortium of Investigators of Modifiers of BRCA1/2,
(2007). AURKA F31I polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a consortium of investigators of modifiers of BRCA1/2 study. Cancer epidemiol biomarkers prev,
Vol.16
(7),
pp. 1416-1421.
show abstract
The AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 cooperate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. Consortium of Investigators of Modifiers of BRCA1/2 was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4,935 BRCA1 and 2,241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations was genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined [hazard ratio (HR), 0.91; 95% confidence interval (95% CI), 0.77-1.06]. Similarly, no significant association was seen in BRCA1 (HR, 0.90; 95% CI, 0.75-1.08) or BRCA2 carriers (HR, 0.93; 95% CI, 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers..
Noble, J.
Dua, R.S.
Locke, I.
Eeles, R.
Gui, G.P.
Isacke, C.M.
(2007). Proteomic analysis of nipple aspirate fluid throughout the menstrual cycle in healthy pre-menopausal women. Breast cancer res treat,
Vol.104
(2),
pp. 191-196.
show abstract
A proteomic approach to nipple aspiration fluid (NAF) has been used in a number of studies comparing women with breast cancer and healthy women. However, to make useful comparisons between women with breast cancer and healthy women it is necessary to establish whether there is physiological variation in the proteomic profiles of NAF. The purpose of this study was, for the first time, to examine how the proteomic profile of NAF using surface-enhanced laser desorption ionisation time-of-flight mass spectrometry varies across the menstrual cycle in healthy pre-menopausal women. Twelve women were recruited and nipple aspiration was carried out weekly from both breasts of each subject for two menstrual cycles. Matching serum samples for luteinising hormone, follicle stimulating hormone and oestradiol were obtained at each aspiration attempt. Statistically significant peaks were found for three healthy volunteers (p < 0.05). However, the peaks that varied across the menstrual cycle were different from one healthy volunteer to another and the differences were small compared with the large variation in proteomic profiles between healthy volunteers. This study provides proof of concept that the NAF proteomic profile does not vary substantially during the menstrual cycle and that therefore it is valid to compare NAF profiles from pre-menopausal women that have been taken at different stages in the menstrual cycle..
Ormondroyd, E.
Moynihan, C.
Watson, M.
Foster, C.
Davolls, S.
Ardern-Jones, A.
Eeles, R.
(2007). Disclosure of genetics research results after the death of the patient participant: a qualitative study of the impact on relatives. J genet couns,
Vol.16
(4),
pp. 527-538.
show abstract
When a gene mutation is identified in a research study following the death of the study participant, it is not clear whether such information should be made available to relatives. We report here an evaluation of the impact on relatives of being informed of study results that detected pathogenic BRCA2 mutations in a male relative, now deceased, who had early onset (under the age of 55) prostate cancer. The breast and ovarian cancer risk was unknown to the living relatives. Qualitative analysis of interviews with thirteen relatives indicated that those who had a higher risk perception, resulting from an awareness of cancer family history or experiential knowledge of cancer in their family, tended to adjust more easily to the results. All participants believed that genetics research results of clinical significance should be fed back to relatives. Those who were fully aware of the BRCA2 results and implications for themselves felt they had benefited from the information, irrespective of whether or not they had elected for genetic testing, because of the consequent availability of surveillance programs. Initial anxiety upon learning about the BRCA2 result was alleviated by genetic counselling. Factors influencing those who have not engaged with the information included scepticism related to the relative who attempted to inform them, young age and fear of cancer. Those who had not sought genetic counselling did not attempt further dissemination, and some were not undergoing regular screening. Implications for informed consent in genetics research programs, and the requirement for genetic counselling when research results are disclosed, are discussed..
Salmon, A.
Amikam, D.
Sodha, N.
Davidson, S.
Basel-Vanagaite, L.
Eeles, R.A.
Abeliovich, D.
Peretz, T.
(2007). Rapid development of post-radiotherapy sarcoma and breast cancer in a patient with a novel germline 'de-novo' TP53 mutation. Clin oncol (r coll radiol),
Vol.19
(7),
pp. 490-493.
show abstract
AIMS: Germline mutations in the TP53 tumour suppressor gene are associated with Li-Fraumeni syndrome, which is characterised by a spectrum of neoplasms occurring in children and young adults that predominantly include early-onset breast cancer, a variety of sarcomas, brain tumours and adrenocortical tumours. The identification of patients carrying TP53 mutations is primarily based on a positive family history of these early-onset characteristic cancer types. The aim of this study is to emphasize the importance of TP53 molecular testing in patients with very early onset breast cancer and no family history of cancer. MATERIALS AND METHODS: A young woman with no family history of cancer presented with bilateral breast cancer at the age of 27 years. Forty months later she developed malignant fibrous histiocytoma of the right clavicle and another primary left breast cancer. Molecular testing of mutations 185delAG, 5382insC in BRCA1 gene and 6174delT in BRCA2 gene was performed using multiplex PCR and separation on a denaturing polyacrylamide gel. TP53 molecular analysis was performed by PCR-SSCP analysis of the whole coding region of the TP53. Exon 8 PCR products were sequenced using an ABI dye terminator kit and examined on an ABI 3100 automated sequencer. RESULTS: Molecular testing of peripheral blood DNA did not reveal mutations in BRCA1 or BRCA2 genes. A novel germline TP53 mutation, c.G841C, p.D281N, was identified. The detected mutation is a missense substitution, c.G841C, resulting in the substitution of the amino acid aspartate to asparagine, p.D281N. Molecular analysis in her parents showed that neither of them carried the mutation. CONCLUSIONS: We describe a novel 'de novo'TP53 mutation and discuss the importance of molecular testing in early-onset breast cancer patients and its effect on the management and outcome of the disease..
Venkitaraman, R.
Barbachano, Y.
Dearnaley, D.P.
Parker, C.C.
Khoo, V.
Huddart, R.A.
Eeles, R.
Horwich, A.
Sohaib, S.A.
(2007). Outcome of early detection and radiotherapy for occult spinal cord compression. Radiother oncol,
Vol.85
(3),
pp. 469-472.
show abstract
Retrospective analysis in 150 patients with metastatic prostate cancer was conducted to determine whether early detection with MRI spine and treatment of clinically occult spinal cord compromise (SCC) facilitate preservation of neurologic function. Our results suggest that prophylactic radiotherapy for patients with back pain or radiological SCC without neurologic deficit may facilitate preservation of neurologic function. Thus MRI surveillance for SCC may be important for prostate cancer patients with bone metastases..
Foster, C.
Watson, M.
Eeles, R.
Eccles, D.
Ashley, S.
Davidson, R.
Mackay, J.
Morrison, P.J.
Hopwood, P.
Evans, D.G.
(2007). Predictive genetic testing for BRCA1/2 in a UK clinical cohort: three-year follow-up. British journal of cancer,
Vol.96
(5),
pp. 718-7.
Friebel, T.M.
Domchek, S.M.
Neuhausen, S.L.
Wagner, T.
Evans, D.G.
Isaacs, C.
Garber, J.E.
Daly, M.B.
Eeles, R.
Matloff, E.
Tomlinson, G.
Lynch, H.T.
Tung, N.
Blum, J.L.
Weitzel, J.
Rubinstein, W.S.
Ganz, P.A.
Couch, F.
Rebbeck, T.R.
(2007). Bilateral prophylactic oophorectomy and bilateral prophylactic mastectomy in a prospective cohort of unaffected BRCA1 and BRCA2 mutation carriers. Clinical breast cancer,
Vol.7
(11),
pp. 875-8.
Ferris, M.
Easton, D.F.
Doherty, R.J.
Briggs, B.H.
Newman, M.
Saraf, I.M.
Scambler, S.
Wagman, L.
Wyndham, M.T.
Ward, A.
Eeles, R.A.
(2007). A population-based audit of ethnicity and breast cancer risk in one general practice catchment area in North London, UK: implications for practice. Hered cancer clin pract,
Vol.5
(3),
pp. 157-160.
show abstract
OBJECTIVES: To conduct a pilot population-based study within a general practice catchment area to determine whether the incidence of breast cancer was increased in the Ashkenazi population. DESIGN: Population-based cohort study. SETTING: A single general practice catchment area in North London. PARTICIPANTS: 1947 women over the age of 16 who responded to a questionnaire about ethnicity and breast cancer. MAIN OUTCOME MEASURES: Incidence of breast cancer, ethnicity. RESULTS: This study showed a 1.5-fold (95% CI 0.93-2.39) increase in breast cancer risk in the Ashkenazim compared with the non-Ashkenazi white population. The increased incidence was for both premenopausal and postmenopausal breast cancer (expected incidence pre:post is 1:4 whereas in the Ashkenazim it was 1:1; 51 and 52% of cases respectively). This increase was not shown in the Sephardim. Asians had a reduction in incidence (OR = 0.44; 95% CI 0.10-1.89). Results were adjusted for other risk factors for breast cancer. CONCLUSION: This study showed a 1.5-fold increase in breast cancer rates in Ashkenazim compared with the non-Jewish white population when adjusted for age (i.e. corrections were made to allow comparison of age groups) and this is not observed in the Sephardic population. The proportion of premenopausal breast cancer was just over double that of the general population. This is the first general practice population-based study in the UK to address this issue and has implications for general practitioners who care for patients from the Ashkenazi community..
Mason, M.D.
Sydes, M.R.
Glaholm, J.
Langley, R.E.
Huddart, R.A.
Sokal, M.
Stott, M.
Robinson, A.C.
James, N.D.
Parmar, M.K.
Dearnaley, D.P.
Medical Research Council PR04 Collaborators,
(2007). Oral sodium clodronate for nonmetastatic prostate cancer--results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J natl cancer inst,
Vol.99
(10),
pp. 765-776.
show abstract
BACKGROUND: The most frequent site of metastases from prostate cancer is bone. Adjuvant bisphosphonate treatment improves outcomes of patients with bone metastasis-negative breast cancer, but the effects of bisphosphonates on bone metastases in prostate cancer are not known. METHODS: We performed a randomized double-blind placebo-controlled trial to determine whether a first-generation bisphosphonate could improve symptomatic bone metastasis-free survival (time to symptomatic bone metastases or death from prostate cancer) in men with nonmetastatic prostate cancer who were at high risk of developing bone metastases. Between June 1, 1994, and December 31, 1997, 508 men from 26 UK sites and one New Zealand site who were within 3 years of initial prostate cancer diagnosis with no evidence of metastases from current bone scanning were randomly assigned to daily oral sodium clodronate (2080 mg/day, n = 254) or placebo (n = 254) for a maximum of 5 years. Estimates of outcome risks were compared using Kaplan-Meier analyses. RESULTS: The groups allocated to each treatment were well balanced. After a median follow-up of nearly 10 years, no evidence of benefit to the clodronate group was observed in terms of bone metastases-free survival (clodronate versus placebo, 80 events versus 68 events; hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 0.88 to 1.68) or overall survival (clodronate versus placebo, 130 deaths versus 127 deaths; HR = 1.02; 95% CI = 0.80 to 1.30). Adverse events, notably gastrointestinal problems and increased lactate dehydrogenase levels, were more frequent in the clodronate group than in the placebo group; otherwise, clodronate was well tolerated. Modification of trial drug dose was more frequent in the clodronate group than the placebo group (HR = 1.63, 95% CI = 1.21 to 2.19). CONCLUSION: Adjuvant sodium clodronate does not modify the natural history of nonmetastatic prostate cancer..
Kote-Jarai, Z.
Powles, T.J.
Mitchell, G.
Tidy, A.
Ashley, S.
Easton, D.
Assersohn, L.
Sodha, N.
Salter, J.
Gusterson, B.
Dowsett, M.
Eeles, R.
(2007). BRCA1/BRCA2 mutation status and analysis of cancer family history in participants of the Royal Marsden Hospital tamoxifen chemoprevention trial. Cancer lett,
Vol.247
(2),
pp. 259-265.
show abstract
We have analysed the pedigrees of all 70 women who developed cancer in the Royal Marsden Hospital (RMH) tamoxifen chemoprevention trial, using the Claus model, to assess breast cancer susceptibility heterozygote risk (HR) and screened the entire coding regions of BRCA1 and 2 genes in 62 of these cases. We found a reduced incidence of breast cancers developing on tamoxifen in women who have a lower HR, but not in women with higher HR. There were too few BRCA1/2 mutations (4 cases) to be able to determine the efficacy of tamoxifen by BRCA status. Immunohistochemical analysis showed a significantly lower frequency of median ER (p=0.03) in the cancers developing in tamoxifen-treated patients. These results suggest that tamoxifen is less likely to be effective at reducing breast cancers which are ER negative and also in some individuals at higher HR..
Clark, J.
Merson, S.
Jhavar, S.
Flohr, P.
Edwards, S.
Foster, C.S.
Eeles, R.
Martin, F.L.
Phillips, D.H.
Crundwell, M.
Christmas, T.
Thompson, A.
Fisher, C.
Kovacs, G.
Cooper, C.S.
(2007). Diversity of TMPRSS2-ERG fusion transcripts in the human prostate. Oncogene,
Vol.26
(18),
pp. 2667-2673.
show abstract
TMPRSS2-ERG gene fusions have recently been reported to be present in a high proportion of human prostate cancers. In the current study, we show that great diversity exists in the precise structure of TMPRSS2-ERG hybrid transcripts found in human prostates. Fourteen distinct hybrid transcripts are characterized, each containing different combinations of sequences from the TMPRSS2 and ERG genes. The transcripts include two that are predicted to encode a normal full-length ERG protein, six that encode N-terminal truncated ERG proteins and one that encodes a TMPRSS2-ERG fusion protein. Interestingly, distinct patterns of hybrid transcripts were found in samples taken from separate regions of individual cancer-containing prostates, suggesting that TMPRSS2-ERG gene fusions may be arising independently in different regions of a single prostate..
Locke, I.
Kote-Jarai, Z.
Fackler, M.J.
Bancroft, E.
Osin, P.
Nerurkar, A.
Izatt, L.
Pichert, G.
Gui, G.P.
Eeles, R.A.
(2007). Gene promoter hypermethylation in ductal lavage fluid from healthy BRCA gene mutation carriers and mutation-negative controls. Breast cancer res,
Vol.9
(1),
p. R20.
show abstract
INTRODUCTION: Female germline BRCA gene mutation carriers are at increased risk for developing breast cancer. The purpose of our study was to establish whether healthy BRCA mutation carriers demonstrate an increased frequency of aberrant gene promoter hypermethylation in ductal lavage (DL) fluid, compared with predictive genetic test negative controls, that might serve as a surrogate marker of BRCA1/2 mutation status and/or breast cancer risk. METHODS: The pattern of CpG island hypermethylation within the promoter region of a panel of four genes (RAR-beta, HIN-1, Twist and Cyclin D2) was assessed by methylation-specific polymerase chain reaction using free DNA extracted from DL fluid. RESULTS: Fifty-one DL samples from 24 healthy women of known BRCA mutation status (7 BRCA1 mutation carriers, 12 BRCA2 mutation carriers and 5 controls) were available for methylation analysis. Eight of 19 (42.1%) BRCA mutation carriers were found to have at least one hypermethylated gene in the four-gene panel. Two BRCA mutation carriers, in whom aberrant methylation was found, also had duct epithelial cell atypia identified. No hypermethylation was found in DL samples from 5 negative controls (p = 0.13). CONCLUSION: We found substantial levels of aberrant methylation, with the use of a four-gene panel, in the fluid from the breasts of healthy BRCA mutation carriers compared with controls. Methylation analysis of free DNA in DL fluid may offer a useful surrogate marker for BRCA1/2 mutation status and/or breast cancer risk. Further studies are required for the evaluation of the specificity and predictive value of aberrant methylation in DL fluid for future breast cancer development in BRCA1/2 mutation carriers..
Shanley, S.
Myhill, K.
Doherty, R.
Ardern-Jones, A.
Hall, S.
Vince, C.
Thomas, S.
Aspinall, P.
Eeles, R.
(2007). Delivery of cancer genetics services: The Royal Marsden telephone clinic model. Fam cancer,
Vol.6
(2),
pp. 213-219.
show abstract
We have conducted a telelink telephone-led cancer genetic counselling model at The Royal Marsden NHS Foundation Trust. The study commenced in March 2004 and evaluation of the clinic was conducted over 17 months from March 2005 to the end of July 2006. A total of 612 patients had telephone consultations during this time, 228 of whom were referred from primary care with a median of 30 patients counselled per month (range of 19-63, depending on staff availability with average of two staff per clinic). Waiting times were measured for General Practitioner referrals and all 228 were counselled within the national target-stipulated 13 weeks (median 6 weeks, range 1-12). An additional 132 patients who were sent appointment letters after receipt of their family history questionnaires did not attend their appointments (18% of all potential referrals) and required recontacting by letter. After telephone counselling, 42% of patients were able to be discharged from the telephone clinic without a subsequent face-to-face appointment, thereby saving resources. The telephone clinic also had a short set-up time with flexibility on timing and day of administration, which would be an advantage in centres where outreach clinic facilities are scarce. The telelink telephone counselling model is highly efficient in triaging high risk individuals for face-to-face counselling as per the Kenilworth model, in effecting concentration of resources and in providing a flexible individual-centred approach to cancer genetic counselling delivery..
Shanley, S.
McReynolds, K.
Ardern-Jones, A.
Ahern, R.
Fernando, I.
Yarnold, J.
Evans, G.
Eccles, D.
Hodgson, S.
Ashley, S.
Ashcroft, L.
Tutt, A.
Bancroft, E.
Short, S.
Smith, I.
Gui, G.
Barr, L.
Baildam, A.
Howell, A.
Royle, G.
Pierce, L.
Easton, D.
Eeles, R.
(2006). Acute chemotherapy-related toxicity is not increased in BRCA1 and BRCA2 mutation carriers treated for breast cancer in the United Kingdom. Clinical cancer research,
Vol.12
(23),
pp. 7033-6.
Shanley, S.
McReynolds, K.
Ardern-Jones, A.
Ahern, R.
Fernando, I.
Yarnold, J.
Evans, G.
Eccles, D.
Hodgson, S.
Ashley, S.
Ashcroft, L.
Tutt, A.
Bancroft, E.
Short, S.
Gui, G.
Barr, L.
Baildam, A.
Howell, A.
Royle, G.
Pierce, L.
Easton, D.
Eeles, R.
(2006). Late toxicity is not increased in BRCA1/BRCA2 mutation carriers undergoing breast radiotherapy in the United Kingdom. Clinical cancer research,
Vol.12
(23),
pp. 7025-8.
Kote-Jarai, Z.
Matthews, L.
Osorio, A.
Shanley, S.
Giddings, I.
Moreews, F.
Locke, I.
Evans, D.G.
Eccles, D.
Carrier Clinic Collaborators,
Williams, R.D.
Girolami, M.
Campbell, C.
Eeles, R.
(2006). Accurate prediction of BRCA1 and BRCA2 heterozygous genotype using expression profiling after induced DNA damage. Clin cancer res,
Vol.12
(13),
pp. 3896-3901.
show abstract
PURPOSE: In this study, the differential gene expression changes following radiation-induced DNA damage in healthy cells from BRCA1/BRCA1 mutation carriers have been compared with controls using high-density microarray technology. We aimed to establish if BRCA1/BRCA2 mutation carriers could be distinguished from noncarriers based on expression profiling of normal cells. EXPERIMENTAL DESIGN: Short-term primary fibroblast cultures were established from skin biopsies from 10 BRCA1 and 10 BRCA2 mutation carriers and 10 controls, all of whom had previously had breast cancer. The cells were subjected to 15 Gy ionizing irradiation to induce DNA damage. RNA was extracted from all cell cultures, preirradiation and at 1 hour postirradiation. For expression profiling, 15 K spotted cDNA microarrays manufactured by the Cancer Research UK DNA Microarray Facility were used. Statistical feature selection was used with a support vector machine (SVM) classifier to determine the best feature set for predicting BRCA1 or BRCA2 heterozygous genotype. To investigate prediction accuracy, a nonprobabilistic classifier (SVM) and a probabilistic Gaussian process classifier were used. RESULTS: In the task of distinguishing BRCA1 and BRCA2 mutation carriers from noncarriers and from each other following radiation-induced DNA damage, the SVM achieved 90%, and the Gaussian process classifier achieved 100% accuracy. This effect could not be achieved without irradiation. In addition, the SVM identified a set of BRCA genotype predictor genes. CONCLUSIONS: We conclude that after irradiation-induced DNA damage, BRCA1 and BRCA2 mutation carrier cells have a distinctive expression phenotype, and this may have a future role in predicting genotypes, with application to clinical detection and classification of mutations..
Thompson, D.
Seal, S.
Schutte, M.
McGuffog, L.
Barfoot, R.
Renwick, A.
Eeles, R.
Sodha, N.
Houlston, R.
Shanley, S.
Klijn, J.
Wasielewski, M.
Chang-Claude, J.
Futreal, P.A.
Weber, B.L.
Nathanson, K.L.
Stratton, M.
Meijers-Heijboer, H.
Rahman, N.
Easton, D.F.
(2006). A multicenter study of cancer incidence in CHEK2 1100delC mutation carriers. Cancer epidemiology biomarkers & prevention,
Vol.15
(12),
pp. 2542-4.
Spurdle, A.B.
Antoniou, A.C.
Kelemen, L.
Holland, H.
Peock, S.
Cook, M.R.
Smith, P.L.
Greene, M.H.
Simard, J.
Plourde, M.
Southey, M.C.
Godwin, A.K.
Beck, J.
Miron, A.
Daly, M.B.
Santella, R.M.
Hopper, J.L.
John, E.M.
Andrulis, I.L.
Durocher, F.
Struewing, J.P.
Easton, D.F.
Chenevix-Trench, G.
Australian Breast Cancer Family Study,
Australian Jewish Breast Cancer Study,
Breast Cancer Family Registry,
Interdisciplinary Health Research International Team on Breast Cancer Susceptibility,
Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer,
Epidemiological Study of Familial Breast Cancer Study Collaborators,
(2006). The AIB1 polyglutamine repeat does not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer epidemiol biomarkers prev,
Vol.15
(1),
pp. 76-79.
show abstract
This is by far the largest study of its kind to date, and further suggests that AIB1 does not play a substantial role in modifying the phenotype of BRCA1 and BRCA2 carriers. The AIB1 gene encodes the AIB1/SRC-3 steroid hormone receptor coactivator, and amplification of the gene and/or protein occurs in breast and ovarian tumors. A CAG/CAA repeat length polymorphism encodes a stretch of 17 to 29 glutamines in the HR-interacting carboxyl-terminal region of the protein which is somatically unstable in tumor tissues and cell lines. There is conflicting evidence regarding the role of this polymorphism as a modifier of breast cancer risk in BRCA1 and BRCA2 carriers. To further evaluate the evidence for an association between AIB1 glutamine repeat length and breast cancer risk in BRCA1 and BRCA2 mutation carriers, we have genotyped this polymorphism in 1,090 BRCA1 and 661 BRCA2 mutation carriers from Australia, Europe, and North America. There was no evidence for an increased risk associated with AIB1 glutamine repeat length. Given the large sample size, with more than adequate power to detect previously reported effects, we conclude that the AIB1 glutamine repeat does not substantially modify risk of breast cancer in BRCA1 and BRCA2 mutation carriers..
Morgan, S.
Lubinski, J.
Manguoglu, E.
Luleci, G.
Doherty, R.
Christie, M.
Craven, P.
Bancroft, E.
Mitra, A.
Zieba, K.
Eeles, R.
(2006). IMPACT and AIDIT: Strengthening Research Ties in Eastern Europe. Hereditary cancer in clinical practice,
Vol.4
(2),
pp. 111-112.
Mitchell, G.
Antoniou, A.C.
Warren, R.
Peock, S.
Brown, J.
Davies, R.
Mattison, J.
Cook, M.
Warsi, I.
Evans, D.G.
Eccles, D.
Douglas, F.
Paterson, J.
Hodgson, S.
Izatt, L.
Cole, T.
Burgess, L.
Eeles, R.
Easton, D.F.
(2006). Mammographic density and breast cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer res,
Vol.66
(3),
pp. 1866-1872.
show abstract
High breast density as measured on mammograms is a strong risk factor for breast cancer in the general population, but its effect in carriers of germline BRCA1 and BRCA2 mutations is unclear. We obtained mammograms from 206 female carriers of BRCA1 or BRCA2 mutations, 96 of whom were subsequently diagnosed with breast cancer and 136 relatives of carriers who were themselves noncarriers. We compared the mammographic densities of affected carriers (cases) and unaffected carriers (controls), and of mutation carriers and noncarriers, using a computer-assisted method of measurement and visual assessment by two observers. Analyses were adjusted for age, parity, body mass index, menopausal status, and hormone replacement therapy use. There was no difference in the mean percent density between noncarriers and carriers. Among carriers, increasing mammographic density was associated with an increased risk of breast cancer (P(trend) = 0.024). The odds ratio (OR; 95% confidence interval) for breast cancer associated with a density of > or =50% was 2.29 (1.23-4.26; P = 0.009). The OR did not differ between BRCA1 and BRCA2 carriers or between premenopausal and postmenopausal carriers. The results suggest that the distribution of breast density in BRCA1 and BRCA2 carriers is similar to that in non-carriers. High breast density in carriers is associated with an increased risk of breast cancer, with the relative risk being similar to that observed in the general population. Use of mammographic density could improve individual risk prediction in carriers..
Domchek, S.M.
Friebel, T.M.
Neuhausen, S.L.
Wagner, T.
Evans, G.
Isaacs, C.
Garber, J.E.
Daly, M.
Eeles, R.
Matloff, E.
Tomlinson, G.E.
Van't Veer, L.
Lynch, H.T.
Olopade, O.
Weber, B.L.
Rebbeck, T.R.
(2006). Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers:: a prospective cohort study. Lancet oncology,
Vol.7
(3),
pp. 223-7.
Hall, J.
Knee, G.
A'Hern, R.P.
Clarke, J.
Glees, J.P.
Ford, H.T.
Eeles, R.A.
(2006). Sweat-gland tumours: a clinical review of cases in one centre over 20 years. Clin oncol (r coll radiol),
Vol.18
(4),
pp. 351-359.
show abstract
AIMS: Sweat-gland tumours (SGTs) are uncommon, but malignant varieties are very rare. We have added our data on 30 new cases seen at the Royal Marsden NHS Foundation Trust to the published literature, particularly concentrating on clinical issues. We include a literature review. MATERIALS AND METHODS: The Royal Marsden NHS Foundation Trust database was searched for cases of SGT from 1972. Data were collected on all cases, including patient demographics and tumour characteristics, treatment and outcome. RESULTS: Thirty cases were confirmed histologically to be SGTs. Fourteen were malignant, 15 benign and the degree of malignancy in one was histologically indistinguishable. Mean age was 55 years (64 for malignant, 47 for benign tumours). The 15 patients with benign tumours were almost all treated with complete excision. Those with local relapse underwent successful re-excision. Their 5-year disease-free survival was 78% and cause-specific survival was 100%. Twelve of the 14 malignant tumours had localised disease at diagnosis, one had nodal disease and one had metastatic tumour nodules. All except one were treated with wide local excision. The patient with nodal involvement also had a lymph-node dissection. Two received adjuvant radiotherapy to the tumour bed. One received a melphalan limb perfusion. Eight of the 14 had no relapse. Six had locoregional relapse, and four of these also developed distant metastases. Visceral disease was always fatal. Radiotherapy and chemotherapy at relapse were unsuccessful. Five-year disease-free survival was 45%, and cause-specific survival was 57%. CONCLUSION: These rare tumours should be treated initially with complete wide local excision. In malignant tumours, lymph-node involvement is a poor prognostic sign. Wide local excision remains the primary treatment. Adjuvant radiotherapy may be useful in high-risk cases..
Kenen, R.
Ardern-Jones, A.
Eeles, R.
(2006). "Social separation" among women under 40 years of age diagnosed with breast cancer and carrying a BRCA1 or BRCA2 mutation. J genet couns,
Vol.15
(3),
pp. 149-162.
show abstract
We conducted an exploratory, qualitative study investigating experiences of women who had developed breast cancer under the age of 40 and who were identified as BRCA1 or BRCA2 mutation carriers. These germline mutation carriers face an increased lifetime risk of a second primary breast cancer and an increased risk for a primary ovarian cancer. Thirteen women who fit this criteria participated in three focus groups conducted at a major cancer center in the UK during Spring 2003. We asked broad, open-ended questions that allowed for a wide range of responses about their cancer and genetic testing experiences, physical and psycho-social concerns, family and partner reactions and their need for social support. The women expressed feelings of devastation, loneliness, feeling different and isolation, ambivalence about having to support family members, worries about partner's anxiety and depression, and anxiety about talking to family members, especially children. These feelings were stronger after the cancer diagnosis and compounded by the genetic test results that occurred at a later time. We also found that, at least temporarily, the women experienced what we call "social separation"--emotional distance from, or dissonance with groups they interact with or are part of, e.g., family and friends, frequently leading to a reduction in communication or a change in previously unstated, but accepted normal interaction. We concentrate on a few characteristics of social separation-feelings of aloneness, isolation and separation, use of silence and verbal discretion, the relationship between estrangement and kinship interaction and norm disruption, and are looking at social patterns of interpersonal relationships that may occur when risk and illness statuses are new and framing and feeling rules have not as yet been clearly developed due to a cultural lag..
Locke, I.
Kote-Jarai, Z.
Bancroft, E.
Bullock, S.
Jugurnauth, S.
Osin, P.
Nerurkar, A.
Izatt, L.
Pichert, G.
Gui, G.P.
Eeles, R.A.
(2006). Loss of heterozygosity at the BRCA1 and BRCA2 loci detected in ductal lavage fluid from BRCA gene mutation carriers and controls. Cancer epidemiol biomarkers prev,
Vol.15
(7),
pp. 1399-1402.
show abstract
Female BRCA gene mutation carriers are at increased risk for developing breast cancer. Ductal lavage is a novel method for sampling breast ductal fluid, providing epithelial cells for cytologic assessment and a source of free DNA for molecular analyses. Loss of heterozygosity (LOH) at the BRCA loci in ductal lavage fluid is a potential biomarker of breast cancer risk. The LOH rate was measured at the BRCA1/2 loci and compared with that at a control locus (APC) using free DNA from the ductal lavage fluid of BRCA carriers and predictive test negative controls. We evaluated the reproducibility of these analyses. Free DNA sufficient for PCR amplification was obtained from 33 ductal lavage samples of 17 healthy women of known BRCA status (14 BRCA carriers and 3 controls). LOH rates of 36.4% to 56.3% at the BRCA1 locus and 45% to 61.5% at the BRCA2 locus were found among BRCA carriers. The LOH rate at the APC locus was lower (18.5%). The interaliquot reproducibility for the D17S855 marker of the BRCA1 locus was 66.7%. Intraaliquot reproducibility was 90%. Although we successfully isolated sufficient free DNA from ductal lavage fluid for PCR amplification, the degree of reproducibility of these LOH studies raises questions about the robustness of this technique as a risk assessment tool in the evaluation of high-risk women. Further studies are required to evaluate the specificity and predictive value of LOH in ductal lavage fluid for breast cancer development..
Smith, P.
McGuffog, L.
Easton, D.F.
Mann, G.J.
Pupo, G.M.
Newman, B.
Chenevix-Trench, G.
Szabo, C.
Southey, M.
Renard, H.
Odefrey, F.
Lynch, H.
Stoppa-Lyonnet, D.
Couch, F.
Hopper, J.L.
Giles, G.G.
McCredie, M.R.
Buys, S.
Andrulis, I.
Senie, R.
Goldgar, D.E.
Oldenburg, R.
Kroeze-Jansema, K.
Kraan, J.
Meijers-Heijboer, H.
Klijn, J.G.
van Asperen, C.
van Leeuwen, I.
Vasen, H.F.
Cornelisse, C.J.
Devilee, P.
Baskcomb, L.
Seal, S.
Barfoot, R.
Mangion, J.
Hall, A.
Edkins, S.
Rapley, E.
Wooster, R.
Chang-Claude, J.
Eccles, D.
Evans, D.G.
Futreal, P.A.
Nathanson, K.L.
Weber, B.L.
Rahman, N.
Stratton, M.R.
(2006). A genome wide linkage search for breast cancer susceptibility genes. Genes chromosomes & cancer,
Vol.45
(7),
pp. 646-10.
full text
Renwick, A.
Thompson, D.
Seal, S.
Kelly, P.
Chagtai, T.
Ahmed, M.
North, B.
Jayatilake, H.
Barfoot, R.
Spanova, K.
McGuffog, L.
Evans, D.G.
Eccles, D.
Breast Cancer Susceptibility Collaboration (UK),
Easton, D.F.
Stratton, M.R.
Rahman, N.
(2006). ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat genet,
Vol.38
(8),
pp. 873-875.
show abstract
We screened individuals from 443 familial breast cancer pedigrees and 521 controls for ATM sequence variants and identified 12 mutations in affected individuals and two in controls (P = 0.0047). The results demonstrate that ATM mutations that cause ataxia-telangiectasia in biallelic carriers are breast cancer susceptibility alleles in monoallelic carriers, with an estimated relative risk of 2.37 (95% confidence interval (c.i.) = 1.51-3.78, P = 0.0003). There was no evidence that other classes of ATM variant confer a risk of breast cancer..
Griebsch, I.
Brown, J.
Boggis, C.
Dixon, A.
Dixon, M.
Easton, D.
Eeles, R.
Evans, D.G.
Gilbert, F.J.
Hawnaur, J.
Kessar, P.
Lakhani, S.R.
Moss, S.M.
Nerurkar, A.
Padhani, A.R.
Pointon, L.J.
Potterton, J.
Thompson, D.
Turnbull, L.W.
Walker, L.G.
Warren, R.
Leach, M.O.
(2006). Cost-effectiveness of screening with contrast enhanced magnetic resonance imaging vs X-ray mammography of women at a high familial risk of breast cancer. British journal of cancer,
Vol.95
(7),
pp. 801-10.
Gui, G.P.
Kadayaprath, G.
Darhouse, N.
Self, J.
Ward, A.
A'Hern, R.
Eeles, R.
(2006). Clinical outcome and service implications of screening women at increased breast cancer risk from a family history. Eur j surg oncol,
Vol.32
(7),
pp. 719-724.
show abstract
INTRODUCTION: The value of special screening for women at moderate breast cancer risk with a family history of breast cancer remains controversial. Little is known about recall rates, false negative outcomes and the impact on clinical service. Despite this, surveillance programmes within breast units have been established in the United Kingdom. PATIENTS AND METHODS: In our institution, screening of women at moderate (lifetime risk, 17-30%) and high risk (>30%) consisted of annual clinical examination and mammography from the age of 35 years. The active study period ran for four months and each patient was followed through a further screening cycle (whole study period), providing information on interval cancers and detection at the subsequent screen. RESULTS: One thousand one hundred and thirty-two women attended for their incident screen: 137 at high risk, 803 at moderate risk and 192 at standard risk. The median age at cancer diagnosis in the moderate risk group was 54 (range, 45-68) years and the high-risk group 51 (46-52) years, compared to 63 (45-69) years in the standard risk group. Seven cancers were diagnosed during the four-month active study period. Two patients were diagnosed with interval cancers and eight at the next screen, giving a cancer incidence in the whole study period of 17/1132 (1.5%). Thirteen patients had invasive cancer and four had ductal carcinoma in situ (DCIS) The median invasive tumour size was 15 had (range, 7-28)mm and the median DCIS size was 4 (2-30)mm. 10/13 (76.9%) invasive cancers were < or =20mm and 2/13 patients (15.4%) with invasive cancer were lymph node positive. The sensitivity and specificity of mammography were 85.7% and 98.8%, respectively. The mammogram recall rate was 27.6 per 1000. The benign to malignant surgery ratio was 8:17. CONCLUSION: Screening women at increased breast cancer risk is effective. Early detection and recall rates are comparable to that of older women attending the British National Breast Screening Programme..
Seal, S.
Thompson, D.
Renwick, A.
Elliott, A.
Kelly, P.
Barfoot, R.
Chagtai, T.
Jayatilake, H.
Ahmed, M.
Spanova, K.
North, B.
McGuffog, L.
Evans, D.G.
Eccles, D.
Breast Cancer Susceptibility Collaboration (UK),
Easton, D.F.
Stratton, M.R.
Rahman, N.
(2006). Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat genet,
Vol.38
(11),
pp. 1239-1241.
show abstract
We identified constitutional truncating mutations of the BRCA1-interacting helicase BRIP1 in 9/1,212 individuals with breast cancer from BRCA1/BRCA2 mutation-negative families but in only 2/2,081 controls (P = 0.0030), and we estimate that BRIP1 mutations confer a relative risk of breast cancer of 2.0 (95% confidence interval = 1.2-3.2, P = 0.012). Biallelic BRIP1 mutations were recently shown to cause Fanconi anemia complementation group J. Thus, inactivating truncating mutations of BRIP1, similar to those in BRCA2, cause Fanconi anemia in biallelic carriers and confer susceptibility to breast cancer in monoallelic carriers..
Hallowell, N.
Arden-Jones, A.
Eeles, R.
Foster, C.
Lucassen, A.
Moynihan, C.
Watson, M.
(2006). Guilt, blame and responsibility: men's understanding of their role in the transmission of BRCA1/2 mutations within their family. Sociology of health & illness,
Vol.28
(7),
pp. 969-20.
Hallowell, N.
(2006). Risky Relations Family, Kinship and the New Genetics by Featherstone, K , Atkinson, P , Bharadwaj, A and Clarke, A. Sociology of health & illness,
Vol.28
(7),
pp. 990-992.
Schaid, D.J.
McDonnell, S.K.
Zarfas, K.E.
Cunningham, J.M.
Hebbring, S.
Thibodeau, S.N.
Eeles, R.A.
Easton, D.F.
Foulkes, W.D.
Simard, J.
Giles, G.G.
Hopper, J.L.
Mahle, L.
Moller, P.
Badzioch, M.
Bishop, D.T.
Evans, C.
Edwards, S.
Meitz, J.
Bullock, S.
Hope, Q.
Guy, M.
Hsieh, C.-.
Halpern, J.
Balise, R.R.
Oakley-Girvan, I.
Whittemore, A.S.
Xu, J.
Dimitrov, L.
Chang, B.-.
Adams, T.S.
Turner, A.R.
Meyers, D.A.
Friedrichsen, D.M.
Deutsch, K.
Kolb, S.
Janer, M.
Hood, L.
Ostrander, E.A.
Stanford, J.L.
Ewing, C.M.
Gielzak, M.
Isaacs, S.D.
Walsh, P.C.
Wiley, K.E.
Isaacs, W.B.
Lange, E.M.
Ho, L.A.
Beebe-Dimmer, J.L.
Wood, D.P.
Cooney, K.A.
Seminara, D.
Ikonen, T.
Baffoe-Bonnie, A.
Fredriksson, H.
Matikainen, M.P.
Tammela, T.L.
Bailey-Wilson, J.
Schleutker, J.
Maier, C.
Herkommer, K.
Hoegel, J.J.
Vogel, W.
Paiss, T.
Wiklund, F.
Emanuelsson, M.
Stenman, E.
Jonsson, B.-.
Grönberg, H.
Camp, N.J.
Farnham, J.
Cannon-Albright, L.A.
Catalona, W.J.
Suarez, B.K.
Roehl, K.A.
(2006). Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics. Hum genet,
Vol.120
(4),
pp. 471-485.
show abstract
While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1-14.3 (LOD = 2.4), and 20p11.21-q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13-22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives..
Sodha, N.
Mantoni, T.S.
Tavtigian, S.V.
Eeles, R.
Garrett, M.D.
(2006). Rare germ line CHEK2 variants identified in breast cancer families encode proteins that show impaired activation. Cancer res,
Vol.66
(18),
pp. 8966-8970.
show abstract
Germ line mutations in CHEK2, the gene that encodes the Chk2 serine/threonine kinase activated in response to DNA damage, have been found to confer an increased risk of some cancers. We have previously reported the presence of the common deleterious 1100delC and four rare CHEK2 mutations in inherited breast cancer. Here, we report that predictions made by bioinformatic analysis on the rare mutations indicate that two of these, delE161 (483-485delAGA) and R117G, are likely to be deleterious. We show that the proteins encoded by 1100delC and delE161 are both unstable and inefficiently phosphorylated at Thr68 in response to DNA damage, a step necessary for the oligomerization of Chk2. Oligomerization is in turn necessary for additional phosphorylation and full activation of the protein. A second rare mutation, R117G, is phosphorylated at Thr68 but fails to show a mobility shift on DNA damage, suggesting that it fails to become further phosphorylated and hence fully activated. Our results indicate that delE161 and R117G encode nonfunctional proteins and are therefore likely to be pathogenic. The findings from the biochemical analysis correlate well with predictions made by bioinformatics analysis. In addition, the results imply that these mutations, as well as 1100delC, cannot act in a dominant-negative manner to cause cancer, and tumorigenesis in association with these mutations may be due to haploinsufficiency..
Andrieu, N.
Goldgar, D.E.
Easton, D.F.
Rookus, M.
Brohet, R.
Antoniou, A.C.
Peock, S.
Evans, G.
Eccles, D.
Douglas, F.
Noguès, C.
Gauthier-Villars, M.
Chompret, A.
Van Leeuwen, F.E.
Kluijt, I.
Benitez, J.
Arver, B.
Olah, E.
Chang-Claude, J.
EMBRACE,
GENEPSO,
GEO-HEBON,
IBCCS Collaborators Group,
(2006). Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS). J natl cancer inst,
Vol.98
(8),
pp. 535-544.
show abstract
BACKGROUND: Multiparity, young age at first childbirth, and breast-feeding are associated with a reduced risk of breast cancer in the general population. The breast cancer predisposition gene, BRCA1, regulates normal cell differentiation. Because mammary gland cells divide and differentiate during pregnancy, reproductive factors may influence breast cancer risk in BRCA1/2 mutation carriers differently than they do in noncarriers. METHODS: We performed a retrospective cohort study of 1601 women in the International BRCA1/2 Carrier Cohort Study cohort, all of whom carried a mutation in BRCA1 or BRCA2. Information on reproductive factors was obtained from a questionnaire. At the time of interview 853 subjects were classified with breast cancer. Data were analyzed by using a weighted cohort approach. All statistical tests were two-sided. RESULTS: There was no statistically significant difference in the risk of breast cancer between parous and nulliparous women. Among parous women, an increasing number of full-term pregnancies was associated with a statistically significant decrease in the risk of breast cancer (Ptrend = .008); risk was reduced by 14% (95% confidence interval [CI] = 6% to 22%) for each additional birth. This association was the same for carriers of mutations in either BRCA1 or BRCA2 and was restricted to women older than 40 years. In BRCA2 mutation carriers, first childbirth at later ages was associated with an increased risk of breast cancer compared with first childbirth before age 20 years (20-24 years, hazard ratio [HR] = 2.33 [95% CI = 0.93 to 5.83]; 25-29 years, HR = 2.68 [95% CI = 1.02 to 7.07]; > or = 30 years, HR = 1.97 [95% CI = 0.67 to 5.81]), whereas in BRCA1 mutation carriers, first childbirth at age 30 years or later was associated with a reduced risk of breast cancer compared with first childbirth before age 20 years (HR = 0.58 [95% CI = 0.36 to 0.94]). Neither history of interrupted pregnancies (induced abortions or miscarriage) nor history of breast-feeding was statistically significantly associated with the risk of breast cancer. CONCLUSIONS: BRCA1 and BRCA2 mutation carriers older than 40 years show a similar reduction in breast cancer risk with increasing parity as non-carriers..
Andrieu, N.
Easton, D.F.
Chang-Claude, J.
Rookus, M.A.
Brohet, R.
Cardis, E.
Antoniou, A.C.
Wagner, T.
Simard, J.
Evans, G.
Peock, S.
Fricker, J.-.
Nogues, C.
Van't Veer, L.
Van Leeuwen, F.E.
Goldgar, D.E.
(2006). Effect of chest X-rays on the risk of breast cancer among BRCA1/2 mutation carriers in the international BRCA1/2 carrier cohort study: a report from the EMBRACE, GENEPSO, GEO-HEBON, and IBCCS Collaborators' Group. J clin oncol,
Vol.24
(21),
pp. 3361-3366.
show abstract
PURPOSE: Women who carry germline mutations in the BRCA1 and BRCA2 genes are at greatly increased risk of breast cancer (BC). Numerous studies have shown that moderate to high doses of ionizing radiation are a risk factor for BC. Because of the role of the BRCA proteins in DNA repair, we hypothesized that BRCA carriers might be more sensitive to ionizing radiation than women in the general population. PATIENTS AND METHODS: A retrospective cohort study of 1,601 female BRCA1/2 carriers was performed. Risk of breast cancer from exposure to chest x-rays, as assessed by questionnaire data, was analyzed using a weighted Cox proportional hazards model. RESULTS: In this cohort, any reported exposure to chest x-rays was associated with an increased risk of BC (hazard ratio [HR] = 1.54; P = .007). This risk was increased in carrier women aged 40 years and younger (HR = 1.97; P < .001) and in women born after 1949 (HR = 2.56; P < .001), particularly those exposed only before the age of 20 years (HR = 4.64; P < .001). CONCLUSION: In our series of BRCA carriers, we detected a relatively large effect on BC risk with a level of radiation exposure that is at least an order of magnitude lower than in previously studied medical radiation-exposed cohorts. Although part of this increase may be attributable to recall bias, the observed patterns of risk in terms of age at exposure and attained age are consistent with those found in previous studies. If confirmed, the results have important implications for the use of x-ray imaging in young BRCA1/2 carriers..
Melia, J.
Dearnaley, D.
Moss, S.
Johns, L.
Coulson, P.
Moynihan, C.
Sweetman, J.
Parkinson, M.C.
Eeles, R.
Watson, M.
(2006). The feasibility and results of a population-based approach to evaluating prostate-specific antigen screening for prostate cancer in men with a raised familial risk. Br j cancer,
Vol.94
(4),
pp. 499-506.
show abstract
The feasibility of a population-based evaluation of screening for prostate cancer in men with a raised familial risk was investigated by studying reasons for non-participation and uptake rates according to postal recruitment and clinic contact. The levels of prostate-specific antigen (PSA) and the positive predictive values (PPV) for cancer in men referred with a raised PSA and in those biopsied were analysed. First-degree male relatives (FDRs) were identified through index cases (ICs): patients living in two regions of England and diagnosed with prostate cancer at age < or =65 years from 1998 to 2004. First-degree relatives were eligible if they were aged 45-69 years, living in the UK and had no prior diagnosis of prostate cancer. Postal recruitment was low (45 of 1687 ICs agreed to their FDR being contacted: 2.7%) but this was partly due to ICs not having eligible FDRs. A third of ICs in clinic had eligible FDRs and 49% (192 out of 389) agreed to their FDR(s) being contacted. Of 220 eligible FDRs who initially consented, 170 (77.3%) had a new PSA test taken and 32 (14.5%) provided a previous PSA result. Among the 170 PSA tests, 10% (17) were > or =4 ng ml(-1) and 13.5% (23) tests above the age-related cutoffs. In 21 men referred, five were diagnosed with prostate cancer (PPV 24%; 95% CI 8, 47). To study further the effects of screening, patients with a raised familial risk should be counselled in clinic about screening of relatives and data routinely recorded so that the effects of screening on high-risk groups can be studied..
Sweetman, J.
Watson, M.
Norman, A.
Bunstead, Z.
Hopwood, P.
Melia, J.
Moss, S.
Eeles, R.
Dearnaley, D.
Moynihan, C.
(2006). Feasibility of familial PSA screening: psychosocial issues and screening adherence. Br j cancer,
Vol.94
(4),
pp. 507-512.
show abstract
This study examined factors that predict psychological morbidity and screening adherence in first-degree relatives (FDRs) taking part in a familial PSA screening study. Prostate cancer patients (index cases - ICs) who gave consent for their FDRs to be contacted for a familial PSA screening study to contact their FDRs were also asked permission to invite these FDRs into a linked psychosocial study. Participants were assessed on measures of psychological morbidity (including the General Health Questionnaire; Cancer Worry Scale; Health Anxiety Questionnaire; Impact of Events Scale); and perceived benefits and barriers, knowledge; perceived risk/susceptibility; family history; and socio-demographics. Of 255 ICs, 155 (61%) consented to their FDRs being contacted. Of 207 FDRs approached, 128 (62%) consented and completed questionnaires. Multivariate logistic regression revealed that health anxiety, perceived risk and subjective stress predicted higher cancer worry (P = 0.05). Measures of psychological morbidity did not predict screening adherence. Only past screening behaviour reliably predicted adherence to familial screening (P = 0.05). First-degree relatives entering the linked familial PSA screening programme do not, in general, have high levels of psychological morbidity. However, a small number of men exhibited psychological distress..
Kote-Jarai, Z.
Salmon, A.
Mengitsu, T.
Copeland, M.
Ardern-Jones, A.
Locke, I.
Shanley, S.
Summersgill, B.
Lu, Y.-.
Shipley, J.
Eeles, R.
(2006). Increased level of chromosomal damage after irradiation of lymphocytes from BRCA1 mutation carriers. Br j cancer,
Vol.94
(2),
pp. 308-310.
show abstract
Deleterious mutations in the BRCA1 gene predispose women to an increased risk of breast and ovarian cancer. Many functional studies have suggested that BRCA1 has a role in DNA damage repair and failure in the DNA damage response pathway often leads to the accumulation of chromosomal aberrations. Here, we have compared normal lymphocytes with those heterozygous for a BRCA1 mutation. Short-term cultures were irradiated (8Gy) using a high dose rate and subsequently metaphases were analysed by 24-colour chromosome painting (M-FISH). We scored the chromosomal rearrangements in the metaphases from five BRCA1 mutation carriers and from five noncarrier control samples 6 days after irradiation. A significantly higher level of chromosomal damage was detected in the lymphocytes heterozygous for BRCA1 mutations compared with normal controls; the average number of aberrations per mitosis was 3.48 compared with 1.62 in controls (P=0.0001). This provides new evidence that heterozygous mutation carriers have a different response to DNA damage compared with noncarriers and that BRCA1 has a role in DNA damage surveillance. Our finding has implications for treatment and screening of BRCA1 mutation carriers using modalities that involve irradiation..
Doherty, R.
Lubinski, J.
Manguoglu, E.
Luleci, G.
Christie, M.
Craven, P.
Bancroft, E.
Mitra, A.
Morgan, S.
Eeles, R.
IMPACT Steering Committee,
(2006). AIDIT and IMPACT: building research collaborations in targeted prostate cancer screening. J buon,
Vol.11
(4),
pp. 415-418.
show abstract
AIDIT (Advancing International Co-operation and Developing Infrastructure for Targeted Screening of Prostate Cancer in Men with Genetic Predisposition) is a project funded by the Sixth Framework Programme of the European Community which is endeavouring to facilitate co-operation between European countries in the field of cancer research. The project also aims to raise awareness of familial prostate cancer among health professionals and the public within the associated candidate countries (ACCs) and new member states of the European Union (EU). AIDIT will focus on linking clinical and research teams in the ACCs and new member states with the IMPACT Consortium (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), an international team investigating screening and diagnosis for men with a genetic risk of prostate cancer predisposition genes BRCA1 or BRCA2). Cancer research has been targeted as a high priority for the European Community; however, research is most successful when centralised and well coordinated, avoiding the duplication and fragmentation associated with smaller, isolated studies. AIDIT will consolidate the current IMPACT consortium and allow research partners from across the world to benefit from shared knowledge and experience. To date, the AIDIT team has established a website to facilitate communication between project collaborators (www.impact-study.co.uk), has been represented at several international meetings and has facilitated a conference for the IMPACT study to bring together international research teams, clinicians and policy makers..
Warren, R.M.
Pointon, L.
Thompson, D.
Hoff, R.
Gilbert, F.J.
Padhani, A.
Easton, D.
Lakhani, S.R.
Leach, M.O.
(2005). Reading protocol for dynamic contrast-enhanced MR images of the breast: Sensitivity and specificity analysis. Radiology,
Vol.236
(3),
pp. 779-10.
Rebbeck, T.R.
Friebel, T.
Wagner, T.
Lynch, H.T.
Garber, J.E.
Daly, M.B.
Isaacs, C.
Olopade, O.I.
Neuhausen, S.L.
van 't Veer, L.
Eeles, R.
Evans, D.G.
Tomlinson, G.
Matloff, E.
Narod, S.A.
Eisen, A.
Domchek, S.
Armstrong, K.
Weber, B.L.
(2005). Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers:: The PROSE Study Group. Journal of clinical oncology,
Vol.23
(31),
pp. 7804-7.
Hallowell, N.
Ardern-Jones, A.
Eeles, R.
Foster, C.
Lucassen, A.
Moynihan, C.
Watson, M.
(2005). Communication about genetic testing in families of male BRCA1/2 carriers and non-carriers: patterns, priorities and problems. Clinical genetics,
Vol.67
(6),
pp. 492-11.
Leegte, B.
van der Hout, A.H.
Deffenbaugh, A.M.
Bakker, M.K.
Mulder, I.M.
ten Berge, A.
Leenders, E.P.
Wesseling, J.
de Hullu, J.
Hoogerbrugge, N.
Ligtenberg, M.J.
Ardern-Jones, A.
Bancroft, E.
Salmon, A.
Barwell, J.
Eeles, R.
Oosterwijk, J.C.
(2005). Phenotypic expression of double heterozygosity for BRCA1 and BRCA2 germline mutations. Journal of medical genetics,
Vol.42
(3),
p. 8.
Hope, Q.
Bullock, S.
Evans, C.
Meitz, J.
Hamel, N.
Edwards, S.M.
Severi, G.
Dearnaley, D.
Jhavar, S.
Southgate, C.
Falconer, A.
Dowe, A.
Muir, K.
Houlston, R.S.
Engert, J.C.
Roquis, D.
Sinnett, D.
Simard, J.
Heimdal, K.
Møller, P.
Maehle, L.
Badzioch, M.
Eeles, R.A.
Easton, D.F.
English, D.R.
Southey, M.C.
Hopper, J.L.
Foulkes, W.D.
Giles, G.G.
Cancer Research UK/British Association of Urological Surgeons' Section of Oncology Collaborators,
(2005). Macrophage scavenger receptor 1 999C>T (R293X) mutation and risk of prostate cancer. Cancer epidemiol biomarkers prev,
Vol.14
(2),
pp. 397-402.
show abstract
BACKGROUND: Variants in the gene encoding the macrophage scavenger receptor 1 (MSR1(4)) protein have been identified in men with prostate cancer, and several small studies have suggested that the 999C>T (R293X) protein-truncating mutation may be associated with an increased risk for this disease. METHODS: Using large case-control, cohort, and prostate cancer family studies conducted in several Western countries, we tested for the 999C>T mutation in 2,943 men with invasive prostate carcinoma, including 401 males from multiple-case families, 1,982 cases unselected for age, and 575 men diagnosed before the age of 56 years, and in 2,870 male controls. Risk ratios were estimated by unconditional logistic regression adjusting for country and by a modified segregation analysis. A meta-analysis was conducted pooling our data with published data. RESULTS: The prevalence of MSR1*999C>T mutation carriers was 0.027 (SE, 0.003) in cases and 0.022 (SE, 0.002) in controls, and did not differ by country, ethnicity, or source. The adjusted risk ratio for prostate cancer associated with being a 999C>T carrier was 1.31 [95% confidence interval (CI), 0.93-1.84; P = 0.16]. The modified segregation analysis estimated the risk ratio to be 1.20 (95% CI, 0.87-1.66; P = 0.16). The risk ratio estimated from the meta-analysis was 1.34 (95% CI, 0.94-1.89; P = 0.10). CONCLUSION: Our large-scale analysis of case and controls from several countries found no evidence that the 999C>T mutation is associated with increased risk of prostate cancer. The meta-analysis suggests it is unlikely that this mutation confers more than a 2-fold increased risk..
Jhavar, S.G.
Fisher, C.
Jackson, A.
Reinsberg, S.A.
Dennis, N.
Falconer, A.
Dearnaley, D.
Edwards, S.E.
Edwards, S.M.
Leach, M.O.
Cummings, C.
Christmas, T.
Thompson, A.
Woodhouse, C.
Sandhu, S.
Cooper, C.S.
Eeles, R.A.
(2005). Processing of radical prostatectomy specimens for correlation of data from histopathological, molecular biological, and radiological studies: a new whole organ technique. J clin pathol,
Vol.58
(5),
pp. 504-508.
show abstract
AIMS: To develop a method of processing non-formalin fixed prostate specimens removed at radical prostatectomy to obtain fresh tissue for research and for correlating diagnostic and molecular results with preoperative imaging. METHODS/RESULTS: The method involves a prostate slicing apparatus comprising a tissue slicer with a series of juxtaposed planar stainless steel blades linked to a support, and a cradle adapted to grip the tissue sample and receive the blades. The fresh prostate gland is held in the cradle and the blades are moved through the cradle slits to produce multiple 4 mm slices of the gland in a plane perpendicular to its posterior surface. One of the resulting slices is preserved in RNAlater. The areas comprising tumour and normal glands within this preserved slice can be identified by matching it to the haematoxylin and eosin stained sections of the adjacent slices that are formalin fixed and paraffin wax embedded. Intact RNA can be extracted from the identified tumour and normal glands within the RNAlater preserved slice. Preoperative imaging studies are acquired with the angulation of axial images chosen to be similar to the slicing axis, such that stained sections from the formalin fixed, paraffin wax embedded slices match their counterparts on imaging. CONCLUSIONS: A novel method of sampling fresh prostate removed at radical prostatectomy that allows tissue samples to be used both for diagnosis and molecular analysis is described. This method also allows the integration of preoperative imaging data with histopathological and molecular data obtained from the prostate tissue slices..
Hardie, C.
Parker, C.
Norman, A.
Eeles, R.
Horwich, A.
Huddart, R.
Dearnaley, D.
(2005). Early outcomes of active surveillance for localized prostate cancer. Bju int,
Vol.95
(7),
pp. 956-960.
show abstract
OBJECTIVE: To describe the preliminary clinical outcomes of active surveillance (AS), a new strategy aiming to individualize the management of early prostate cancer by selecting only those men with significant cancers for curative therapy, and illustrate the contrast with a policy of watchful waiting (WW). PATIENTS AND METHODS: Eighty men with early prostate cancer began AS at the authors' institution between 1993 and 2002. Eligibility included histologically confirmed prostatic adenocarcinoma, fitness for radical treatment, clinical stage T1/T2, N0/X, M0/X, a prostate specific antigen (PSA) level of < or = 20 ng/mL, and a Gleason score of < or = 7. PSA was measured and a digital rectal examination conducted at 3-6 month intervals. The decision between continued monitoring or radical treatment was informed by the rate of rise of PSA, and was made according to the judgement of each patient and clinician. During the same period, 32 men with localized prostate cancer (any T stage, N0/X, M0/X, any PSA, Gleason score < or = 7) were managed by WW; hormonal treatment was indicated for symptomatic prostate cancer progression. The PSA doubling time (DT) was calculated using linear regression of ln(PSA) against time, using all pretreatment PSA values. RESULTS: At a median follow-up of 42 months, 64 (80%) of the 80 patients on AS remained under observation, 11 (14%) received radical treatment and five (6%) died from other causes. No patient developed evidence of metastatic disease, none started palliative hormone therapy, and there were no deaths from prostate cancer. Of the 11 patients who received radical treatment all remained biochemically controlled with no clinical evidence of recurrent disease. The median PSA DT while on AS was 12 years. Twenty (62%) of the 32 patients on WW remained on observation, eight (25%) received palliative hormonal therapy and four (12%) died, including one from prostate cancer. CONCLUSIONS: AS is feasible in selected men with early prostate cancer. The natural history of this disease often appears extremely indolent, and most men on AS will avoid radical treatment. There is a marked contrast between AS (with radical treatment for biochemical progression) and WW (with palliative treatment for symptomatic progression). Ongoing studies are seeking to optimize the AS protocol, and to compare the long-term outcomes with those of immediate radical treatment..
Jefferies, S.
Kote-Jarai, Z.
Goldgar, D.
Houlston, R.
Frazer-Williams, M.-.
A'Hern, R.
Eeles, R.
Henk, J.
Gore, M.
Rhys-Evans, P.
Archer, D.
Bishop, K.
Solomon, E.
Hodgson, S.
McGurk, M.
Hibbert, J.
O'Connell, M.
Partridge, M.
Chevretton, E.
Calman, F.
Saunders, M.
Shotton, K.
Brown, A.
Whittaker, S.
Foulkes, W.
MPT Collaborators,
MPT Collaborators:,
(2005). Association between polymorphisms of the GPX1 gene and second primary tumours after index squamous cell cancer of the head and neck. Oral oncol,
Vol.41
(5),
pp. 455-461.
show abstract
We investigated the association between genetic polymorphisms in GPX1 gene amongst patients who had index squamous cell carcinoma (SCCHN) and a second primary tumour (SPT) after a primary SCCHN in a case-control study. GPX1 genotypes were determined for 61 patients with SPT and for 259 control subjects by a PCR technique using a fluorescent-labelled primer. Analysis was by an ABI automated fluorescent sequencer. The associations between specific genotypes and the development of SPT were examined by logistic regression. A significant difference was found between the control group and the SPT cases in allele frequencies of GPX1 ALA( *)6 and ALA( *)7 (p(trend)=0.04). These results suggest that polymorphisms in the GPX1 gene may be a marker for SPT development and further studies are indicated..
Doneux, A.
Parker, C.C.
Norman, A.
Eeles, R.
Howich, A.
Huddart, R.
Dearnaley, D.
(2005). The utility of digital rectal examination after radical radiotherapy for prostate cancer. Clin oncol (r coll radiol),
Vol.17
(3),
pp. 172-173.
show abstract
AIMS: The aim of the current study was to determine the utility of routine digital rectal examination (DRE) after radical radiotherapy for prostate cancer. MATERIALS AND METHODS: Between 1990 and 1999, 899 patients with clinically localised prostatic adenocarcinoma (T1-4, N0/Nx, M0/Mx) underwent neoadjuvant androgen deprivation and radical radiotherapy at the Royal Marsden Hospital. Patients were followed with serum prostate-specific antigen (PSA) test and DRE carried out at 6-monthly intervals for the first 2 years, and then annually. RESULTS: At a median follow-up of 5 years, 39 out of 899 cases (4.3%) had local recurrence detected on DRE. DRE failed to detect any local recurrences in the absence of a rising PSA. The lowest serum PSA concentration at the time of clinically detectable local recurrence was 1.7 ng/ml. CONCLUSIONS: These findings question the standard model of follow-up after radiotherapy for prostate cancer, and suggest that alternatives, such as telephone clinics, should be considered..
Hallowell, N.
Ardern-Jones, A.
Eeles, R.
Foster, C.
Lucassen, A.
Moynihan, C.
Watson, M.
(2005). Men's decision-making about predictive BRCA1/2 testing: the role of family. J genet couns,
Vol.14
(3),
pp. 207-217.
show abstract
Men who have a family history of breast and/or ovarian cancer may be offered a predictive genetic test to determine whether or not they carry the family specific BRCA1/2 mutation. Male carriers may be at increased risk of breast and prostate cancers. Relatively little is known about at-risk men's decision-making about BRCA1/2 testing. This qualitative study explores the influences on male patients' genetic test decisions. Twenty-nine in-depth interviews were undertaken with both carrier and noncarrier men and immediate family members (17 male patients, 8 female partners, and 4 adult children). These explored family members' experiences of cancer and genetic testing, decision-making about testing, family support, communication of test results within the family, risk perception and risk management. Implicit influences on men's testing decisions such as familial obligations are examined. The extent to which other family members--partners and adult children--were involved in testing decisions is also described. It is demonstrated that mothers of potential mutation carriers not only perceive themselves as having a right to be involved in making this decision, but also were perceived by their male partners as having a legitimate role to play in decision-making. There was evidence that (adult) children were excluded from the decision-making, and some expressed resentment about this. The implications of these findings for the practice of genetic counseling are discussed..
Ardern-Jones, A.
Kenen, R.
Eeles, R.
(2005). Too much, too soon? Patients and health professionals' views concerning the impact of genetic testing at the time of breast cancer diagnosis in women under the age of 40. Eur j cancer care (engl),
Vol.14
(3),
pp. 272-281.
show abstract
Recent research suggests that women who develop breast cancer between the ages of 30-34 may have specific tumour characteristics: Those with high grade, oestrogen receptor negative, human epidermal growth factor receptor 2 (HER-2) negative tumours have between a 10% and 27% chance of being a BRCA1 gene carrier. Carriers of BRCA1 and BRCA2 mutations have an increased risk of contralateral breast cancer and cancer of the ovary. Furthermore, recent research indicates that prophylactic mastectomy and/or oophorectomy offer a significant risk reduction in the development of breast/ovarian cancer. In the near future, women in the UK may be offered the choice of a genetic test close to the time of diagnosis. This timing not only provides additional dimensions to treatment decisions, but has psycho-social and familial implications as well. This exploratory study investigates, first, whether or not women diagnosed with breast cancer under the age of 40 would want to be offered information about genetic testing close to the time of their diagnosis. Then secondly, it explores whether the health care professionals treating them support this idea. Third, it highlights the reasons for the women and the health professionals perspectives and concerns. We held focus groups of 13 women who had their only, or first, breast cancer under the age of 40 and who were subsequently identified as BRCA1 or BRCA2 mutation carriers, asking them how they felt about this timing. We also interviewed 17 health care professionals involved in various aspect of breast cancer care and cancer genetics. The majority of former breast cancer women and professionals believed that there was already emotional overload in coping with the cancer diagnosis and decisions regarding existing cancer treatment options and that offering genetic testing would add too much additional stress. Some members of both groups, however, thought that offering genetic testing around the time of breast cancer diagnosis would be more important if the results could alter treatment decisions..
Xu, J.
Dimitrov, L.
Chang, B.-.
Adams, T.S.
Turner, A.R.
Meyers, D.A.
Eeles, R.A.
Easton, D.F.
Foulkes, W.D.
Simard, J.
Giles, G.G.
Hopper, J.L.
Mahle, L.
Moller, P.
Bishop, T.
Evans, C.
Edwards, S.
Meitz, J.
Bullock, S.
Hope, Q.
Hsieh, C.-.
Halpern, J.
Balise, R.N.
Oakley-Girvan, I.
Whittemore, A.S.
Ewing, C.M.
Gielzak, M.
Isaacs, S.D.
Walsh, P.C.
Wiley, K.E.
Isaacs, W.B.
Thibodeau, S.N.
McDonnell, S.K.
Cunningham, J.M.
Zarfas, K.E.
Hebbring, S.
Schaid, D.J.
Friedrichsen, D.M.
Deutsch, K.
Kolb, S.
Badzioch, M.
Jarvik, G.P.
Janer, M.
Hood, L.
Ostrander, E.A.
Stanford, J.L.
Lange, E.M.
Beebe-Dimmer, J.L.
Mohai, C.E.
Cooney, K.A.
Ikonen, T.
Baffoe-Bonnie, A.
Fredriksson, H.
Matikainen, M.P.
Tammela, T.L.
Bailey-Wilson, J.
Schleutker, J.
Maier, C.
Herkommer, K.
Hoegel, J.J.
Vogel, W.
Paiss, T.
Wiklund, F.
Emanuelsson, M.
Stenman, E.
Jonsson, B.-.
Gronberg, H.
Camp, N.J.
Farnham, J.
Cannon-Albright, L.A.
Seminara, D.
ACTANE Consortium,
(2005). A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics. Am j hum genet,
Vol.77
(2),
pp. 219-229.
show abstract
Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study..
Mitchell, G.
Farndon, P.A.
Brayden, P.
Murday, V.A.
Eeles, R.A.
(2005). Genetic predisposition to cancer: the consequences of a delayed diagnosis of Gorlin syndrome. Clin oncol (r coll radiol),
Vol.17
(8),
pp. 650-654.
show abstract
This report outlines a case of Gorlin syndrome, the diagnosis of which was delayed for many years, and raises a number of important issues. These are the spectrum of late radiotherapy effects, particularly after treatment for benign disease, and the importance of considering the possibility of the presence of a genetic syndrome predisposing to cancer in all individuals before starting any treatment. As our knowledge of genetic syndromes expands, this will become increasingly important. Finally, if a genetic predisposition to cancer is suspected, consideration should be given to obtaining a blood sample from the affected patient for DNA storage, particularly if their prognosis is limited. Currently, genetic testing can only be instituted in most families by first obtaining DNA from an individual affected by cancer, as most genetic mutations are unique to a family. If all relatives with cancer have died, then, at this time, genetic testing cannot usually be attempted, unless such samples have previously been stored..
Dearnaley, D.P.
Hall, E.
Lawrence, D.
Huddart, R.A.
Eeles, R.
Nutting, C.M.
Gadd, J.
Warrington, A.
Bidmead, M.
Horwich, A.
(2005). Phase III pilot study of dose escalation using conformal radiotherapy in prostate cancer: PSA control and side effects. Br j cancer,
Vol.92
(3),
pp. 488-498.
show abstract
Radical radiotherapy is a standard form of management of localised prostate cancer. Conformal treatment planning spares adjacent normal tissues reducing treatment-related side effects and may permit safe dose escalation. We have tested the effects on tumour control and side effects of escalating radiotherapy dose and investigated the appropriate target volume margin. After an initial 3-6 month period of androgen suppression, 126 men were randomised and treated with radiotherapy using a 2 by 2 factorial trial design. The initial radiotherapy tumour target volume included the prostate and base of seminal vesicles (SV) or complete SV depending on SV involvement risk. Treatments were randomised to deliver a dose of 64 Gy with either a 1.0 or 1.5 cm margin around the tumour volume (1.0 and 1.5 cm margin groups) and also to treat either with or without a 10 Gy boost to the prostate alone with no additional margin (64 and 74 Gy groups). Tumour control was monitored by prostate-specific antigen (PSA) testing and clinical examination with additional tests as appropriate. Acute and late side effects of treatment were measured using the Radiation Treatment and Oncology Groups (RTOG) and LENT SOM systems. The results showed that freedom from PSA failure was higher in the 74 Gy group compared to the 64 Gy group, but this did not reach conventional levels of statistical significance with 5-year actuarial control rates of 71% (95% CI 58-81%) in the 74 Gy group vs 59% (95% CI 45-70%) in the 64 Gy group. There were 23 failures in the 74 Gy group and 33 in the 64 Gy group (Hazard ratio 0.64, 95% CI 0.38-1.10, P=0.10). No difference in disease control was seen between the 1.0 and 1.5 cm margin groups (5-year actuarial control rates 67%, 95% CI 53-77% vs 63%, 95% CI 50-74%) with 28 events in each group (Hazard ratio 0.97, 95% CI 0.50-1.86, P=0.94). Acute side effects were generally mild and 18 weeks after treatment, only four and five of the 126 men had persistent > or =Grade 1 bowel or bladder side effects, respectively. Statistically significant increases in acute bladder side effects were seen after treatment in the men receiving 74 Gy (P=0.006), and increases in both acute bowel side effects during treatment (P=0.05) and acute bladder sequelae (P=0.002) were recorded for men in the 1.5 cm margin group. While statistically significant, these differences were of short duration and of doubtful clinical importance. Late bowel side effects (RTOG> or =2) were seen more commonly in the 74 Gy and 1.5 cm margin groups (P=0.02 and P=0.05, respectively) in the first 2 years after randomisation. Similar results were found using the LENT SOM assessments. No significant differences in late bladder side effects were seen between the randomised groups using the RTOG scoring system. Using the LENT SOM instrument, a higher proportion of men treated in the 74 Gy group had Grade > or =3 urinary frequency at 6 and 12 months. Compared to baseline scores, bladder symptoms improved after 6 months or more follow-up in all groups. Sexual function deteriorated after treatment with the number of men reporting some sexual dysfunction (Grade> or =1) increasing from 38% at baseline to 66% at 6 months and 1 year and 81% by year 5. However, no consistent differences were seen between the randomised groups. In conclusion, dose escalation from 64 to 74 Gy using conformal radiotherapy may improve long-term PSA control, but a treatment margin of 1.5 cm is unnecessary and is associated with increased acute bowel and bladder reactions and more late rectal side effects. Data from this randomised pilot study informed the Data Monitoring Committee of the Medical Research Council RT 01 Trial and the two studies will be combined in subsequent meta-analysis..
Schaid, D.J.
Chang, B.L.
International Consortium For Prostate Cancer Genetics,
(2005). Description of the International Consortium For Prostate Cancer Genetics, and failure to replicate linkage of hereditary prostate cancer to 20q13. Prostate,
Vol.63
(3),
pp. 276-290.
show abstract
The International Consortium for Prostate Cancer Genetics (ICPCG) is an international collaborative effort to pool pedigrees with hereditary prostate cancer (PC) in order to replicate linkage findings for PC. A strength of the ICPCG is the large number of well-characterized pedigrees, allowing linkage analyses within large subsets. Given the heterogeneity and complexity of PC, the historical difficulties of synthesizing different studies reporting positive and negative linkage replication, and the use of different statistical analysis methods and different stratification criteria, the ICPCG provides a valuable resource to evaluate linkage for hereditary PC. To date, linkage of chromosome 20 (HPC20) to hereditary PC has been one of the strongest linkage signals, yet the efforts to replicate this linkage have been limited. This paper reports a linkage analysis of chromosome 20 markers for 1,234 pedigrees with multiple cases of PC ascertained through the ICPCG, and represents the most thorough attempt to confirm or refute linkage to chromosome 20. From the original 158 Mayo pedigrees in which linkage was detected, the maximum heterogeneity LOD (HLOD) score, under a recessive model, was 2.78. In contrast, for the 1,076 pedigrees not included in the original study, the maximum HLOD score (recessive model) was 0.06. Although, a few small linkage signals for chromosome 20 were found in various strata of this pooled analysis, this large study failed to replicate linkage to HPC20. This study illustrates the value of the ICPCG family collection to evaluate reported linkage signals and suggests that the HPC20 region does not make a major contribution to PC susceptibility..
Leach, M.O.
Boggis, C.R.
Dixon, A.K.
Easton, D.F.
Eeles, R.A.
Evans, D.G.
Gilbert, F.J.
Griebsch, I.
Hoff, R.J.
Kessar, P.
Lakhani, S.R.
Moss, S.M.
Nerurkar, A.
Padhani, A.R.
Pointon, L.J.
Thompson, D.
Warren, R.M.
MARIBS study group,
(2005). Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). Lancet,
Vol.365
(9473),
pp. 1769-1778.
show abstract
BACKGROUND: Women genetically predisposed to breast cancer often develop the disease at a young age when dense breast tissue reduces the sensitivity of X-ray mammography. Our aim was, therefore, to compare contrast enhanced magnetic resonance imaging (CE MRI) with mammography for screening. METHODS: We did a prospective multicentre cohort study in 649 women aged 35-49 years with a strong family history of breast cancer or a high probability of a BRCA1, BRCA2, or TP53 mutation. We recruited participants from 22 centres in the UK, and offered the women annual screening with CE MRI and mammography for 2-7 years. FINDINGS: We diagnosed 35 cancers in the 649 women screened with both mammography and CE MRI (1881 screens): 19 by CE MRI only, six by mammography only, and eight by both, with two interval cases. Sensitivity was significantly higher for CE MRI (77%, 95% CI 60-90) than for mammography (40%, 24-58; p=0.01), and was 94% (81-99) when both methods were used. Specificity was 93% (92-95) for mammography, 81% (80-83) for CE MRI (p<0.0001), and 77% (75-79) with both methods. The difference between CE MRI and mammography sensitivities was particularly pronounced in BRCA1 carriers (13 cancers; 92%vs 23%, p=0.004). INTERPRETATION: Our findings indicate that CE MRI is more sensitive than mammography for cancer detection. Specificity for both procedures was acceptable. Despite a high proportion of grade 3 cancers, tumours were small and few women were node positive. Annual screening, combining CE MRI and mammography, would detect most tumours in this risk group..
Jhavar, S.
Corbishley, C.M.
Dearnaley, D.
Fisher, C.
Falconer, A.
Parker, C.
Eeles, R.
Cooper, C.S.
(2005). Construction of tissue microarrays from prostate needle biopsy specimens. Br j cancer,
Vol.93
(4),
pp. 478-482.
show abstract
Needle biopsies are taken as standard diagnostic specimens for many cancers, but no technique exists for the high-throughput analysis of multiple individual immunohistochemical (IHC) markers using these samples. Here we present a simple and highly reliable technique for constructing tissue microarrays (TMAs) from prostatic needle biopsies. Serial sectioning of the TMAs, called 'Checkerboard TMAs', facilitated expression analysis of multiple proteins using IHC markers. In total, 100% of the analysed biopsies within the TMA both preserved their antigenicity and maintained their morphology. Checkerboard TMAs will allow the use of needle biopsies (i) alongside other tissue specimens (trans-urethral resection of prostates and prostatectomies in the case of prostate cancer) in clinical correlation studies when searching for new prognostic markers, and (ii) in a diagnostic context for assessing expression of multiple proteins in cancers from patients prior to treatment..
Forrest, M.S.
Edwards, S.M.
Houlston, R.
Kote-Jarai, Z.
Key, T.
Allen, N.
Knowles, M.A.
Turner, F.
Ardern-Jones, A.
Murkin, A.
Williams, S.
Oram, R.
Bishop, D.T.
Eeles, R.A.
CR-UK/BPG UK prostate cancer study collaborators,
(2005). Association between hormonal genetic polymorphisms and early-onset prostate cancer. Prostate cancer prostatic dis,
Vol.8
(1),
pp. 95-102.
show abstract
We investigated the association between seven polymorphisms in four candidate genes involved in vitamin D and androgen metabolism with early-onset prostate cancer (CaP) risk. The polymorphisms were genotyped in 288 UK males who were diagnosed with CaP at the age of 55 y or younger and up to 700 population-based controls. An additional 50 cases (not selected for age) and 76 controls were also genotyped. Short (< or =22 repeats) AR (CAG)(n) repeats were associated with a significantly reduced risk of early onset CaP (OR 0.68, 95% CI 0.50-0.91) compared with men with long (> 22) repeats. Men homozygous for the leucine variant of SRD5A2 p.89V > L were also found to be at a significantly increased risk of CaP compared with men who were homozygous for the valine allele (OR 1.84, 95% CI 1.15-2.98). No associations were found with the AR (GGC)(n), CYP17 Msp A1 I, VDR Taq I, SRD5A2 (TA)(n) and p.49A >T polymorphisms and CaP risk. These findings suggest that common polymorphisms in the AR and SRD5A2 genes may be associated with early-onset CaP in British men..
Watson, M.
Kash, K.M.
Homewood, J.
Ebbs, S.
Murday, V.
Eeles, R.
(2005). Does genetic counseling have any impact on management of breast cancer risk?. Genet test,
Vol.9
(2),
pp. 167-174.
show abstract
Despite there being an increasing literature on the impact of cancer genetic counseling on risk perception and mental health, there is a lack of data describing impact on risk management. Genetic counseling and testing for cancer predisposition genes aims to improve the future health of those at high risk through appropriate surveillance and screening. However, management of breast cancer risk in women with a family history of this disease is an area of controversy. Counseling services may recommend specific risk management options to women, who then rely on their local screening service to make provision. This study investigated the impact of genetic counseling on management of breast cancer risk in women attending Cancer Family Clinics. A total of 293 women attending four genetic clinics were enrolled. Rates of breast self-examination, clinical breast examination, mammography, biopsy, detected cancers, and other screenings were documented. Participants' perceived benefits and barriers to mammography were assessed along with cancer worry. Results show that rates of mammography, clinical breast examination, and breast self-examination were increased following clinic attendance (p < 0.001). Women in the under 35 age-group had limited access to screening. Rates for biopsy and detected cancers were low. Women reported positive attitudes to mammography, with few reported barriers. Contrary to previous studies, there was no evidence that anxiety about breast cancer impedes uptake of health surveillance methods. Genetic counseling had a positive impact on management of breast cancer risk. Whether this translates into future health gains remains to be established..
Spurdle, A.B.
Antoniou, A.C.
Duffy, D.L.
Pandeya, N.
Kelemen, L.
Chen, X.
Peock, S.
Cook, M.R.
Smith, P.L.
Purdie, D.M.
Newman, B.
Dite, G.S.
Apicella, C.
Southey, M.C.
Giles, G.G.
Hopper, J.L.
Chenevix-Trench, G.
Easton, D.F.
EMBRACE Study Collaborators,
(2005). The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Breast cancer res,
Vol.7
(2),
pp. R176-R183.
show abstract
INTRODUCTION: The androgen receptor (AR) gene exon 1 CAG repeat polymorphism encodes a string of 9-32 glutamines. Women with germline BRCA1 mutations who carry at least one AR allele with 28 or more repeats have been reported to have an earlier age at onset of breast cancer. METHODS: A total of 604 living female Australian and British BRCA1 and/or BRCA2 mutation carriers from 376 families were genotyped for the AR CAG repeat polymorphism. The association between AR genotype and disease risk was assessed using Cox regression. AR genotype was analyzed as a dichotomous covariate using cut-points previously reported to be associated with increased risk among BRCA1 mutation carriers, and as a continuous variable considering smaller allele, larger allele and average allele size. RESULTS: There was no evidence that the AR CAG repeat polymorphism modified disease risk in the 376 BRCA1 or 219 BRCA2 mutation carriers screened successfully. The rate ratio associated with possession of at least one allele with 28 or more CAG repeats was 0.74 (95% confidence interval 0.42-1.29; P = 0.3) for BRCA1 carriers, and 1.12 (95% confidence interval 0.55-2.25; P = 0.8) for BRCA2 carriers. CONCLUSION: The AR exon 1 CAG repeat polymorphism does not appear to have an effect on breast cancer risk in BRCA1 or BRCA2 mutation carriers..
Kote-Jarai, Z.
Williams, R.D.
Cattini, N.
Copeland, M.
Giddings, I.
Wooster, R.
tePoele, R.H.
Workman, P.
Gusterson, B.
Peacock, J.
Gui, G.
Campbell, C.
Eeles, R.
(2004). Gene expression profiling after radiation-induced DNA damage is strongly predictive of BRCA1 mutation carrier status. Clin cancer res,
Vol.10
(3),
pp. 958-963.
show abstract
PURPOSE: The impact of the presence of a germ-line BRCA1 mutation on gene expression in normal breast fibroblasts after radiation-induced DNA damage has been investigated. EXPERIMENTAL DESIGN: High-density cDNA microarray technology was used to identify differential responses to DNA damage in fibroblasts from nine heterozygous BRCA1 mutation carriers compared with five control samples without personal or family history of any cancer. Fibroblast cultures were irradiated, and their expression profile was compared using intensity ratios of the cDNA microarrays representing 5603 IMAGE clones. RESULTS: Class comparison and class prediction analysis has shown that BRCA1 mutation carriers can be distinguished from controls with high probability (approximately 85%). Significance analysis of microarrays and the support vector machine classifier identified gene sets that discriminate the samples according to their mutation status. These include genes already known to interact with BRCA1 such as CDKN1B, ATR, and RAD51. CONCLUSIONS: The results of this initial study suggest that normal cells from heterozygous BRCA1 mutation carriers display a different gene expression profile from controls in response to DNA damage. Adaptations of this pilot result to other cell types could result in the development of a functional assay for BRCA1 mutation status..
Foster, C.
Eeles, R.
Ardern-Jones, A.
Moynihan, C.
Watson, M.
(2004). Juggling roles and expectations: Dilemmas faced by women talking to relatives about cancer and genetic testing. Psychology & health,
Vol.19
(4),
pp. 439-17.
Kenen, R.
Arden-Jones, A.
Eeles, R.
(2004). Healthy women from suspected hereditary breast and ovarian cancer families: the significant others in their lives. European journal of cancer care,
Vol.13
(2),
pp. 169-11.
Angèle, S.
Falconer, A.
Foster, C.S.
Taniere, P.
Eeles, R.A.
Hall, J.
(2004). ATM protein overexpression in prostate tumors: possible role in telomere maintenance. Am j clin pathol,
Vol.121
(2),
pp. 231-236.
show abstract
It has been postulated that telomere dysfunction and telomerase activation have important roles in prostate tumorigenesis. Since the ataxia-telangiectasia mutated gene product (ATM protein) is involved in maintaining telomere length and integrity, we hypothesized that its expression might be altered in prostate tumors and, thus, examined its profile in 49 tumor samples. The majority (32/49) had ATM protein levels higher than those observed in normal tissues, with only 5 of 49 tissue samples showing reduced or absent ATM levels. Three of these were from the group of 6 young-onset or sibling-pair tumors. There was a trend toward higher ATM expression in tumors with a higher Gleason score (23/32 [72%] for grade 8-10 vs 9/17 [53%] for grades 5-7), although this difference was not statistically significant. These findings support our hypothesis that the presence of the ATM protein at the same or a higher level than that in normal prostate cells might have an important role in the maintenance of the shortened telomeres commonly found in prostate cancer cells..
Foster, C.
Evans, D.G.
Eeles, R.
Eccles, D.
Ashley, S.
Brooks, L.
Cole, T.
Cook, J.
Davidson, R.
Gregory, H.
Mackay, J.
Morrison, P.J.
Watson, M.
(2004). Non-uptake of predictive genetic testing for BRCA1/2 among relatives of known carriers: Attributes, cancer worry, and barriers to testing in a multicenter clinical cohort. Genetic testing,
Vol.8
(1),
pp. 23-7.
Foster, C.S.
Falconer, A.
Dodson, A.R.
Norman, A.R.
Dennis, N.
Fletcher, A.
Southgate, C.
Dowe, A.
Dearnaley, D.
Jhavar, S.
Eeles, R.
Feber, A.
Cooper, C.S.
(2004). Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome. Oncogene,
Vol.23
(35),
pp. 5871-9.
Kenen, R.
Ardern-Jones, A.
Eeles, R.
(2004). We are talking, but are they listening? Communication patterns in families with a history of breast/ovarian cancer (HBOC). Psycho-oncology,
Vol.13
(5),
pp. 335-11.
Easton, D.
McGuffog, L.
Thompson, D.
Dunning, A.
Tee, L.
Baynes, C.
Healey, C.
Pharoah, P.
Ponder, B.
Seal, S.
Barfoot, R.
Sodha, N.
Eeles, R.
Stratton, M.
Rahman, N.
Peto, J.
Spurdle, A.B.
Chen, X.Q.
Chenevix-Trench, G.
Hopper, J.L.
Giles, G.G.
McCredie, M.R.
Syrjäkoski, K.
Holli, K.
Kallioniemi, O.
Eerola, H.
Vahteristo, P.
Blomqvist, C.
Nevanlinna, H.
Kataja, V.
Mannermaa, A.
Dörk, T.
Bremer, M.
Devilee, P.
de Bock, G.H.
Krol-Warmerdam, E.M.
Kroese-Jansema, K.
Wijers-Koster, P.
Cornelisse, C.J.
Tollenaar, R.A.
Meijers-Heijboer, H.
Berns, E.
Nagel, J.
Foekens, J.
Klijn, J.G.
Schutte, M.
(2004). CHEK2*1100delC and susceptibility to breast cancer:: A collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. American journal of human genetics,
Vol.74
(6),
pp. 1175-8.
Brooks, L.
Lennard, F.
Shenton, A.
Lalloo, F.
Ambus, I.
Ardern-Jones, A.
Belk, R.
Kerr, B.
Craufurd, D.
Eeles, R.
Evans, D.G.
(2004). BRCA1/2 predictive testing:: a study of uptake in two centres. European journal of human genetics,
Vol.12
(8),
pp. 654-9.
Hallowell, N.
Foster, C.
Eeles, R.
Ardern-Jones, A.
Watson, M.
(2004). Accommodating risk: Responses to BRCA1/2 genetic testing of women who have had cancer. Social science & medicine,
Vol.59
(3),
pp. 553-13.
Watson, M.
Foster, C.
Eeles, R.
Eccles, D.
Ashley, S.
Davidson, R.
Mackay, J.
Morrison, P.J.
Hopwood, P.
Evans, D.G.
(2004). Psychosocial impact of breast/ovarian (BRCA 1/2) cancer-predictive genetic testing in a UK multi-centre clinical cohort. British journal of cancer,
Vol.91
(10),
pp. 1787-8.
Ardern-Jones, A.
Eeles, R.
(2004). Developments in Clinical Practice: Follow up Clinic for BRCA Mutation Carriers: a Case Study Highlighting the "Virtual Clinic". Hered cancer clin pract,
Vol.2
(2),
pp. 77-79.
show abstract
This paper highlights the need for carriers to be followed up by health professionals who understand the complexities of the BRCA syndrome. A BRCA carrier clinic has been established in London and regular follow up is an essential part of the care for families. An open door policy has been set up for patients who may meet or telephone the cancer genetic nurse specialist for support and care at any time. An example of the follow up work is discussed in the format of a case of a young woman with a BRCA1 alteration who developed a primary peritoneal cancer following prophylactic oophorectomy. This case illustrates the work of the multi-disciplinary team caring for BRCA carriers..
Rebbeck, T.R.
Friebel, T.
Lynch, H.T.
Neuhausen, S.L.
van 't Veer, L.
Garber, J.E.
Evans, G.R.
Narod, S.A.
Isaacs, C.
Matloff, E.
Daly, M.B.
Olopade, O.I.
Weber, B.L.
(2004). Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J clin oncol,
Vol.22
(6),
pp. 1055-1062.
show abstract
PURPOSE: Data on the efficacy of bilateral prophylactic mastectomy for breast cancer risk reduction in women with BRCA1 and BRCA2 (BRCA1/2) mutations are limited, despite the clinical use of this risk-management strategy. Thus, we estimated the degree of breast cancer risk reduction after surgery in women who carry these mutations. PATIENTS AND METHODS: Four hundred eighty-three women with disease-associated germline BRCA1/2 mutations were studied for the occurrence of breast cancer. Cases were mutation carriers who underwent bilateral prophylactic mastectomy and who were followed prospectively from the time of their center ascertainment and their surgery, with analyses performed for both follow-up periods. Controls were BRCA1/2 mutation carriers with no history of bilateral prophylactic mastectomy matched to cases on gene, center, and year of birth. Both cases and controls were excluded for previous or concurrent diagnosis of breast cancer. Analyses were adjusted for duration of endogenous ovarian hormone exposure, including age at bilateral prophylactic oophorectomy if applicable. RESULTS: Breast cancer was diagnosed in two (1.9%) of 105 women who had bilateral prophylactic mastectomy and in 184 (48.7%) of 378 matched controls who did not have the procedure, with a mean follow-up of 6.4 years. Bilateral prophylactic mastectomy reduced the risk of breast cancer by approximately 95% in women with prior or concurrent bilateral prophylactic oophorectomy and by approximately 90% in women with intact ovaries. CONCLUSION: Bilateral prophylactic mastectomy reduces the risk of breast cancer in women with BRCA1/2 mutations by approximately 90%..
Angèle, S.
Falconer, A.
Edwards, S.M.
Dörk, T.
Bremer, M.
Moullan, N.
Chapot, B.
Muir, K.
Houlston, R.
Norman, A.R.
Bullock, S.
Hope, Q.
Meitz, J.
Dearnaley, D.
Dowe, A.
Southgate, C.
Ardern-Jones, A.
Easton, D.F.
Eeles, R.A.
Hall, J.
(2004). ATM polymorphisms as risk factors for prostate cancer development. Br j cancer,
Vol.91
(4),
pp. 783-787.
show abstract
The risk of prostate cancer is known to be elevated in carriers of germline mutations in BRCA2, and possibly also in carriers of BRCA1 and CHEK2 mutations. These genes are components of the ATM-dependent DNA damage signalling pathways. To evaluate the hypothesis that variants in ATM itself might be associated with prostate cancer risk, we genotyped five ATM variants in DNA from 637 prostate cancer patients and 445 controls with no family history of cancer. No significant differences in the frequency of the variant alleles at 5557G>A (D1853N), 5558A>T (D1853V), ivs38-8t>c and ivs38-15g>c were found between the cases and controls. The 3161G (P1054R) variant allele was, however, significantly associated with an increased risk of developing prostate cancer (any G vs CC OR 2.13, 95% CI 1.17-3.87, P=0.016). A lymphoblastoid cell line carrying both the 3161G and the 2572C (858L) variant in the homozygote state shows a cell cycle progression profile after exposure to ionising radiation that is significantly different to that seen in cell lines carrying a wild-type ATM gene. These results provide evidence that the presence of common variants in the ATM gene, may confer an altered cellular phenotype, and that the ATM 3161C>G variant might be associated with prostate cancer risk..
Kadouri, L.
Kote-Jarai, Z.
Hubert, A.
Durocher, F.
Abeliovich, D.
Glaser, B.
Hamburger, T.
Eeles, R.A.
Peretz, T.
(2004). A single-nucleotide polymorphism in the RAD51 gene modifies breast cancer risk in BRCA2 carriers, but not in BRCA1 carriers or noncarriers. Br j cancer,
Vol.90
(10),
pp. 2002-2005.
show abstract
Variation in the penetrance estimates for BRCA1 and BRCA2 mutation carriers suggests that other genetic polymorphisms may modify the cancer risk in carriers. The RAD51 gene, which participates in homologous recombination double-strand breaks (DSB) repair in the same pathway as the BRCA1 and BRCA2 gene products, is a candidate for such an effect. A single-nucleotide polymorphism (SNP), RAD51-135g-->c, in the 5' untranslated region of the gene has been found to elevate breast cancer (BC) risk among BRCA2 carriers. We genotyped 309 BRCA1/2 mutation carriers, of which 280 were of Ashkenazi origin, 166 noncarrier BC patients and 152 women unaffected with BC (a control group), for the RAD51-135g-->c SNP. Risk analyses were conducted using COX proportional hazard models for the BRCA1/2 carriers and simple logistic regression analysis for the noncarrier case-control population. BRCA2 carriers were also studied using logistic regression and Kaplan-Meier survival analyses. The estimated BC hazard ratio (HR) for RAD51-135c carriers adjusted for origin (Ashkenazi vs non-Ashkenazi) was 1.28 (95% CI 0.85-1.90, P=0.23) for BRCA1/2 carriers, and 2.09 (95% CI 1.04-4.18, P=0.04) when the analysis was restricted to BRCA2 carriers. The median BC age was younger in BCRA2-RAD51-135c carriers (45 (95% CI 36-54) vs 52 years (95% CI 48-56), P=0.05). In a logistic regression analysis, the odds ratio (OR) was 5.49 (95% CI 0.5-58.8, P=0.163). In noncarrier BC cases, carrying RAD51-135c was not associated with BC risk (0.97; 95% CI 0.47-2.00). These results indicate significantly elevated risk for BC in carriers of BRCA2 mutations who also carry a RAD51-135c allele. In BRCA1 carriers and noncarriers, no effect for this SNP was found..
Kadouri, L.
Kote-Jarai, Z.
Easton, D.F.
Hubert, A.
Hamoudi, R.
Glaser, B.
Abeliovich, D.
Peretz, T.
Eeles, R.A.
(2004). Polyglutamine repeat length in the AIB1 gene modifies breast cancer susceptibility in BRCA1 carriers. Int j cancer,
Vol.108
(3),
pp. 399-403.
show abstract
Variation in the penetrance estimates for BRCA1 and BRCA2 mutation carriers suggests that other factors may modify cancer risk from specific mutations. One possible mechanism is an epigenetic effect of polymorphisms in other genes. Genes involved in hormonal signal transduction are possible candidates. The AIB1 gene, an estrogen receptor (ER) coactivator, is frequently amplified in breast and ovarian tumors. Variation of a CAG repeat length has been reported within this gene that encodes a polyglutamine repeat in the C-terminus of the protein. Three hundred eleven BRCA1/2 mutation carriers (257 were of Ashkenazi origin) were genotyped for the AIB1 polyglutamine repeat. Relative risks (RR) were estimated using a maximum likelihood approach. The estimated breast cancer (BC) RR per average repeat length adjusted for population type (Ashkenazi vs. non-Ashkenazi) was 1.15 (95% CI = 1.02-1.30; p = 0.01) for BRCA1/2 carriers, and 1.25 (95% CI = 1.09-1.42; p = 0.001) when analysis was restricted to BRCA1 carriers. RR of BC was 1.17 (95% CI = 0.91-1.74), for individuals with 2 alleles >/=29 polyglutamine repeats and 0.78 (95% CI = 0.50-1.16) for those with at least 1 allele of /=29 repeats respectively (p = 0.025). These results indicate significant association of the risk for BC in carriers of BRCA1 mutations with the polyglutamine chain of the AIB1 gene. Longer repeat length correlates with elevated risk, whereas in carriers of a shorter AIB1 allele BC risk was reduced. The AIB1 polyglutamine length did not affect BC risk among BRCA2 mutation carriers..
Sodha, N.
Wilson, C.
Bullock, S.L.
Phillimore, H.
Houlston, R.S.
Eeles, R.A.
(2004). Analysis of familial male breast cancer for germline mutations in CHEK2. Cancer lett,
Vol.215
(2),
pp. 187-189.
show abstract
We have previously shown that the1100delC variant of the cell-cycle-checkpoint kinase gene CHEK2, which is carried by approximately 1% of the population confers a two-fold increase in female breast cancer and a 10-fold increase in male breast cancer. To extend our knowledge on the role of CHEK2 in susceptibility to male breast cancer we have screened a series of 26 breast cancer cases with male representation for germline sequence variation in the CHEK2 gene. One individual was found to harbour the 1100delC variant. No other mutations were identified. Variants other than 1100delC are rare in male breast cancer..
Murday, V.
Pears, R.
Ball, J.
Eeles, R.
Hodgson, S.
(2004). An audit of screening for familial breast cancer before 50 years in the South Thames Region - have we got it right?. Fam cancer,
Vol.3
(1),
pp. 29-34.
show abstract
We have carried out an audit of breast screening by mammography under 50 years of age in a cohort of 192 women attending family cancer clinics run by the South Thames genetic services. Of these women, six came from families in which a BRCA mutation had been identified, 61 had > 50%, 35 a 20-50% and 90 had < 20% chance of carrying a high risk mutation. In the 192 women in the screened cohort, 9 breast cancers were diagnosed (4.7%), all in high-risk women. Three were diagnosed at the prevalence screen. Three were detected mammographically at subsequent screening rounds; three were detected by breast self-examination (BSE) between screening episodes. One interval cancer was visible on mammogram at presentation but not at screening five months previously. A second cancer was also visible on mammogram at presentation but the normal screening mammogram had been 17 months earlier, outside the recommended interval. The remaining interval cancer was not visible on the mammogram. A total of 363 two-view screening mammograms were performed in the 280 person-years of follow-up; 109 additional investigations were generated: 23 recall mammograms, 18 symptomatic mammograms, 45 ultrasounds, 12 aspiration cytologies and 11 biopsies. Cytology diagnosed malignancy in 1 of 12 cases; breast biopsy in 9 of 11 cases. Twenty-three additional women had ultrasound screening only. This audit suggests that screening below the age 50 years may be unnecessary in families with a low chance of having a BRCA1 or -2 mutation, but it is important to screen high-risk women at least annually and possibly under 35 years..
Edwards, S.M.
Kote-Jarai, Z.
Meitz, J.
Hamoudi, R.
Hope, Q.
Osin, P.
Jackson, R.
Southgate, C.
Singh, R.
Falconer, A.
Dearnaley, D.P.
Ardern-Jones, A.
Murkin, A.
Dowe, A.
Kelly, J.
Williams, S.
Oram, R.
Stevens, M.
Teare, D.M.
Ponder, B.A.
Gayther, S.A.
Easton, D.F.
Eeles, R.A.
Cancer Research UK/Bristish Prostate Group UK Familial Prostate Cancer Study Collaborators,
British Association of Urological Surgeons Section of Oncology,
(2003). Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am j hum genet,
Vol.72
(1),
pp. 1-12.
show abstract
Studies of families with breast cancer have indicated that male carriers of BRCA2 mutations are at increased risk of prostate cancer, particularly at an early age. To evaluate the contribution of BRCA2 mutations to early-onset prostate cancer, we screened the complete coding sequence of BRCA2 for germline mutations, in 263 men with diagnoses of prostate cancer who were
Edwards, S.
Meitz, J.
Hope, Q.
Bullock, S.
Hamoudi, R.
Ardern-Jones, A.
Southgate, C.
Dowe, A.
Coleman, K.
Dearnaley, D.
Eeles, R.
Evans, C.
Teare, M.D.
Easton, D.
Hopper, J.
Giles, G.
English, D.
Southey, M.
Foulkes, W.D.
Hamel, N.
Narod, S.
Simard, J.
Badzioch, M.
Amos, C.
Heimdal, K.
Mahle, L.
Moller, P.
Wessel, N.
Andersen, T.
Bishop, T.
(2003). Results of a genome-wide linkage analysis in prostate cancer families ascertained through the ACTANE consortium. Prostate,
Vol.57
(4),
pp. 270-10.
Hallowell, N.
Foster, C.
Eeles, R.
Ardern-Jones, A.
Murday, V.
Watson, M.
(2003). Balancing autonomy and responsibility: the ethics of generating and disclosing genetic information. Journal of medical ethics,
Vol.29
(2),
pp. 74-6.
Kote-Jarai, Z.
Singh, R.
Durocher, F.
Easton, D.
Edwards, S.M.
Ardern-Jones, A.
Dearnaley, D.P.
Houlston, R.
Kirby, R.
Eeles, R.
(2003). Association between leptin receptor gene polymorphisms and early-onset prostate cancer. Bju int,
Vol.92
(1),
pp. 109-112.
show abstract
OBJECTIVE: To report a case-control study examining the relationship between polymorphisms in the leptin receptor (OBR) gene and the development of young-onset prostate cancer, because epidemiological studies report that prostate cancer risk is associated with animal fat intake, and thus we investigated if this association occurs via this genetic mechanism. PATIENTS, SUBJECTS AND METHODS: The Lys109Arg (OBR1) and Gln223Arg (OBR2) polymorphisms in the coding region of OBR were studied in blood DNA from 271 patients with prostate cancer aged < 56 years at diagnosis and 277 geographically matched control subjects. Cases were collected through the Cancer Research UK/British Prostate Group Familial Prostate Cancer Study. Blood DNA was genotyped using the polymerase chain reaction and a restriction enzyme digest. RESULTS: There was no statistically significant association between the OBR genotype and prostate cancer risk; men homozygous for 109Arg genotype had a slightly increased risk for prostate cancer, with a relative risk (95% confidence interval) of 1.36 (0.65-2.85), and those homozygous for the 223Arg allele had some reduction in prostate cancer risk, at 0.82 (0.58-1.26), but neither was statistically significant. CONCLUSION: This case-control study showed no significant association between leptin receptor gene polymorphisms and the risk of young-onset prostate cancer, suggesting that genetic variations in OBR are unlikely to have a major role in the development of early-onset prostate cancer in the UK..
Kenen, R.
Ardern-Jones, A.
Eeles, R.
(2003). Family stories and the use of heuristics: women from suspected hereditary breast and ovarian cancer (HBOC) families. Sociology of health & illness,
Vol.25
(7),
pp. 838-28.
Kenen, R.
Ardern-Jones, A.
Eeles, R.
(2003). Living with chronic risk: healthy women with a family history of breast/ovarian cancer. Health risk & society,
Vol.5
(3),
pp. 315-17.
Lintz, K.
Moynihan, C.
Steginga, S.
Norman, A.
Eeles, R.
Huddart, R.
Dearnaley, D.
Watson, M.
(2003). Prostate cancer patients' support and psychological care needs: Survey from a non-surgical oncology clinic. Psychooncology,
Vol.12
(8),
pp. 769-783.
show abstract
While there are numerous uncertainties surrounding prostate cancer's detection and treatment, more research focusing on the psychological needs of prostate patients is required. This study investigated the support and psychological care needs of men with prostate cancer. Patients were approached during urological oncology clinics and asked to complete the: Support Care Needs Survey (SCNS), Support Care Preferences Questionnaire, EORTC QLQ-C30 (Version 3) Measure plus Prostate Module, and the Hospital Anxiety and Depression Scale (HADS). Of the 249 patients meeting study entry criteria, there was an 89% response rate resulting in a cohort of 210 patients. The data showed that significant unmet need exists across a number of domains in the areas of psychological and health system/information. The more commonly reported needs were 'fears about cancer spreading (44%),' 'concerns about the worries of those close to you (43%),' and 'changes in sexual feelings (41%).' Half of all patients reported some need in the domain of sexuality, especially men younger than 65 years. Needs were being well met in the domain of patient care and support. A significant number of patients reported having used or desiring support services, such as information about their illness, brochures about services and benefits for patients with cancer (55%), a series of talks by staff members about aspects of prostate cancer (44%), and one-on-one counselling (48%). Quality of life (QoL) was most negatively impacted in those who: were < or =65 years old, had been diagnosed within one year, or had metastatic disease. Men < or =65 had decreased social functioning, greater pain, increased sleep disturbance, and were more likely to be uncomfortable about being sexually intimate. Patients recently diagnosed had increased fatigue, more frequent urination, greater disturbance of sleep, and were more likely to have hot flushes. Those with advanced disease scored lower on 12 out of 15 QoL categories. PSA level had no effect on QoL or anxiety/depression scores. Men with advanced disease had greater levels of depression and those < or =65 years old were more likely to be anxious. Although most men with prostate cancer seem to function quite well, a substantial minority report areas of unmet need that may be targets for improving care..
Olivier, M.
Goldgar, D.E.
Sodha, N.
Ohgaki, H.
Kleihues, P.
Hainaut, P.
Eeles, R.A.
(2003). Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer res,
Vol.63
(20),
pp. 6643-6650.
show abstract
A database has been created to collect information on families carrying a germ-line mutation in the TP53 gene and on families affected with Li-Fraumeni syndromes [Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL)]. Data from the published literature have been included. The database is available online at http://www.iarc.fr/p53, as part of the IARC TP53 Database. The analysis of the 265 families/individuals that have been included thus far has revealed several new findings. In classical LFS families with a germ-line TP53 mutation (83 families), the mean age of onset of breast cancer was significantly lower than in LFS families (16 families) without a TP53 mutation (34.6 versus 42.5 years; P = 0.0035). In individuals with a TP53 mutation, a correlation between the genotype and phenotype was found. Brain tumors were associated with missense TP53 mutations located in the DNA-binding loop that contact the minor groove of DNA (P = 0.01), whereas adrenal gland carcinomas were associated with missense mutations located in the loops opposing the protein-DNA contact surface (P = 0.003). Finally, mutations likely to result in a null phenotype (absence of the protein or loss of function) were associated with earlier onset brain tumors (P = 0.004). These observations have clinical implications for genetic testing and tumor surveillance in LFS/LFL families..
Bevan, S.
Edwards, S.M.
Ardern Jones, A.
Dowe, A.
Southgate, C.
Dearnaley, D.
Easton, D.F.
Houlston, R.S.
Eeles, R.A.
CRC/BPG UK Familial Prostate Cancer Study Collaborators,
(2003). Germline mutations in fumarate hydratase (FH) do not predispose to prostate cancer. Prostate cancer prostatic dis,
Vol.6
(1),
pp. 12-14.
show abstract
Inherited susceptibility to prostate cancer has been linked to a number of chromosomal regions, however no genes have been unequivocally shown to underlie reported linkages. The putative gene localised to chromosome 1q42-q43, has been designated PCaP. We have recently shown that germline mutations in the fumarate hydratase (FH) gene located on 1q43 cause smooth muscle tumours and renal cell carcinoma. It is conceivable that germline FH mutations might confer an increased risk of prostate cancer and underlie linkage of prostate cancer to PCaP. To examine this proposition we have analysed the entire coding region of FH in 160 prostate cancer cases in 77 multiple case families. No pathogenic mutations in FH were identified in any of the cases. This data makes it highly unlikely that mutations in FH confer susceptibility to prostate cancer..
Warren, R.M.
Pointon, L.
Caines, R.
Hayes, C.
Thompson, D.
Leach, M.O.
(2002). What is the recall rate of breast MRI when used for screening asymptomatic women at high risk?. Magnetic resonance imaging,
Vol.20
(7),
pp. 557-9.
Yuille, M.
Condie, A.
Hudson, C.
Kote-Jarai, Z.
Stone, E.
Eeles, R.
Matutes, E.
Catovsky, D.
Houlston, R.
(2002). Relationship between glutathione S-transferase M1, T1, and P1 polymorphisms and chronic lymphocytic leukemia. Blood,
Vol.99
(11),
pp. 4216-4218.
show abstract
Interindividual differences in susceptibility to hematologic malignancies may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The glutathione S-transferases (GSTs) have been implicated as susceptibility genes in this context for a number of cancers. The aim of this study was to examine whether polymorphic variation in GSTs confers susceptibility to chronic lymphocytic leukemia (CLL). GSTM1, GSTT1, and GSTP1 genotypes were determined in 138 patients and 280 healthy individuals. The frequency of both GSTM1 and GSTT1 null genotypes and the GSTP1-Ile allele was higher in cases than in controls. There was evidence of a trend in increasing risk with the number of putative "high-risk" alleles of the GST family carried (P =.04). The risk of CLL associated with possession of all 3 "high-risk" genotypes was increased 2.8-fold (OR = 2.8, 95% confidence interval: 1.1-6.9). Our findings suggest that heritable GST status may influence the risk of developing CLL..
Sodha, N.
Houlston, R.S.
Williams, R.
Yuille, M.A.
Mangion, J.
Eeles, R.A.
(2002). A robust method for detecting CHK2/RAD53 mutations in genomic DNA. Hum mutat,
Vol.19
(2),
pp. 173-177.
show abstract
While screening for germline CHK2 mutations in cancer cases by heteroduplex CSGE, we observed that additional PCR fragments were generated from the 3' end region of the gene that includes exons 11-14. Direct sequencing of these fragments suggested that homologous loci (possibly pseudogenes) were concomitantly being amplified. Searches of public sequence databases showed that a number of areas of the genome show a high degree of homology to exons 10-14 of the CHK2 gene. The presence of these homologous regions means that standard screening methods for detecting mutations in CHK2, based on PCR of genomic DNA, are prone to error. To circumvent this problem, we have developed a strategy, based on long-range PCR, to screen the functional copy of CHK2. Using this approach it is possible to carry out a comprehensive mutational analysis of CHK2 from genomic DNA..
Sodha, N.
Bullock, S.
Taylor, R.
Mitchell, G.
Guertl-Lackner, B.
Williams, R.D.
Bevan, S.
Bishop, K.
McGuire, S.
Houlston, R.S.
Eeles, R.A.
(2002). CHEK2 variants in susceptibility to breast cancer and evidence of retention of the wild type allele in tumours. Br j cancer,
Vol.87
(12),
pp. 1445-1448.
show abstract
We have recently shown that the CHEK2*1100delC mutation acts as a low penetrance breast cancer susceptibility allele. To investigate if other CHEK2 variants confer an increased risk of breast cancer, we have screened an affected individual with breast cancer from 68 breast cancer families. Five of these individuals were found to harbour germline variants in CHEK2. Three carried the 1100delC variant (4%). One of these three individuals also carried the missense variant, Arg180His. In the other two individuals, missense variants, Arg117Gly and Arg137Gln, were identified. These two missense variants reside within the Forkhead-associated domain of CHEK2, which is important for the function of the expressed protein. None of these missense variants were present in 300 healthy controls. Microdissected tumours with a germline mutation showed loss of the mutant allele suggesting a mechanism for tumorigenesis other than a loss of the wild type allele. This study provides further evidence that sequence variation in CHEK2 is associated with an increased risk of breast cancer, and implies that tumorigenesis in association with CHEK2 mutations does not involve loss of the wild type allele..
Ardern-Jones, A.
Eeles, R.
(2002). Forum for Applied Cancer Education and Training (FACET). Eur j cancer care (engl),
Vol.11
(1),
pp. 63-68.
Meijers-Heijboer, H.
van den Ouweland, A.
Klijn, J.
Wasielewski, M.
de Snoo, A.
Oldenburg, R.
Hollestelle, A.
Houben, M.
Crepin, E.
van Veghel-Plandsoen, M.
Elstrodt, F.
van Duijn, C.
Bartels, C.
Meijers, C.
Schutte, M.
McGuffog, L.
Thompson, D.
Easton, D.F.
Sodha, N.
Seal, S.
Barfoot, R.
Mangion, J.
Chang-Claude, J.
Eccles, D.
Eeles, R.
Evans, D.G.
Houlston, R.
Murday, V.
Narod, S.
Peretz, T.
Peto, J.
Phelan, C.
Zhang, H.X.
Szabo, C.
Devilee, P.
Goldgar, D.
Futreal, P.A.
Nathanson, K.L.
Weber, B.L.
Rahman, N.
Stratton, M.R.
(2002). Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature genetics,
Vol.31
(1),
pp. 55-5.
Meitz, J.C.
Edwards, S.M.
Easton, D.F.
Murkin, A.
Ardern-Jones, A.
Jackson, R.A.
Williams, S.
Dearnaley, D.P.
Stratton, M.R.
Houlston, R.S.
Eeles, R.A.
Cancer Research UK/BPG UK Familial Prostate Cancer Study Collaborators,
(2002). HPC2/ELAC2 polymorphisms and prostate cancer risk: analysis by age of onset of disease. Br j cancer,
Vol.87
(8),
pp. 905-908.
show abstract
The candidate prostate cancer susceptibility gene HPC2/ELAC2 has two common coding polymorphisms: (Ser-->Leu 217) and (Ala-->Thr 541). The Thr541 variant in the HPC2/ELAC2 gene has previously been reported to be at an increased frequency in prostate cancer cases. To evaluate this hypothesis we genotyped 432 prostate cancer patients (including 262 patients diagnosed 55 years (OR=1.27, 95% CI 0.59-2.74). We conclude that any association between the Thr541 variant and prostate cancer is likely to be weak..
Foster, C.
Watson, M.
Moynihan, C.
Ardern-Jones, A.
Eeles, R.
(2002). Genetic testing for breast and ovarian cancer predisposition: Cancer burden and responsibility. Journal of health psychology,
Vol.7
(4),
pp. 469-16.
Leach, M.O.
Eeles, R.A.
Turnbull, L.W.
Dixon, A.K.
Brown, J.
Hoff, R.J.
Coulthard, A.
Dixon, J.M.
Easton, D.F.
Evans, D.G.
Gilbert, F.J.
Hawnaur, J.
Hayes, C.
Kessar, P.
Lakhani, S.
Liney, G.
Moss, S.M.
Padhani, A.P.
Pointon, L.J.
Sydenham, M.
Walker, L.G.
Warren, R.M.
Haites, N.E.
Morrison, P.
Cole, T.
Rayter, Z.
Donaldson, A.
Shere, M.
Rankin, J.
Goudie, D.
Steel, C.M.
Davidson, R.
Chu, C.
Ellis, I.
Mackay, J.
Hodgson, S.V.
Homfray, T.
Douglas, F.
Quarrell, O.W.
Eccles, D.M.
Gilbert, F.G.
Crothers, G.
Walker, C.P.
Jones, A.
Slack, N.
Britton, P.
Sheppard, D.G.
Walsh, J.
Whitehouse, G.
Teh, W.
Rankin, S.
Boggis, C.
Potterton, J.
McLean, L.
Gordon, P.A.
Rubin, C.
Magnetic Resonance Imaging as a Method of Screening for Breast Cancer Advisory Group,
(2002). The UK national study of magnetic resonance imaging as a method of screening for breast cancer (MARIBS). J exp clin cancer res,
Vol.21
(3 Suppl),
pp. 107-114.
show abstract
The UK national study of magnetic resonance imaging as a method of screening for breast cancer (MARIBS) is in progress. The study design, accrual to date, and related research projects are described. Revised accrual rates and expected recruitment are given. 15 cancers have been detected to date, from a total of 1236 screening measurements. This event rate and the tumour grades reported are compared with recent reports from other studies in women at high risk of breast cancer..
Degenhard, A.
Tanner, C.
Hayes, C.
Hawkes, D.J.
Leach, M.O.
UK MRI Breast Screening Study,
(2002). Comparison between radiological and artificial neural network diagnosis in clinical screening. Physiol meas,
Vol.23
(4),
pp. 727-739.
show abstract
The imaging protocol of the UK multicentre magnetic resonance imaging study for screening in women at genetic risk of breast cancer aims to assist in detecting and diagnosing malignant breast lesions. In this paper, we evaluate a three-layer, feed-forward, backpropagation neural network as an artificial radiological classifier using receiver operating characteristic (ROC) curve analysis and compare the results with those obtained using a proposed radiological scoring system for the study which currently supplements the radiologist's clinical opinion, in comparison with histological diagnosis. Based on the 76 symptomatic cases evaluated, descriptive features scored by radiologists showed considerable overlap between benign and malignant, although some features such as irregular contours and heterogeneous enhancement were more often associated with malignant pathology. In this preliminary evaluation, ROC analysis showed that the proposed scoring scheme did not perform well, indicating further refinement is required. When all 23 features were used in the neural network, its performance was poorer than that of the scoring scheme. When only ten features were used, limited to descriptors of enhancement characteristics, the neural network performed similar to the scoring scheme. This comparison shows that the neural network approach to clinical diagnosis has considerable potential and warrants further development..
Sodha, N.
Houlston, R.S.
Bullock, S.
Yuille, M.A.
Chu, C.
Turner, G.
Eeles, R.A.
(2002). Increasing evidence that germline mutations in CHEK2 do not cause Li-Fraumeni syndrome. Hum mutat,
Vol.20
(6),
pp. 460-462.
McCarron, S.L.
Edwards, S.
Evans, P.R.
Gibbs, R.
Dearnaley, D.P.
Dowe, A.
Southgate, C.
Easton, D.F.
Eeles, R.A.
Howell, W.M.
(2002). Influence of cytokine gene polymorphisms on the development of prostate cancer. Cancer res,
Vol.62
(12),
pp. 3369-3372.
show abstract
Polymorphisms in the promoter regions of cytokine genes may influence prostate cancer (PC) development via regulation of the antitumor immune response and/or pathways of tumor angiogenesis. PC patients (247) and 263 controls were genotyped for interleukin (IL)-1beta-511, IL-8-251, IL-10-1082, tumor necrosis factor-alpha-308, and vascular endothelial growth factor (VEGF)-1154 single nucleotide polymorphisms. Patient control comparisons revealed that IL-8 TT and VEGF AA genotypes were decreased in patients compared with controls [23.9 versus 32.3%; P = 0.04, odds ratio (OR) = 0.66, 95% confidence interval (CI) 0.44-0.99 and 6.3 versus 12.9%; P = 0.01, OR = 0.45, 95% CI 0.24-0.86, respectively], whereas the IL-10 AA genotype was significantly increased in patients compared with controls (31.6 versus 20.6%; P = 0.01, OR = 1.78, 95% CI 1.14-2.77). Stratification according to prognostic indicators showed association between IL-8 genotype and log prostate-specific antigen level (P = 0.05). These results suggest that single nucleotide polymorphisms associated with differential production of IL-8, IL-10, and VEGF are risk factors for PC, possibly acting via their influence on angiogenesis..
Thompson, D.
Szabo, C.I.
Mangion, J.
Oldenburg, R.A.
Odefrey, F.
Seal, S.
Barfoot, R.
Kroeze-Jansema, K.
Teare, D.
Rahman, N.
Renard, H.
Mann, G.
Hopper, J.L.
Buys, S.S.
Andrulis, I.L.
Senie, R.
Daly, M.B.
West, D.
Ostrander, E.A.
Offit, K.
Peretz, T.
Osorio, A.
Benitez, J.
Nathanson, K.L.
Sinilnikova, O.M.
Olàh, E.
Bignon, Y.-.
Ruiz, P.
Badzioch, M.D.
Vasen, H.F.
Futreal, A.P.
Phelan, C.M.
Narod, S.A.
Lynch, H.T.
Ponder, B.A.
Eeles, R.A.
Meijers-Heijboer, H.
Stoppa-Lyonnet, D.
Couch, F.J.
Eccles, D.M.
Evans, D.G.
Chang-Claude, J.
Lenoir, G.
Weber, B.L.
Devilee, P.
Easton, D.F.
Goldgar, D.E.
Stratton, M.R.
KConFab Consortium,
(2002). Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium. Proc natl acad sci u s a,
Vol.99
(2),
pp. 827-831.
show abstract
full text
The known susceptibility genes for breast cancer, including BRCA1 and BRCA2, only account for a minority of the familial aggregation of the disease. A recent study of 77 multiple case breast cancer families from Scandinavia found evidence of linkage between the disease and polymorphic markers on chromosome 13q21. We have evaluated the contribution of this candidate "BRCA3" locus to breast cancer susceptibility in 128 high-risk breast cancer families of Western European ancestry with no identified BRCA1 or BRCA2 mutations. No evidence of linkage was found. The estimated proportion (alpha) of families linked to a susceptibility locus at D13S1308, the location estimated by Kainu et al. [(2000) Proc. Natl. Acad. Sci. USA 97, 9603-9608], was 0 (upper 95% confidence limit 0.13). Adjustment for possible bias due to selection of families on the basis of linkage evidence at BRCA2 did not materially alter this result (alpha = 0, upper 95% confidence limit 0.18). The proportion of linked families reported by Kainu et al. (0.65) is excluded with a high degree of confidence in our dataset [heterogeneity logarithm of odds (HLOD) at alpha = 0.65 was -11.0]. We conclude that, if a susceptibility gene does exist at this locus, it can only account for a small proportion of non-BRCA1/2 families with multiple cases of early-onset breast cancer..
Foster, C.
Evans, D.G.
Eeles, R.
Eccles, D.
Ashley, S.
Brooks, L.
Davidson, R.
Mackay, J.
Morrison, P.J.
Watson, M.
(2002). Predictive testing for BRCA1/2: attributes, risk perception and management in a multi-centre clinical cohort. British journal of cancer,
Vol.86
(8),
pp. 1209-8.
Rebbeck, T.R.
Lynch, H.T.
Neuhausen, S.L.
Narod, S.A.
Van't Veer, L.
Garber, J.E.
Evans, G.
Isaacs, C.
Daly, M.B.
Matloff, E.
Olopade, O.I.
Weber, B.L.
Prevention and Observation of Surgical End Points Study Group,
(2002). Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N engl j med,
Vol.346
(21),
pp. 1616-1622.
show abstract
BACKGROUND: Data concerning the efficacy of bilateral prophylactic oophorectomy for reducing the risk of gynecologic cancer in women with BRCA1 or BRCA2 mutations are limited. We investigated whether this procedure reduces the risk of cancers of the coelomic epithelium and breast in women who carry such mutations. METHODS: A total of 551 women with disease-associated germ-line BRCA1 or BRCA2 mutations were identified from registries and studied for the occurrence of ovarian and breast cancer. We determined the incidence of ovarian cancer in 259 women who had undergone bilateral prophylactic oophorectomy and in 292 matched controls who had not undergone the procedure. In a subgroup of 241 women with no history of breast cancer or prophylactic mastectomy, the incidence of breast cancer was determined in 99 women who had undergone bilateral prophylactic oophorectomy and in 142 matched controls. The length of postoperative follow-up for both groups was at least eight years. RESULTS: Six women who underwent prophylactic oophorectomy (2.3 percent) received a diagnosis of stage I ovarian cancer at the time of the procedure; two women (0.8 percent) received a diagnosis of papillary serous peritoneal carcinoma 3.8 and 8.6 years after bilateral prophylactic oophorectomy. Among the controls, 58 women (19.9 percent) received a diagnosis of ovarian cancer, after a mean follow-up of 8.8 years. With the exclusion of the six women whose cancer was diagnosed at surgery, prophylactic oophorectomy significantly reduced the risk of coelomic epithelial cancer (hazard ratio, 0.04; 95 percent confidence interval, 0.01 to 0.16). Of 99 women who underwent bilateral prophylactic oophorectomy and who were studied to determine the risk of breast cancer, breast cancer developed in 21 (21.2 percent), as compared with 60 (42.3 percent) in the control group (hazard ratio, 0.47; 95 percent confidence interval, 0.29 to 0.77). CONCLUSIONS: Bilateral prophylactic oophorectomy reduces the risk of coelomic epithelial cancer and breast cancer in women with BRCA1 or BRCA2 mutations..
Mitchell, G.
Sibley, P.E.
Wilson, A.P.
Sauter, E.
A'Hern, R.
Eeles, R.A.
(2002). Prostate-specific antigen in nipple aspiration fluid: menstrual cycle variability and correlation with serum prostate-specific antigen. Tumour biol,
Vol.23
(5),
pp. 287-297.
show abstract
OBJECTIVES: To determine the variability of prostate-specific antigen (PSA) in the breast ductal fluid (nipple aspiration fluid, NAF) during the menstrual cycles of healthy premenopausal women. METHODS: Fifteen female volunteers underwent weekly nipple aspiration of ductal fluid from both breasts for the duration of two menstrual cycles. A highly sensitive and specific Third Generation PSA Assay (IMMULITE); Diagnostic Products Corporation, DPC) was used to detect NAF and serum PSA. Associations between NAF PSA and paired serum hormone levels of the pituitary-ovarian axis were tested using the Spearman rank correlation and the Wilcoxon signed rank test. Analysis of variance on log transformed NAF PSA was used to determine the intra- and intervolunteer variability. RESULTS: NAF PSA ranged from <0.003 to 133,330 ng PSA/g total protein (median 2,030 ng/g). No repeatable pattern of change was observed for individual volunteers and no significant association between NAF PSA and any pituitary-ovarian axis serum hormone was detected. There was no correlation between serum and NAF PSA. CONCLUSIONS: Weekly NAF sampling in healthy premenopausal women to provide adequate volumes for PSA analysis was successfully achieved. Considerable variation was observed for NAF PSA, which may limit the future potential for this tumor marker in NAF. This variability was not associated with hormones of the pituitary-ovarian axis and did not show repeated cyclical variability during the menstrual cycle. Serum PSA does not appear to be an acceptable indicator of NAF PSA levels..
Kote-Jarai, Z.
Durocher, F.
Edwards, S.M.
Hamoudi, R.
Jackson, R.A.
Ardern-Jones, A.
Murkin, A.
Dearnaley, D.P.
Kirby, R.
Houlston, R.
Easton, D.F.
Eeles, R.
CRC/BPG UK Familial Prostrate Cancer Collaborators,
(2002). Association between the GCG polymorphism of the selenium dependent GPX1 gene and the risk of young onset prostate cancer. Prostate cancer prostatic dis,
Vol.5
(3),
pp. 189-192.
show abstract
Epidemiological studies have suggested an association between low selenium levels and the development of prostate cancer. Human cellular glutathione peroxidase I (hGPX1) is a selenium-dependent enzyme that protects against oxidative damage and its peroxidase activity is a plausible mechanism for cancer prevention by selenium. The GPX1 gene has a GCG repeat polymorphism in exon 1, coding for a polyalanine tract of five to seven alanine residues. To test if the GPX1 GCG repeat polymorphism associates with the risk of young-onset prostate cancer we conducted a case-control study. The GPX1Ala genotypes were determined for 267 prostate cancer cases and 260 control individuals using polymerase chain reaction (PCR) amplification with fluorescently labelled primers and an ABI 377 automated genotyper. Associations between specific genotypes and the risk of prostate cancer were examined by logistic regression. We found no significant association between the GPX1 genotypes and prostate cancer. There was however an increased frequency of the GPX1Ala6/Ala6 genotype in the prostate cancer cases compared to controls (OR: 1.67; 95% CI: 0.97-2.87). The result of this study suggests that the GPX1 genotype is unlikely to be associated with the risk of developing prostate cancer..
Hallowell, N.
Foster, C.
Ardern-Jones, A.
Eeles, R.
Murday, V.
Watson, M.
(2002). Genetic testing for women previously diagnosed with breast/ovarian cancer: examining the impact of BRCA1 and BRCA2 mutation searching. Genet test,
Vol.6
(2),
pp. 79-87.
show abstract
This study sought to investigate the impact of BRCA1 and BRCA2 mutation searching on women previously diagnosed with breast or ovarian cancer. In-depth interviews were undertaken with 30 women who had undergone a BRCA1 and BRCA2 mutation search within the clinical setting. The main reasons reported for undergoing mutation searching were: to provide genetic information for other family members, general altruism, curiosity about the aetiology of cancer, and to provide information to facilitate risk management decisions. In the main, the process of undergoing genetic testing was not experienced as anxiety provoking. The benefit of receiving a result confirming the presence of a genetic mutation was seen as an end to uncertainty, whereas the costs included difficulties in disclosing information to kin and potentially increased anxiety about one's own or others' cancer risks. Women receiving an inconclusive test result reported a range of emotional reactions. There was evidence that some women misunderstood the meaning of this result, interpreting it as definitive confirmation that a cancer-predisposing mutation was not present within the family. It is concluded that women with cancer who participate in BRCA1 and BRCA2 testing need to receive clear information about the meaning and implications of the different types of test results. Some recommendations for clinical practice are discussed..
Olivier, M.
Eeles, R.
Hollstein, M.
Khan, M.A.
Harris, C.C.
Hainaut, P.
(2002). The IARC TP53 database: New Online mutation analysis and recommendations to users. Human mutation,
Vol.19
(6),
pp. 607-8.
Jefferies, S.
Edwards, S.M.
Hamoudi, R.A.
A'Hern, R.
Foulkes, W.
Goldgar, D.
Eeles, R.
MPT Collaborators,
(2001). No germline mutations in CDKN2A (p16) in patients with squamous cell cancer of the head and neck and second primary tumours. Br j cancer,
Vol.85
(9),
pp. 1383-1386.
show abstract
There is increasing evidence that predisposition to some cancers has a genetic component. There is a high incidence of loss of heterozygosity on chromosome 9, in the region of tumour suppressor gene, CDKN2A (also known as p16), in sporadic squamous cell cancer of the head and neck (SCCHN). To investigate the possibility that CDKN2A may be involved in the inherited susceptibility to SCCHN, the 3 coding exons of CDKN2A were sequenced in 40 patients who had developed a second primary cancer after an index squamous cell cancer of the head and neck. No mutations were found and we conclude that CDKN2A mutations do not play a major role in cancer susceptibility in this group..
Thompson, D.
Easton, D.
Breast Cancer Linkage Consortium,
(2001). Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am j hum genet,
Vol.68
(2),
pp. 410-419.
show abstract
Cancer occurrence in 164 families with breast/ovarian cancer and germline BRCA2 mutations was studied to evaluate the evidence for genotype-phenotype correlations. Mutations in a central portion of the gene (the "ovarian cancer cluster region" [OCCR]) were associated with a significantly higher ratio of cases of ovarian:breast cancer in female carriers than were mutations 5' or 3' of this region (P<.0001), extending previous observations. The optimal definition of the OCCR, as judged on the basis of deviance statistics, was bounded by nucleotides 3059-4075 and 6503-6629. The relative and absolute risks of breast and ovarian cancer associated with OCCR and non-OCCR mutations were estimated by a conditional likelihood approach, conditioning on the set of mutations observed in the families. OCCR mutations were associated both with a highly significantly lower risk of breast cancer (relative risk [RR] 0.63; 95% confidence interval (95% CI) 0.46-0.84; P=.0012) and with a significantly higher risk of ovarian cancer (RR = 1.88; 95% CI = 1.08-3.33; P=.026). No other differences in breast or ovarian cancer risk, by mutation position, were apparent. There was some evidence for a lower risk of prostate cancer in carriers of an OCCR mutation (RR = 0.52; 95% CI = 0.24-1.00; P=.05), but there was no evidence of a difference in breast cancer risk in males. By age 80 years, the cumulative risk of breast cancer in male carriers of a BRCA2 mutation was estimated as 6.92% (95% CI = 1.20%-38.57%). Possible mechanisms for the variation in cancer risk are suggested by the coincidence of the OCCR with the RAD51-binding domain..
Edwards, S.M.
Kote-Jarai, Z.
Hamoudi, R.
Eeles, R.A.
(2001). An improved high throughput heteroduplex mutation detection system for screening BRCA2 mutations-fluorescent mutation detection (F-MD). Hum mutat,
Vol.17
(3),
pp. 220-232.
show abstract
We describe an improved, fast, automated method for screening large genes such as BRCA2 for germline genomic mutations. The method is based on heteroduplex analysis, and has been adapted for a high throughput application by combining the fluorescent technology of automated sequencers and robotic sample handling. This novel approach allows the entire BRCA2 gene to be screened with appropriate overlaps in four lanes of an ABI 377 gel. The method will detect all types of mutations, especially point mutations, more reliably and robustly than other commonly used conformational sensitive methods (e.g. CSGE). In addition we show that this approach, which relies on band shift detection, is able to detect single base substitutions that have hitherto only been detectable by direct sequencing methods..
Mitchell, G.
Trott, P.A.
Morris, L.
Coleman, N.
Sauter, E.
Eeles, R.A.
(2001). Cellular characteristics of nipple aspiration fluid during the menstrual cycle in healthy premenopausal women. Cytopathology,
Vol.12
(3),
pp. 184-196.
show abstract
Cellular characteristics of nipple aspiration fluid during the menstrual cycle in healthy premenopausal women Fifteen healthy premenopausal female volunteers underwent weekly nipple aspiration of ductal fluid from both breasts during two menstrual cycles to investigate the variability of the cellular profile of the ductal fluid. Ductal fluid was successfully obtained using breast massage and nipple-areolar suction from 247/280 (89%) breasts. 83% of samples available for cytological analysis were cellular and 30% of cellular aspirates contained ductal epithelial cells identified using standard morphological criteria. No significant variation in cell number or cell type was identified during the menstrual cycle. All samples tested had an 'H' score of zero for oestrogen receptor. Seven out of 14 women expressed the proliferation marker Mcm-2 in the cells of at least one of the specimens, with no evidence of a menstrual cycle influence on expression. In conclusion, the cellular profile of breast ductal fluid did not vary consistently during the menstrual cycle, permitting future breast cancer screening studies incorporating serial nipple aspirations to be performed independent of the phase of the cycle..
Kadouri, L.
Easton, D.F.
Edwards, S.
Hubert, A.
Kote-Jarai, Z.
Glaser, B.
Durocher, F.
Abeliovich, D.
Peretz, T.
Eeles, R.A.
(2001). CAG and GGC repeat polymorphisms in the androgen receptor gene and breast cancer susceptibility in BRCA1/2 carriers and non-carriers. Br j cancer,
Vol.85
(1),
pp. 36-40.
show abstract
Variation in the penetrance estimates for BRCA1 and BRCA2 mutations carriers suggests that other genetic polymorphisms may modify the cancer risk in carriers. A previous study has suggested that BRCA1 carriers with longer lengths of the CAG repeat in the androgen receptor (AR) gene are at increased risk of breast cancer (BC). We genotyped 188 BRCA1/2 carriers (122 affected and 66 unaffected with breast cancer), 158 of them of Ashkenazi origin, 166 BC cases without BRCA1/2 mutations and 156 Ashkenazi control individuals aged over 56 for the AR CAG and GGC repeats. In carriers, risk analyses were conducted using a variant of the log-rank test, assuming two sets of risk estimates in carriers: penetrance estimates based on the Breast Cancer Linkage Consortium (BCLC) studies of multiple case families, and lower estimates as suggested by population-based studies. We found no association of the CAG and GGC repeats with BC risk in either BRCA1/2 carriers or in the general population. Assuming BRCA1/2 penetrance estimates appropriate to the Ashkenazi population, the estimated RR per repeat adjusted for ethnic group (Ashkenazi and non-Ashkenazi) was 1.05 (95%CI 0.97-1.17) for BC and 1.00 (95%CI 0.83-1.20) for ovarian cancer (OC) for CAG repeats and 0.96 (95%CI 0.80-1.15) and 0.90 (95%CI 0.60-1.22) respectively for GGC repeats. The corresponding RR estimates for the unselected case-control series were 1.00 (95%CI 0.91-1.10) for the CAG and 1.05 (95%CI 0.90-1.22) for the GGC repeats. The estimated relative risk of BC in carriers associated with > or =28 CAG repeats was 1.08 (95%CI 0.45-2.61). Furthermore, no significant association was found if attention was restricted to the Ashkenazi carriers, or only to BRCA1 or BRCA2 carriers. We conclude that, in contrast to previous observations, if there is any effect of the AR repeat length on BRCA1 penetrance, it is likely to be weak..
Kote-Jarai, Z.
Easton, D.
Edwards, S.M.
Jefferies, S.
Durocher, F.
Jackson, R.A.
Singh, R.
Ardern-Jones, A.
Murkin, A.
Dearnaley, D.P.
Shearer, R.
Kirby, R.
Houlston, R.
Eeles, R.
CRC/BPG UK Familial Prostate Cancer Study Collaborators,
(2001). Relationship between glutathione S-transferase M1, P1 and T1 polymorphisms and early onset prostate cancer. Pharmacogenetics,
Vol.11
(4),
pp. 325-330.
show abstract
There is evidence suggesting that polymorphic variations in the glutathione S-transferases (GSTs) are associated with cancer susceptibility. Inter-individual differences in cancer susceptibility may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The GSTs have been consistently implicated as cancer susceptibility genes in this context. The GST supergene family includes several loci with well characterized polymorphisms. Approximately 50% of the Caucasian population are homozygous for deletions in GSTM1 and approximately 20% are homozygous for deletions in GSTT1, resulting in conjugation deficiency of mutagenic electrophiles to glutathione. The GSTP1 gene has a polymorphism at codon 105 resulting in an Ile to Val substitution which consequently alters the enzymatic activity of the protein and this has been suggested as a putative high-risk genotype in various cancers. We investigated the relationship between GST polymorphisms and young onset prostate cancer in a case-control study. GSTM1, GSTT1 and GSTP1 genotypes were determined for 275 prostate cancer patients and for 280 geographically matched control subjects. We found no significant difference in the frequency of GSTM1 or GSTT1 null genotypes between cases and controls. GSTP1 genotype was, however, significantly associated with prostate cancer risk: the Ile/Ile homozygotes had the lowest risk and there was a trend in increasing the risk with the number of 105 Val alleles: Ile/Val odds ratio (OR)= 1.30 (95% FCI 0.99-1.69), Val/Val OR = 1.80 (95% FCI 1.11-2.91); Ptrend = 0.026. These results suggest that the GSTP1 polymorphism may be a risk factor for developing young onset prostate cancer. We also found that carrying more than one putative high-risk allele in the carcinogen metabolizing GST family was associated with an elevated risk for early onset prostate cancer (OR 2.48, 95% FCI 1.22-5.04, Ptrend = 0.017)..
Gui, G.P.
Hogben, R.K.
Walsh, G.
A'Hern, R.
Eeles, R.
(2001). The incidence of breast cancer from screening women according to predicted family history risk: Does annual clinical examination add to mammography?. Eur j cancer,
Vol.37
(13),
pp. 1668-1673.
show abstract
In breast cancer, mutations of predisposition genes such as BRCA-1/2 and other genes as yet uncharacterised are manifest in up to 10% of cases. Although the prior probability of the presence of a breast cancer predisposing gene can be calculated for individual women, there is no published evidence to justify predicted risk as a selection criteria for screening. This study aims to define which patient groups with a significant family history should be screened, and whether clinical examination is necessary in addition to mammography. The Claus model was used to predict breast cancer risk in women with a family history. Women were divided into two groups according to their predicted risk: group I consisted of women at standard risk (lifetime risk less than 1:6) and group II with moderate/high risk (lifetime risk greater than or equal to 1:6). Women were cancer-free at the point of entry, and screening consisted of annual clinical examination and mammography from the age of 35 years. This study consisted of 1500 women in group I and 1078 in group II. The period of observation was 5902.0 and 4327.8 women years, respectively. A total of 31 cancers were detected, 12 in group I and 19 in group II. The median age at diagnosis in group II was 45 years (range 26-66 years) compared with 54.5 years (range 38-63 years) in group I (P=0.03). The relative risk of developing breast cancer in group II was 2.6 (95% confidence interval (CI) 1.2-5.8). When compared with breast cancer incidence in the normal population, the standardised incidence ratio in group II was significantly higher at 2.8 (95% CI: 1.7-4.2). The standardised incidence ratio of women in group I was similar to that of the general population (1.1 (95% CI: 0.6-1.8)). A total of 26/31 (84%) cancers detected were palpable, of which 14 (54%) were not visible on mammography. Approximately one-third of all palpable cancers were detected at routine follow-up. Mammography correctly identified 17/31 cancers (55%), but 29% of these were not palpable. Family history screening programmes are effective and women should be selected for screening according to predicted risk. The younger age of diagnosis in group II justifies screening from an earlier age using both annual clinical examination and mammography..
Wonderling, D.
Hopwood, P.
Cull, A.
Douglas, F.
Watson, M.
Burn, J.
McPherson, K.
(2001). A descriptive study of UK cancer genetics services: an emerging clinical response to the new genetics. Br j cancer,
Vol.85
(2),
pp. 166-170.
show abstract
The objective was to describe NHS cancer genetic counselling services and compare UK regions. The study design was a cross-sectional study over 4 weeks and attendee survey. The setting was 22 of the 24 regional cancer genetics services in the UK NHS. Participants were individuals aged over 18 attending clinics at these services. Outcome measures were staff levels, referral rates, consultation rates, follow-up plans, waiting time. There were only 11 dedicated cancer geneticists across the 22 centres. Referrals were mainly concerned with breast (63%), bowel (18%) and ovarian (12%) cancers. Only 7% of referrals were for men and 3% were for individuals from ethnic minorities. Referral rates varied from 76 to 410 per million per annum across the regions. Median waiting time for an initial appointment was 19 weeks, ranging across regions from 4 to 53 weeks. Individuals at population-level genetic risk accounted for 27% of consultations (range 0%, 58%). Shortfalls in cancer genetics staff and in the provision of genetic testing and cancer surveillance have resulted in large regional variations in access to care. Initiatives to disseminate referral and management guidelines to cancer units and primary care should be adequately resourced so that clinical genetics teams can focus on the genetic testing and management of high-risk families..
Mitchell, G.
Ardern-Jones, A.
Kissin Mchir, M.
Taylor, R.
Eeles, R.A.
(2001). A paradox: urgent BRCA genetic testing. Fam cancer,
Vol.1
(1),
pp. 25-29.
show abstract
Diagnostic or predictive testing for germline mutations in cancer predisposition genes is inherently slow as result of both genetic counselling and mutation analysis. The overall time taken for mutation testing is not generally perceived as harmful to the individual and may be positively beneficial in order to permit full reflection on the implication of the genetic test results. However, we present three cases where we considered urgent genetic testing for the presence of mutations in th BRCA 1 and 2 genes to be necessary as the test result would have altered the subsequent clinical management of these individuals or their families..
Lipton, L.
Thomas, H.J.
Eeles, R.A.
Houlston, R.S.
Longmuir, M.
Davison, R.
Hodgson, S.V.
Murday, V.A.
Norbury, C.G.
Taylor, C.
Tomlinson, I.P.
(2001). Apparent Mendelian inheritance of breast and colorectal cancer: chance, genetic heterogeneity or a new gene?. Fam cancer,
Vol.1
(3-4),
pp. 189-195.
show abstract
It is not uncommon for cancer geneticists to be referred families with apparently Mendelian co-inheritance of breast and bowel cancer. Such families present a particular problem as regards the intensity of their screening for these diseases and the utility of genetic testing. Many 'breast-colon' cancer families probably result from chance clustering of two common cancers. Other 'breast-colon' cancer families may result from known cancer syndromes, such as hereditary breast-ovarian cancer or hereditary non-polyposis colon cancer, either by conferring a high risk of one cancer type and a slightly increased risk of the other, or through a predisposition to one of the two cancers and chance occurrence of the other. Anecdotally, however, many geneticists wonder about the existence of a distinct 'breast-colon cancer syndrome', since some families present good a priori evidence of genetic disease and yet cannot readily be accounted for by known genes or chance. The identification of unknown 'breast-colon cancer' genes is likely to be difficult, relying primarily on candidate gene analysis, including loci separately implicated in breast or colorectal cancer, or in other multiple cancer syndromes. Studies such as those on APC I1307K and CHEK2 1100delC may suggest the way forward for the identification of 'breast-colon cancer' genes..
Sibtain, A.
Eeles, R.
Wellwood, J.
Plowman, P.N.
(2000). Simultaneous breast cancer in non-identical Ashkenazi Jewish twins: Management dilemmas when genetic testing is negative. Clinical oncology,
Vol.12
(5),
pp. 305-4.
Kote-Jarai, Z.
Powles, T.P.
Ashley, S.
Easton, D.F.
Assersohn, L.
Sodha, N.
Dowsett, M.
Gusterson, B.
Tidy, A.
Mitchell, G.
Eeles, R.A.
(2000). BRCA1, BRCA2 and pedigree genetic analysis to determine genetic risk in the UK Royal Marsden Hospital tamoxifen prevention trial. Breast cancer research : bcr,
Vol.2
(Suppl 1),
pp. P1.06-P1.06.
Camplejohn, R.S.
Sodha, N.
Gilchrist, R.
Lomax, M.E.
Duddy, P.M.
Miner, C.
Alarcon-Gonzalez, P.
Barnes, D.M.
Eeles, R.A.
(2000). The value of rapid functional assays of germline p53 status in LFS and LFL families. Br j cancer,
Vol.82
(6),
pp. 1145-1148.
show abstract
We have tested two rapid assays of p53 function, namely the apoptotic assay and the FASAY as means of detecting germline p53 mutations in members of Li-Fraumeni and Li-Fraumeni-like families. Results of the functional assays have been compared with direct sequencing of all 11 exons of the p53 gene. The results show good agreement between the two functional assays and between them and sequencing. No false-positives or negatives were seen with either functional assay although the apoptotic assay gave one borderline result for an individual without a mutation. As an initial screen the apoptotic assay is not only rapid but inexpensive and very simple to perform. It would be expected to detect any germline defect that leads to loss of p53 function. The apoptotic assay could be ideal as a means of prescreening large numbers of samples and identifying those that require further investigation. The FASAY detects mutations in exons 4-10, is rapid and distinguishes between functionally important and silent mutations..
Forrest, M.S.
Edwards, S.M.
Hamoudi, R.A.
Dearnaley, D.P.
Arden-Jones, A.
Dowe, A.
Murkin, A.
Kelly, J.
Teare, M.D.
Easton, D.F.
Knowles, M.A.
Bishop, D.T.
Eeles, R.A.
(2000). No evidence of germline PTEN mutations in familial prostate cancer. J med genet,
Vol.37
(3),
pp. 210-212.
Xu, J.
(2000). Combined analysis of hereditary prostate cancer linkage to 1q24-25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics. Am j hum genet,
Vol.66
(3),
pp. 945-957.
show abstract
A previous linkage study provided evidence for a prostate cancer-susceptibility locus at 1q24-25. Subsequent reports in additional collections of families have yielded conflicting results. In addition, evidence for locus heterogeneity has been provided by the identification of other putative hereditary prostate cancer loci on Xq27-28, 1q42-43, and 1p36. The present study describes a combined analysis for six markers in the 1q24-25 region in 772 families affected by hereditary prostate cancer and ascertained by the members of the International Consortium for Prostate Cancer Genetics (ICPCG) from North America, Australia, Finland, Norway, Sweden, and the United Kingdom. Overall, there was some evidence for linkage, with a peak parametric multipoint LOD score assuming heterogeneity (HLOD) of 1.40 (P=.01) at D1S212. The estimated proportion of families (alpha) linked to the locus was.06 (1-LOD support interval.01-.12). This evidence was not observed by a nonparametric approach, presumably because of the extensive heterogeneity. Further parametric analysis revealed a significant effect of the presence of male-to-male disease transmission within the families. In the subset of 491 such families, the peak HLOD was 2.56 (P=.0006) and alpha =.11 (1-LOD support interval.04-.19), compared with HLODs of 0 in the remaining 281 families. Within the families with male-to-male disease transmission, alpha increased with the early mean age at diagnosis (<65 years, alpha =.19, with 1-LOD support interval.06-.34) and the number of affected family members (five or more family members, alpha =.15, with 1-LOD support interval.04-.28). The highest value of alpha was observed for the 48 families that met all three criteria (peak HLOD = 2.25, P=.001, alpha=.29, with 1-LOD support interval.08-.53). These results support the finding of a prostate cancer-susceptibility gene linked to 1q24-25, albeit in a defined subset of prostate cancer families. Although HPC1 accounts for only a small proportion of all families affected by hereditary prostate cancer, it appears to play a more prominent role in the subset of families with several members affected at an early age and with male-to-male disease transmission..
Macmillan, R.D.
(2000). Screening women with a family history of breast cancer--results from the British Familial Breast Cancer Group. Eur j surg oncol,
Vol.26
(2),
pp. 149-152.
show abstract
AIMS: To determine the efficacy of screening women under age 50 with a significant family history of breast cancer. METHODS: Results from 22 Breast Units in the UK identified as being able to provide data were surveyed and pooled through regional data managers or consultant breast specialists. RESULTS: Data relating to 8783 women screened and 9075 woman years of follow-up was analysed. Cancer incidence was 11.3/1000/year. The rate of cancer detection was 4. 78/1000 at prevalent screening and 4.52/1000 at incident screening. Median age at diagnosis was 43 years. Interval cancers presented at a rate of 2.45/1000. Comparison with the National Health Service Breast Screening Programme for women aged 50-64 revealed a similar rate of cancer detection and a similar incidence of ductal carcinoma in situ. The pathological features of screen-detected cancers in this study strongly suggest that prognosis for these women is more favourable than if they had presented symptomatically. CONCLUSIONS: This study provides evidence to suggest that screening young women with a significant family history of breast cancer is effective and that a survival benefit can be expected. As a result the British Familial Breast Cancer Group proposes a co-ordinated prospective observational study..
Brown, J.
Coulthard, A.
Dixon, A.K.
Dixon, J.M.
Easton, D.F.
Eeles, R.A.
Evans, D.G.
Gilbert, F.G.
Hayes, C.
Jenkins, J.P.
Leach, M.O.
Moss, S.M.
Padhani, A.P.
Pointon, L.J.
Ponder, B.A.
Sloane, J.P.
Turnbull, L.W.
Walker, L.G.
Warren, R.M.
Watson, W.
UK MRI Breast Screening Study Advisory Group,
(2000). Rationale for a national multi-centre study of magnetic resonance imaging screening in women at genetic risk of breast cancer. Breast,
Vol.9
(2),
pp. 72-77.
show abstract
In 1994, the UK National Health Service identified as a research priority that magnetic resonance imaging (MRI) should be assessed as a screening tool for young, pre-menopausal women who are at a high genetic risk of developing breast cancer. In 1997 a national multicentre study was established to compare MRI with X-ray mammography as a method for screening for breast cancer in this group of women. This paper reviews the relevant literature and describes the rationale that led to the setting up of this study..
Brown, J.
Coulthard, A.
Dixon, A.K.
Dixon, J.M.
Easton, D.F.
Eeles, R.A.
Evans, D.G.
Gilbert, F.G.
Hayes, C.
Jenkins, J.P.
Leach, M.O.
Moss, S.M.
Padhani, A.P.
Pointon, L.J.
Ponder, B.A.
Sloane, J.P.
Turnbull, L.W.
Walker, L.G.
Warren, R.M.
Watson, W.
UK MRI Breast Screening Study Advisory Group,
(2000). Protocol for a national multi-centre study of magnetic resonance imaging screening in women at genetic risk of breast cancer. Breast,
Vol.9
(2),
pp. 78-82.
show abstract
The protocol of the national multicentre study of Magnetic Resonance Imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The sensitivity and specificity of contrast-enhanced MRI will be compared with two-view X-ray mammography in a comparative trial. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for 3 years, with annual MRI and X-ray examination continuing for up to 5 years. A symptomatic cohort will be measured in the initial phase of the study to ensure consistent reporting between centres. The MRI examination will comprise an initial high-sensitivity screening measurement, followed by a high-specificity measurement in equivocal cases. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. The psychological impact of screening in this high-risk group will be ascertained..
Brown, J.
Buckley, D.
Coulthard, A.
Dixon, A.K.
Dixon, J.M.
Easton, D.F.
Eeles, R.A.
Evans, D.G.
Gilbert, F.G.
Graves, M.
Hayes, C.
Jenkins, J.P.
Jones, A.P.
Keevil, S.F.
Leach, M.O.
Liney, G.P.
Moss, S.M.
Padhani, A.R.
Parker, G.J.
Pointon, L.J.
Ponder, B.A.
Redpath, T.W.
Sloane, J.P.
Turnbull, L.W.
Walker, L.G.
Warren, R.M.
(2000). Magnetic resonance imaging screening in women at genetic risk of breast cancer: imaging and analysis protocol for the UK multicentre study UK MRI Breast Screening Study Advisory Group. Magn reson imaging,
Vol.18
(7),
pp. 765-776.
show abstract
The imaging and analysis protocol of the UK multicentre study of magnetic resonance imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The study will compare the sensitivity and specificity of contrast-enhanced MRI with two-view x-ray mammography. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for three years, with annual MRI and x-ray mammography continuing for up to 5 years. A symptomatic cohort will be measured in the first year to ensure consistent reporting between centres. The MRI examination comprises a high-sensitivity three-dimensional contrast-enhanced assessment, followed by a high-specificity contrast-enhanced study in equivocal cases. Multiparametric analysis will encompass morphological assessment, the kinetics of contrast agent uptake and determination of quantitative pharmacokinetic parameters. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. Mammography, lesion localisation, pathology and cytology will be performed in accordance with the UK NHS Breast Screening Programme quality assurance standards. Similar standards of quality assurance will be applied for MR measurements and evaluation..
Dunsmuir, W.D.
Gillett, C.E.
Meyer, L.C.
Young, M.P.
Corbishley, C.
Eeles, R.A.
Kirby, R.S.
(2000). Molecular markers for predicting prostate cancer stage and survival. Bju int,
Vol.86
(7),
pp. 869-878.
show abstract
OBJECTIVE: To assess several molecular markers (detected by immunohistochemistry, IHC) to determine whether they can be used to improve the prognostic value of histological grade alone in predicting the behaviour of prostate cancer. PATIENTS AND METHODS: Tumour tissue was retrieved from 156 men in whom tumour grade, stage and survival were known. The outcome measures were: (i) local stage (T-stage, organ-confined vs extraprostatic); (ii) metastatic status (M-stage, bone metastasis vs no bone metastasis); and (iii) survival. The IHC markers used were chosen to provide a broad representation of various aspects of tumour biology, i.e. the androgen receptor (AR) and oestrogen receptor (ER), adhesion molecules (E-cadherin), proliferation markers (MIB-1), tumour-suppressor genes (TP53 and the retinoblastoma gene product, Rb) and other novel cancer-related proteins (cyclin D1 and the breast cancer susceptibility gene product, BRCA2). All factors were assessed using logistic regression and Cox proportional-hazards survival models for predictive value, after adjusting for effects. RESULTS: MIB-1, ER, cyclin D1 and E-cadherin all showed close statistically significant univariate associations with histological grade. Univariate analysis also identified close statistically significant associations between T-stage and both MIB-1 and E-cadherin. Likewise, there were close univariate associations for both M-stage and survival, and MIB-1, cyclin D1 and ER. Logistic regression modelling identified MIB-1, cyclin D1 and ER as statistically significant predictors of M-stage and, once MIB-1 was entered into the model, the effects of grade no longer made a significant contribution. MIB-1 was a significant predictor for T-stage, but the effects of grade remained significant in this model. Cox proportional-hazards modelling identified MIB-1, cyclin D1 and ER as being statistically significant predictors of survival, after adjusting for grade. After adjusting for both grade and MIB-1, the effects of cyclin D1 and ER were no longer statistically significant. Excess MIB-1, cyclin D1 or ER expression tended to be present within the most poorly differentiated and advanced-stage lesions; this provides an inherent instability to the models described. TP53, Rb, AR and BRCA2 were of limited prognostic value. CONCLUSIONS: MIB-1, ER and cyclin D1 provide prognostic information that is clearly independent of grade. However, their true clinical value is probably limited because they are expressed mainly in the most advanced lesions. Nevertheless, MIB-1 expression is of sufficient value to warrant inclusion in future prognostic models. Furthermore, the expression of cyclin D1 and ER may reflect aspects of tumour biology that individually are worthy of further investigation. However, none of the IHC markers used in this study can be recommended for use in routine histological preparations..
Singh, R.
Eeles, R.A.
Durocher, F.
Simard, J.
Edwards, S.
Badzioch, M.
Kote-Jarai, Z.
Teare, D.
Ford, D.
Dearnaley, D.
Ardern-Jones, A.
Murkin, A.
Dowe, A.
Shearer, R.
Kelly, J.
Labrie, F.
Easton, D.
Narod, S.A.
Tonin, P.N.
Foulkes, W.D.
(2000). High risk genes predisposing to prostate cancer development-do they exist?. Prostate cancer prostatic dis,
Vol.3
(4),
pp. 241-247.
show abstract
There is evidence for genetic predisposition to prostate cancer. However, prostate cancer genes have been more difficult to find than genes for some of the other common cancers, such as breast and colon cancer. The reasons for this are discussed in this article and it is now becoming clear that prostate cancer is probably due to multiple genes, many of which are moderate or low penetrance. The advances in the Human Genome Project and technology, especially that of robotics, will help to overcome these problems. Prostate Cancer and Prostatic Diseases (2000) 3, 241-247.
Singh, R.
ACTANE consortium. Anglo, Canada, Texas, Australia, Norway, EU Biomed,
(2000). No evidence of linkage to chromosome 1q42 2-43 in 131 prostate cancer families from the ACTANE consortium Anglo, Canada, Texas, Australia, Norway, EU Biomed. Br j cancer,
Vol.83
(12),
pp. 1654-1658.
show abstract
Genetic linkage studies worldwide have proposed various chromosomal localizations for prostate cancer susceptibility genes. A recent study found evidence for linkage to chromosome 1q42.2-43. The aim of our study was to attempt to confirm these findings by performing linkage analysis in 131 families with multiple prostate cancer cases selected from the ACTANE (Anglo, Canada, Texas, Australia, Norway, EU Biomed) Consortium. Parametric and non-parametric linkage (NPL) analyses were performed. Two-point LOD scores failed to show evidence of linkage at any marker (maximum two-point LOD score = 0. 40 at recombination fraction theta = 0.2 with marker D1S2850). Using a multipoint heterogeneity analysis, the estimated proportion of families linked to this putative locus (alpha) was 0% (95% CI = 0. 00-0.33). Non-parametric linkage analysis also found no evidence of linkage (maximum NPL score = -0.12, P = 0.55). This analysis of 131 ACTANE families does not support the presence of a locus for a prostate cancer susceptibility gene at 1q42.2-43. Although we cannot rule out the existence of such a locus, analysis indicates that less than 16% of families could be linked to this region. These findings may be a reflection of the locus heterogeneity involved in this disease indicating that there are still other major susceptibility loci to be identified..
Badzioch, M.
Eeles, R.
Leblanc, G.
Foulkes, W.D.
Giles, G.
Edwards, S.
Goldgar, D.
Hopper, J.L.
Bishop, D.T.
Møller, P.
Heimdal, K.
Easton, D.
Simard, J.
(2000). Suggestive evidence for a site specific prostate cancer gene on chromosome 1p36 The CRC/BPG UK Familial Prostate Cancer Study Coordinators and Collaborators The EU Biomed Collaborators. J med genet,
Vol.37
(12),
pp. 947-949.
Gayther, S.A.
de Foy, K.A.
Harrington, P.
Pharoah, P.
Dunsmuir, W.D.
Edwards, S.M.
Gillett, C.
Ardern-Jones, A.
Dearnaley, D.P.
Easton, D.F.
Ford, D.
Shearer, R.J.
Kirby, R.S.
Dowe, A.L.
Kelly, J.
Stratton, M.R.
Ponder, B.A.
Barnes, D.
Eeles, R.A.
(2000). The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. Cancer res,
Vol.60
(16),
pp. 4513-4518.
show abstract
Predisposition to prostate cancer has a genetic component, and there are reports of familial clustering of breast and prostate cancer. Two highly penetrant genes that predispose individuals to breast cancer (BRCA1 and BRCA2) are known to confer an increased risk of prostate cancer of about 3-fold and 7-fold, respectively, in breast cancer families. Blood DNA from affected individuals in 38 prostate cancer clusters was analyzed for germ-line mutations in BRCA1 and BRCA2 to assess the contribution of each of these genes to familial prostate cancer. Seventeen DNA samples were each from an affected individual in families with three or more cases of prostate cancer at any age; 20 samples were from one of affected sibling pairs where one was < or = 67 years at diagnosis. No germ-line mutations were found in BRCA1. Two germ-line mutations in BRCA2 were found, and both were seen in individuals whose age at diagnosis was very young (< or = 56 years) and who were members of an affected sibling pair. One is a 4-bp deletion at base 6710 (exon 11) in a man who had prostate cancer at 54 years, and the other is a 2-bp deletion at base 5531 (exon 11) in a man who had prostate cancer at 56 years. In both cases, the wild-type allele was lost in the patient's prostate tumor at the BRCA2 locus. However, intriguingly, in neither case did the affected brother also carry the mutation. Germ-line mutations in BRCA2 may therefore account for about 5% of prostate cancer in familial clusters..
Sodha, N.
Williams, R.
Mangion, J.
Bullock, S.L.
Yuille, M.R.
Eeles, R.A.
(2000). Screening hCHK2 for mutations. Science,
Vol.289
(5478),
p. 359.
Nutting, C.
Camplejohn, R.S.
Gilchrist, R.
Tait, D.
Blake, P.
Knee, G.
Yao, W.Q.
Ross, G.
Fisher, C.
Eeles, R.
(2000). A patient with 17 primary tumours and a germ line mutation in TP53: tumour induction by adjuvant therapy?. Clin oncol (r coll radiol),
Vol.12
(5),
pp. 300-304.
show abstract
We report the case history of a woman with a germ line mutation in the TP53 gene who developed 17 separate primary tumours. The incidence of new tumours rose steeply after adjuvant tamoxifen treatment for breast cancer and adjuvant vaginal vault radiotherapy for endometrial cancer. This increase could be due to cumulative genetic damage from environmental agents and the fact that the patient lived to the relatively late age of 60 years, or to a high inherent deleterious somatic mutation rate, which could represent the inability of cells from patients with TP53 mutations to repair therapy-induced genetic damage..
Stone, J.G.
Eeles, R.A.
Sodha, N.
Murday, V.
Sheriden, E.
Houlston, R.S.
(1999). Analysis of Li-Fraumeni syndrome and Li-Fraumeni-like families for germline mutations in Bcl10. Cancer lett,
Vol.147
(1-2),
pp. 181-185.
show abstract
The Li-Fraumeni syndrome (LFS) is a dominant disease whose hallmark is an increased risk of breast cancers, brain tumours, sarcomas, leukaemia and adrenal carcinoma. Some, but not all LFS and Li-Fraumeni-like (LFL) families are caused by TP53 mutations. Bcl10 is a recently identified tumour suppressor reported to be commonly mutated in a wide range of cancers. To investigate the possibility that Bcl10 is a susceptibility gene for LFS and LFL we have analysed 27 LFS/LFL families. No mutations were observed. This indicates that Bcl10 is unlikely to act as a susceptibility gene for LFS and LFL..
Gill, S.
Broni, J.
Jefferies, S.
Osin, P.
Kovacs, G.
Maitland, N.J.
Eeles, R.
Edwards, S.M.
Dyer, M.J.
Willis, T.G.
Cooper, C.S.
(1999). BCL10 is rarely mutated in human prostate carcinoma, small-cell lung cancer, head and neck tumours, renal carcinoma and sarcomas. British journal of cancer,
Vol.80
(10),
pp. 1565-4.
Watson, M.
Lloyd, S.
Davidson, J.
Meyer, L.
Eeles, R.
Ebbs, S.
Murday, V.
(1999). The impact of genetic counselling on risk perception and mental health in women with a family history of breast cancer. Br j cancer,
Vol.79
(5-6),
pp. 868-874.
show abstract
The present study investigated: (1) perception of genetic risk and, (2) the psychological effects of genetic counselling in women with a family history of breast cancer. Using a prospective design, with assessment pre- and post-genetic counselling at clinics and by postal follow-up at 1, 6 and 12 months, attenders at four South London genetic clinics were assessed. Participants included 282 women with a family history of breast cancer. Outcome was measured in terms of mental health, cancer-specific distress and risk perception. High levels of cancer-specific distress were found pre-genetic counselling, with 28% of participants reporting that they worried about breast cancer 'frequently or constantly' and 18% that worry about breast cancer was 'a severe or definite problem'. Following genetic counselling, levels of cancer-specific distress were unchanged. General mental health remained unchanged over time (33% psychiatric cases detected pre-genetic counselling, 27% at 12 months after genetic counselling). Prior to their genetics consultation, participants showed poor knowledge of their lifetime risk of breast cancer since there was no association between their perceived lifetime risk (when they were asked to express this as a 1 in x odds ratio) and their actual risk, when the latter was calculated by the geneticist at the clinic using the CASH model. In contrast, women were more accurate about their risk of breast cancer pre-genetic counselling when this was assessed in broad categorical terms (i.e. very much lower/very much higher than the average woman) with a significant association between this rating and the subsequently calculated CASH risk figure (P = 0.001). Genetic counselling produced a modest shift in the accuracy of perceived lifetime risk, expressed as an odds ratio, which was maintained at 12 months' follow-up. A significant minority failed to benefit from genetic counselling; 77 women continued to over-estimate their risk and maintain high levels of cancer-related worry. Most clinic attenders were inaccurate in their estimates of the population risk of breast cancer with only 24% able to give the correct figure prior to genetic counselling and 36% over-estimating this risk. There was some improvement following genetic counselling with 62% able to give the correct figure, but this information was poorly retained and this figure had dropped to 34% by the 1-year follow-up. The study showed that women attending for genetic counselling are worried about breast cancer, with 34% indicating that they had initiated the referral to the genetic clinic themselves. This anxiety is not alleviated by genetic counselling, although women reported that it was less of a problem at follow-up. Women who continue to over-estimate their risk and worry about breast cancer are likely to go on seeking unnecessary screening if they are not reassured..
Breast Cancer Linkage Consortium,
(1999). Cancer risks in BRCA2 mutation carriers. J natl cancer inst,
Vol.91
(15),
pp. 1310-1316.
show abstract
BACKGROUND: Carriers of germline mutations in the BRCA2 gene are known to be at high risk of breast and ovarian cancers, but the risks of other cancers in mutation carriers are uncertain. We investigated these risks in 173 breast-ovarian cancer families with BRCA2 mutations identified at 20 centers in Europe and North America. METHODS: Other cancer occurrence was determined in a final cohort of 3728 individuals, among whom 681 persons had breast or ovarian cancer and 3047 persons either were known mutation carriers, were first-degree relatives of known mutation carriers, or were first-degree relatives of breast or ovarian cancer patients. Incidence rates were compared with population-specific incidence rates, and relative risks (RRs) to carriers, together with 95% confidence intervals (CIs), were estimated by use of a maximum likelihood approach. Three hundred thirty-three other cancers occurred in this cohort. RESULTS: Statistically significant increases in risks were observed for prostate cancer (estimated RR = 4.65; 95% CI = 3.48-6.22), pancreatic cancer (RR = 3.51; 95% CI = 1. 87-6.58), gallbladder and bile duct cancer (RR = 4.97; 95% CI = 1. 50-16.52), stomach cancer (RR = 2.59; 95%CI = 1.46-4.61), and malignant melanoma (RR = 2.58; 95% CI = 1.28-5.17). The RR for prostate cancer for men below the age of 65 years was 7.33 (95% CI = 4.66-11.52). Among women who had already developed breast cancer, the cumulative risks of a second, contralateral breast cancer and of ovarian cancer by the age of 70 years were estimated to be 52.3% (95% CI = 41.7%-61.0%) and 15.9% (95% CI = 8.8%-22.5%), respectively. CONCLUSIONS: In addition to the large risks of breast and ovarian cancers, BRCA2 mutations may be associated with increased risks of several other cancers..
Hodgson, S.V.
Heap, E.
Cameron, J.
Ellis, D.
Mathew, C.G.
Eeles, R.A.
Solomon, E.
Lewis, C.M.
(1999). Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish women with breast or ovarian cancer. J med genet,
Vol.36
(5),
pp. 369-373.
show abstract
We ascertained 184 Ashkenazi Jewish women with breast/ovarian cancer (171 breast and 13 ovarian cancers, two of the former also had ovarian cancer) in a self-referral study. They were tested for germline founder mutations in BRCA1 (185delAG, 5382insC, 188del11) and BRCA2 (6174delT). Personal/family histories were correlated with mutation status. Logistic regression was used to develop a model to predict those breast cancer cases likely to be germline BRCA1/BRCA2 mutation carriers in this population. The most important factors were age at diagnosis, personal/family history of ovarian cancer, or breast cancer diagnosed before 60 years in a first degree relative. A total of 15.8% of breast cancer cases, one of 13 ovarian cancer cases (7.7%), and both cases with ovarian and breast cancer carried one of the founder mutations. Age at diagnosis in carriers (44.6 years) was significantly lower than in non-carriers (52.1 years) (p<0.001), and was slightly lower in BRCA1 than BRCA2 carriers. Thirty three percent of carriers had no family history of breast or ovarian cancer in first or second degree relatives. Conversely, 12% of non-mutation carriers had strong family histories, with both a first and a second degree relative diagnosed with breast or ovarian cancer. The predicted values from the logistic model can be used to define criteria for identifying Ashkenazi Jewish women with breast cancer who are at high risk of carrying BRCA1 and BRCA2 mutations. The following criteria would identify those at approximately 10% risk: (1) breast cancer <50 years, (2) breast cancer <60 years with a first degree relative with breast cancer <60 years, or (3) breast cancer <70 years and a first or second degree relative with ovarian cancer..
Edwards, S.M.
Badzioch, M.D.
Minter, R.
Hamoudi, R.
Collins, N.
Ardern-Jones, A.
Dowe, A.
Osborne, S.
Kelly, J.
Shearer, R.
Easton, D.F.
Saunders, G.F.
Dearnaley, D.P.
Eeles, R.A.
(1999). Androgen receptor polymorphisms: association with prostate cancer risk, relapse and overall survival. Int j cancer,
Vol.84
(5),
pp. 458-465.
show abstract
Several reports have suggested that one or both of the trinucleotide repeat polymorphisms in the human androgen receptor (hAR) gene, (CAG)n coding for polyglutamine and (GGC)n coding for polyglycine, may be associated with prostate cancer risk; but no study has investigated their association with disease progression. We present here a study of both hAR trinucleotide repeat polymorphisms not only as they relate to the initial diagnosis but also as they are associated with disease progression after therapy. Lymphocyte DNA samples from 178 British Caucasian prostate cancer patients and 195 control individuals were genotyped by PCR for the (CAG)n and (GGC)n polymorphisms in hAR. Univariate Cox proportional hazard analysis indicated that stage, grade and GGC repeat length were individually significant factors associated with disease-free survival (DFS) and overall survival (OS). The relative risk (RR) of relapse for men with more than 16 GGC repeats was 1.74 (95% CI 1. 08-2.79) and of dying from any cause, 1.98 (1.13-3.45). Adjusting for stage and grade, GGC effects remained but were not significant (RR(DFS)= 1.60, p = 0.052; RR(OS)= 1.65, p = 0.088). The greatest effects were in stage T1-T2 (RR(DFS)= 3.56, 95% CI 1.13-11.21) and grade 1 (RR(DFS)= 6.47, 95% CI 0.57-72.8) tumours. No differences between patient and control allele distributions were found by odds-ratio analysis, nor were trends with stage or grade evident in the proportion of short CAG alleles. Non-significant trends with stage and grade were found in the proportion of short GGC alleles. The (GGC)n polymorphism in this population is a significant predictor of disease outcome. Since the (GGC)(n) effect is strongest in early-stage tumours, this marker may help forecast aggressive behaviour and could be used to identify those patients meriting more radical treatment..
Marsh, D.J.
Dahia, P.L.
Coulon, V.
Zheng, Z.
Dorion-Bonnet, F.
Call, K.M.
Little, R.
Lin, A.Y.
Eeles, R.A.
Goldstein, A.M.
Hodgson, S.V.
Richardson, A.L.
Robinson, B.G.
Weber, H.C.
Longy, M.
Eng, C.
(1998). Allelic imbalance, including deletion of PTEN/MMACI, at the Cowden disease locus on 10q22-23, in hamartomas from patients with Cowden syndrome and germline PTEN mutation. Genes chromosomes cancer,
Vol.21
(1),
pp. 61-69.
show abstract
Cowden disease (CD) is a rare, autosomal dominant inherited cancer syndrome characterized by multiple benign and malignant lesions in a wide spectrum of tissues. While individuals with CD have an increased risk of breast and thyroid neoplasms, the primary features of CD are hamartomas. The gene for CD has been mapped by linkage analysis to a 6 cM region on the long arm of chromosome 10 at 10q22-23. Loss of heterozygosity (LOH) studies of sporadic follicular thyroid adenomas and carcinomas, both component tumors of CD, have suggested that the putative susceptibility gene for CD is a tumor suppressor gene. Somatic missense and nonsense mutations have recently been identified in breast, prostate, and brain tumor cell lines in a gene encoding a dual specificity phosphatase, PTEN/MMACI, mapped at 10q23.3. Furthermore, germline PTEN/MMACI mutations are associated with CD. In the present study, 20 hamartomas from 11 individuals belonging to ten unrelated families with CD have been examined for LOH of markers flanking and within PTEN/MMACI. Eight of these ten families have germline PTEN/MMACI mutations. LOH involving microsatellite markers within the CD interval, and including PTEN/MMACI, was identified in two fibroadenomas of the breast, a thyroid adenoma, and a pulmonary hamartoma belonging to 3 to 11 (27%) of these patients. The wild-type allele was lost in these hamartomas. Semi-quantitative PCR performed on RNA from hamartomas from three different tissues from a CD patient suggested substantial reduction of PTEN/MMACI RNA levels in all of these tissues. The LOH identified in samples from individuals with CD and the suggestion of allelic loss and reduced transcription in hamartomas from a CD patient provide evidence that PTEN/MMACI functions as a tumor suppressor in CD..
Daltrey, I.R.
Eeles, R.A.
Kissin, M.W.
(1998). Bilateral prophylactic mastectomy: not just a woman's problem!. Breast,
Vol.7
(4),
pp. 236-2.
Marsh, D.J.
Coulon, V.
Lunetta, K.L.
Rocca-Serra, P.
Dahia, P.L.
Zheng, Z.
Liaw, D.
Caron, S.
Duboué, B.
Lin, A.Y.
Richardson, A.L.
Bonnetblanc, J.M.
Bressieux, J.M.
Cabarrot-Moreau, A.
Chompret, A.
Demange, L.
Eeles, R.A.
Yahanda, A.M.
Fearon, E.R.
Fricker, J.P.
Gorlin, R.J.
Hodgson, S.V.
Huson, S.
Lacombe, D.
Eng, C.
(1998). Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum mol genet,
Vol.7
(3),
pp. 507-515.
show abstract
The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families..
Eeles, R.A.
Durocher, F.
Edwards, S.
Teare, D.
Badzioch, M.
Hamoudi, R.
Gill, S.
Biggs, P.
Dearnaley, D.
Ardern-Jones, A.
Dowe, A.
Shearer, R.
McLellan, D.L.
Norman, R.L.
Ghadirian, P.
Aprikian, A.
Ford, D.
Amos, C.
King, T.M.
Labrie, F.
Simard, J.
Narod, S.A.
Easton, D.
Foulkes, W.D.
(1998). Linkage analysis of chromosome 1q markers in 136 prostate cancer families The Cancer Research Campaign/British Prostate Group U K Familial Prostate Cancer Study Collaborators. Am j hum genet,
Vol.62
(3),
pp. 653-658.
show abstract
Prostate cancer shows evidence of familial aggregation, particularly at young ages at diagnosis, but the inherited basis of familial prostate cancer is poorly understood. Smith et al. recently found evidence of linkage to markers on 1q, at a locus designated "HPC1," in 91 families with multiple cases of early-onset prostate cancer. Using both parametric and nonparametric methods, we attempted to confirm this finding, in 60 affected related pairs and in 76 families with three or more cases of prostate cancer, but we found no significant evidence of linkage. The estimated proportion of linked families, under a standard autosomal dominant model, was 4%, with an upper 95% confidence limit of 31%. We conclude that the HPC1 locus is responsible for only a minority of familial prostate cancer cases and that it is likely to be most important in families with at least four cases of the disease..
Watson, M.
Duvivier, V.
Wade Walsh, M.
Ashley, S.
Davidson, J.
Papaikonomou, M.
Murday, V.
Sacks, N.
Eeles, R.
(1998). Family history of breast cancer: what do women understand and recall about their genetic risk?. J med genet,
Vol.35
(9),
pp. 731-738.
show abstract
The current study has two aims: (1) to look at people's recall of risk information after genetic counselling and (2) to determine the impact of receiving an audiotape of the genetic consultation on level of recall, cancer related worry, and women's uptake of risk management methods. Using a prospective randomised controlled design, subjects receiving an audiotape were compared with a standard consultation group. Participants were drawn from attenders at the genetic clinics of two London hospitals and included 115 women with a family history of breast cancer. Assessment of perceived genetic risk, mental health, cancer worry, and health behaviour was made before counselling at the clinic (baseline) and by postal follow up. Usefulness of audiotapes and satisfaction with the clinical service was assessed by study specific measures. The data indicate that cancer worry is reduced by provision of an audiotape of the genetic consultation. Recall of the genetic risk figure, however, is not affected by provision of an audiotape and neither is it related to women's overall perception of being more or less at risk of breast cancer than the average woman. Forty-one percent of women accurately recalled their personal risk of breast cancer at one month follow up; however, 25% overestimated, 11% underestimated, and 23% could not remember or did not know their breast cancer risk. Recall of the risk figure is more accurate when the clinical geneticist has given this to the woman as an odds ratio rather than in other formats. Subsequent health behaviour is unaffected by whether women have an audiotape record of their genetic consultation. Results suggest that having a precise risk figure may be less important than women taking away from the consultation an impression that something can be offered to help them manage that risk. Provision of an audiotape of the consultation is of limited usefulness. The need for psychological care to be better integrated into genetic counselling at cancer family clinics was highlighted by the study. The results are discussed in terms of future service development..
Marsh, D.J.
Dahia, P.L.
Caron, S.
Kum, J.B.
Frayling, I.M.
Tomlinson, I.P.
Hughes, K.S.
Eeles, R.A.
Hodgson, S.V.
Murday, V.A.
Houlston, R.
Eng, C.
(1998). Germline PTEN mutations in Cowden syndrome-like families. J med genet,
Vol.35
(11),
pp. 881-885.
show abstract
Cowden syndrome (CS) or multiple hamartoma syndrome (MIM 158350) is an autosomal dominant disorder with an increased risk for breast and thyroid carcinoma. The diagnosis of CS, as operationally defined by the International Cowden Consortium, is made when a patient, or family, has a combination of pathognomonic major and/or minor criteria. The CS gene has recently been identified as PTEN, which maps at 10q23.3 and encodes a dual specificity phosphatase. PTEN appears to function as a tumour suppressor in CS, with between 13-80% of CS families harbouring germline nonsense, missense, and frameshift mutations predicted to disrupt normal PTEN function. To date, only a small number of tumour suppressor genes, including BRCA1, BRCA2, and p53, have been associated with familial breast or breast/ovarian cancer families. Given the involvement of PTEN in CS, we postulated that PTEN was a likely candidate to play a role in families with a "CS-like" phenotype, but not classical CS. To answer these questions, we gathered a series of patients from families who had features reminiscent of CS but did not meet the Consortium Criteria. Using a combination of denaturing gradient gel electrophoresis (DGGE), temporal temperature gel electrophoresis (TTGE), and sequence analysis, we screened 64 unrelated CS-like subjects for germline mutations in PTEN. A single male with follicular thyroid carcinoma from one of these 64 (2%) CS-like families harboured a germline point mutation, c.209T-->C. This mutation occurred at the last nucleotide of exon 3 and within a region homologous to the cytoskeletal proteins tensin and auxilin. We conclude that germline PTEN mutations play a relatively minor role in CS-like families. In addition, our data would suggest that, for the most part, the strict International Cowden Consortium operational diagnostic criteria for CS are quite robust and should remain in place..
Powles, T.
Eeles, R.
Ashley, S.
Easton, D.
Chang, J.
Dowsett, M.
Tidy, A.
Viggers, J.
Davey, J.
(1998). Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet,
Vol.352
(9122),
pp. 98-4.
Dunsmuir, W.D.
Edwards, S.M.
Lakhani, S.R.
Young, M.
Corbishley, C.
Kirby, R.S.
Dearnaley, D.P.
Dowe, A.
Ardern-Jones, A.
Kelly, J.
Eeles, R.A.
(1998). Allelic imbalance in familial and sporadic prostate cancer at the putative human prostate cancer susceptibility locus, HPC1 CRC/BPG UK Familial Prostate Cancer Study Collaborators Cancer Research Campaign/British Prostate Group. Br j cancer,
Vol.78
(11),
pp. 1430-1433.
show abstract
full text
A recent report has provided strong evidence for a major prostate cancer susceptibility locus (HPC1) on chromosome 1q24-25 (Smith et al, 1996). Most inherited cancer susceptibility genes function as tumour-suppressor genes (TSGs). Allelic loss or imbalance in tumour tissue is often the hallmark of a TSG. Studies of allelic loss have not previously implicated the chromosomal region 1q24-25 in prostate cancer. However, analysis of tumour DNA from cases in prostate cancer families has not been reported. In this study, we have evaluated DNA from tissue obtained from small families [3-5 affected members (n = 17)], sibling pairs (n = 15) and sporadic (n = 40) prostate tumours using the three markers from Smith et al (1996) that defined the maximum multipoint linkage lod score. Although widely spaced (12-50 cM), each marker showed evidence of allelic imbalance in only approximately 7.5% of informative tumours. There was no difference between the familial and sporadic cases. We conclude that the incidence of allelic imbalance at HPC1 is low in both sporadic tumours and small prostate cancer families. In this group of patients, HPC1 is unlikely to be acting as a TSG in the development of prostate cancer..
Edwards, S.M.
Dunsmuir, W.D.
Gillett, C.E.
Lakhani, S.R.
Corbishley, C.
Young, M.
Kirby, R.S.
Dearnaley, D.P.
Dowe, A.
Ardern-Jones, A.
Kelly, J.
Spurr, N.
Barnes, D.M.
Eeles, R.A.
(1998). Immunohistochemical expression of BRCA2 protein and allelic loss at the BRCA2 locus in prostate cancer CRC/BPG UK Familial Prostate Cancer Study Collaborators. Int j cancer,
Vol.78
(1),
pp. 1-7.
show abstract
Many epidemiological studies have reported an association between breast and prostate cancer. BRCA2 functions as a tumour-suppressor gene in about 35% of large familial breast-cancer clusters; its role in the pathogenesis of sporadic breast cancer is less clear. We have evaluated immunohistochemical expression of BRCA2 protein and allelic loss of markers at the BRCA2 locus in tissue derived both from sporadic and from familial cases of prostate cancer. Immunohistochemical analysis was performed in 167 paraffin-embedded archival specimens. Normal prostate and 75% (120/160) of prostate-cancer tissue did not express BRCA2 protein. However, 25% (40/160) of cancer cases did express patchy staining; of these, 17% (2711 60) expressed positive nuclear staining in normal glandular tissue adjacent to tumour (either in addition to, or, independent of tumour). Allelic loss is the hallmark of a tumour-suppressor gene. Markers flanking (D13S267, D13S260) and within (D13S171) the BRCA2 gene indicated allelic loss in at least one locus in 23% (17/73) of tumours analyzed. There was no difference in the rates of allelic loss between sporadic and familial tumours, nor was there any association between immunohistochemical staining and allelic loss. Although immunohistochemical staining provided no useful prognostic information, allelic loss at BRCA2 was shown in univariate analysis to be associated with poorer survival (log-rank test, p = 0.046)..
Andersen, T.I.
Wooster, R.
Laake, K.
Collins, N.
Warren, W.
Skrede, M.
Eeles, R.
Tveit, K.M.
Johnston, S.R.
Dowsett, M.
Olsen, A.O.
Moller, P.
Stratton, M.R.
BorresenDale, A.L.
(1997). Screening for ESR mutations in breast and ovarian cancer patients. Human mutation,
Vol.9
(6),
pp. 531-6.
Edwards, S.M.
Dearnaley, D.P.
Ardern-Jones, A.
Hamoudi, R.A.
Easton, D.F.
Ford, D.
Shearer, R.
Dowe, A.
Eeles, R.A.
(1997). No germline mutations in the dimerization domain of MXI1 in prostate cancer clusters The CRC/BPG UK Familial Prostate Cancer Study Collaborators Cancer Research Campaign/British Prostate Group. Br j cancer,
Vol.76
(8),
pp. 992-1000.
show abstract
full text
There is evidence that predisposition to cancer has a genetic component. Genetic models have suggested that there is at least one highly penetrant gene predisposing to this disease. The oncogene MXI1 on chromosome band 10q24-25 is mutated in a proportion of prostate tumours and loss of heterozygosity occurs at this site, suggesting the location of a tumour suppressor in this region. To investigate the possibility that MXI1 may be involved in inherited susceptibility to prostate cancer, we have sequenced the HLH and ZIP regions of the gene in 38 families with either three cases of prostate cancer or two affected siblings both diagnosed below the age of 67 years. These are the areas within which mutations have been described in some sporadic prostate cancers. No mutations were found in these two important coding regions and we therefore conclude that MXI1 does not make a major contribution to prostate cancer susceptibility..
Nelen, M.R.
Padberg, G.W.
Peeters, E.A.
Lin, A.Y.
van den Helm, B.
Frants, R.R.
Coulon, V.
Goldstein, A.M.
van Reen, M.M.
Easton, D.F.
Eeles, R.A.
Hodgsen, S.
Mulvihill, J.J.
Murday, V.A.
Tucker, M.A.
Mariman, E.C.
Starink, T.M.
Ponder, B.A.
Ropers, H.H.
Kremer, H.
Longy, M.
Eng, C.
(1996). Localization of the gene for Cowden disease to chromosome 10q22-23. Nat genet,
Vol.13
(1),
pp. 114-116.
show abstract
Cowden disease (CD) (MIM 158350), or multiple hamartoma syndrome, is a rare autosomal dominant familial cancer syndrome with a high risk of breast cancer. Its clinical features include a wide array of abnormalities but the main characteristics are hamartomas of the skin, breast, thyroid, oral mucosa and intestinal epithelium. The pathognomonic hamartomatous features of CD include multiple smooth facial papules, acral keratosis and multiple oral papillomas. The pathological hallmark of the facial papules are multiple trichilemmomas. Expression of the disease is variable and penetrance of the dermatological lesions is assumed to be virtually complete by the age of twenty. Central nervous system manifestations of CD were emphasized only recently and include megalencephaly, epilepsy and dysplastic gangliocytomas of the cerebellum (Lhermitte-Duclos disease, LDD). Early diagnosis is important since female patients with CD are at risk of developing breast cancer. Other lesions include benign and malignant disease of the thyroid, intestinal polyps and genitourinary abnormalities. To localize the gene for CD, an autosomal genome scan was performed. A total of 12 families were examined, resulting in a maximum lod score of 8.92 at theta = 0.02 with the marker D10S573 located on chromosome 10q22-23..
Eeles, R.
(1996). Testing for the breast cancer predisposition gene, BRCA1 - Documenting the outcome in gene carriers is essential. British medical journal,
Vol.313
(7057),
pp. 572-2.
full text
Lloyd, S.
Watson, M.
Waites, B.
Meyer, L.
Eeles, R.
Ebbs, S.
Tylee, A.
(1996). Familial breast cancer: a controlled study of risk perception, psychological morbidity and health beliefs in women attending for genetic counselling. Br j cancer,
Vol.74
(3),
pp. 482-487.
show abstract
full text
The present study set out to evaluate perceptions of risk, psychological morbidity and health behaviours in women with a family history of breast cancer who have attended genetic counselling and determine how these differ from general population risk women. Data were collected from 62 genetic counselees (cases) attending the Royal Marsden and Mayday University Hospital genetic counselling services and 62 matched GP attenders (controls). Levels of general psychological morbidity were found to be similar between cases and controls; however, cases reported significantly higher breast cancer-specific distress despite clinic attendance [mean (s.d.) total Impact of Event Scale score, 14.1 (14.3) cases; 2.4 (6.7) controls, P < 0.001]. Although cases perceived themselves to be more susceptible to breast cancer, many women failed correctly to recall risk figures provided by the clinic; 66% could not accurately recall their own lifetime chance. Clinics appeared to have a positive impact on preventive behaviours and cases tended to engage more regularly in breast self-examination (monthly, 66% of cases vs 47% of controls), although few differences were found between groups in terms of health beliefs. We conclude that counselees and GP controls showed considerable similarities on many of the outcome measures, and risk of breast cancer was not predictive of greater psychological morbidity; although cases were more vulnerable to cancer-specific distress. Despite genetic counselling, many cases continued to perceive their risk of breast cancer inaccurately..
Watson, M.
Lloyd, S.M.
Eeles, R.
Ponder, B.
Easton, D.
Seal, S.
Averill, D.
Daly, P.
Ormiston, W.
Murday, V.
(1996). Psychosocial impact of testing (by linkage) for the BRCA1 breast cancer gene: An investigation of two families in the research setting. Psycho-oncology,
Vol.5
(3),
pp. 233-7.
Eeles, R.
Cole, T.
Taylor, R.
Lunt, P.
Baum, M.
(1996). Prophylactic mastectomy for genetic predisposition to breast cancer: the proband's story. Clin oncol (r coll radiol),
Vol.8
(4),
pp. 222-225.
show abstract
The identification of the BRCA1 gene may prove a mixed blessing in the short term. First, the demand for testing might outstrip available resources, the ethics of testing are complex and the advice to give someone who tests positive is as yet unclear. Furthermore, the psychological dynamics within such families have not yet been considered seriously. As these families might be widespread, there will inevitably be problems involving clinical genetic centres in different parts of the country, or for that matter, in different areas of the world. In this paper we provide a case report, which might be considered an adumbration of things to come. The proband in this story (a co-author) was known to have inherited a genetic predisposition to cancer. This was because her identical twin had already developed the disease and she came from a kindred with a very high probability for carrying a dominant breast cancer gene in the germ line. We describe the personal reactions of an individual woman faced with these difficult decisions, the impact on her family and the impact on the clinical genetic services in different parts of the country. Our experience could help to provide a template for the development of regional services once genetic testing for predisposition to breast cancer becomes widely available..
GRUIS, N.A.
WEAVERFELDHAUS, J.
LIU, Q.Y.
FRYE, C.
EELES, R.
ORLOW, I.
LACOMBE, L.
PONCECASTANEDA, V.
LIANES, P.
LATRES, E.
SKOLNICK, M.
CORDONCARDO, C.
KAMB, A.
(1995). GENETIC-EVIDENCE IN MELANOMA AND BLADDER CANCERS THAT P16 AND P53 FUNCTION IN SEPARATE PATHWAYS OF TUMOR SUPPRESSION. American journal of pathology,
Vol.146
(5),
pp. 1199-8.
Eeles, R.
(1995). Developments in the study of familial breast cancer. Nurs times,
Vol.91
(5),
pp. 29-33.
show abstract
About 5% of breast cancer may be caused by dominant susceptibility genes, which can be inherited. This would equate to 1250 cases per year in the UK and 9000 in the USA. Even within these cases, there is genetic heterogeneity, meaning there are several genes involved, each giving rise to different patterns of other cancers associated with the familial breast cancer. The identification of these genes will enable the entity of familial breast cancer to be more precisely defined and has implications for management of these breast cancer patients, and their at-risk relatives. The problem with this new area of cancer genetics is that the identification of gene carriers may become possible, and this raises ethical and social issues..
WOOSTER, R.
BIGNELL, G.
LANCASTER, J.
SWIFT, S.
SEAL, S.
MANGION, J.
COLLINS, N.
GREGORY, S.
GUMBS, C.
MICKLEM, G.
BARFOOT, R.
HAMOUDI, R.
PATEL, S.
RICE, C.
BIGGS, P.
HASHIM, Y.
SMITH, A.
CONNOR, F.
ARASON, A.
GUDMUNDSSON, J.
FICENEC, D.
KELSELL, D.
FORD, D.
TONIN, P.
BISHOP, D.T.
SPURR, N.K.
PONDER, B.A.
EELES, R.
PETO, J.
DEVILEE, P.
CORNELISSE, C.
LYNCH, H.
NAROD, S.
LENOIR, G.
EGILSSON, V.
BARKADOTTIR, R.B.
EASTON, D.F.
BENTLEY, D.R.
FUTREAL, P.A.
ASHWORTH, A.
STRATTON, M.R.
(1995). IDENTIFICATION OF THE BREAST-CANCER SUSCEPTIBILITY GENE BRCA2. Nature,
Vol.378
(6559),
pp. 789-4.
WATSON, M.
MURDAY, V.
LLOYD, S.
PONDER, B.
AVERILL, D.
EELES, R.
(1995). GENETIC TESTING IN BREAST OVARIAN-CANCER (BRCA1) FAMILIES. Lancet,
Vol.346
(8974),
pp. 583-1.
Eng, C.
Murday, V.
Seal, S.
Mohammed, S.
Hodgson, S.V.
Chaudary, M.A.
Fentiman, I.S.
Ponder, B.A.
Eeles, R.A.
(1994). Cowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy?. J med genet,
Vol.31
(6),
pp. 458-461.
show abstract
Cowden syndrome is an autosomal dominant condition of multiple hamartomas. Patients with this phakomatosis have an increased risk of breast cancer and thyroid tumours. Lhermitte-Duclos disease is usually a sporadic condition of cerebellar ganglion cell hypertrophy, ataxia, mental retardation, and self-limited seizure disorder. We describe a three generation family with Cowden syndrome and Lhermitte-Duclos disease. Karyotyping performed on the peripheral lymphocytes of the proband and her affected mother showed a 46,XX complement. Single strand conformational polymorphism analysis failed to show any germline p53 mutations as a cause of the syndrome in this family..
KAMB, A.
SHATTUCKEIDENS, D.
EELES, R.
LIU, Q.
GRUIS, N.A.
DING, W.
HUSSEY, C.
TRAN, T.
MIKI, Y.
WEAVERFELDHAUS, J.
MCCLURE, M.
AITKEN, J.F.
ANDERSON, D.E.
BERGMAN, W.
FRANTS, R.
GOLDGAR, D.E.
GREEN, A.
MACLENNAN, R.
MARTIN, N.G.
MEYER, L.J.
YOUL, P.
ZONE, J.J.
SKOLNICK, M.H.
CANNONALBRIGHT, L.A.
(1994). ANALYSIS OF THE P16 GENE (CDKN2) AS A CANDIDATE FOR THE CHROMOSOME 9P MELANOMA SUSCEPTIBILITY LOCUS. Nature genetics,
Vol.8
(1),
pp. 22-5.
ENG, C.
STRATTON, M.
PONDER, B.
MURDAY, V.
EASTON, D.
SACKS, N.
WATSON, M.
EELES, R.
(1994). FAMILIAL CANCER SYNDROMES. Lancet,
Vol.343
(8899),
pp. 709-5.
Eeles, R.A.
Warren, W.
Knee, G.
Bartek, J.
Averill, D.
Stratton, M.R.
Blake, P.R.
Tait, D.M.
Lane, D.P.
Easton, D.F.
(1993). Constitutional mutation in exon 8 of the p53 gene in a patient with multiple primary tumours: molecular and immunohistochemical findings. Oncogene,
Vol.8
(5),
pp. 1269-1276.
show abstract
We report a constitutional mutation of codon 273 in exon 8 of the p53 gene. The affected individual has developed multiple independent benign and malignant tumours (tricholemmoma of the scalp, multiple trichoepitheliomata of the face, osteosarcoma of the ovary, bilateral breast cancer, malignant fibrous histiocytoma of the thigh and endometrial adenocarcinoma) and belongs to a family with some, but not all, features of the Li-Fraumeni syndrome. The mutation, found in both blood lymphocyte and tumour specimens, is a cytosine to thymine transition at codon 273, resulting in an amino acid change from arginine to cysteine. The mother and sister of the index case both died of tumours at an early age. We have demonstrated that formalin-preserved material from these tumours contains the same C-->T mutation at codon 273, indicating that this mutation has probably been transmitted through the germline. All tumours from the index case, both benign and malignant, showed immunohistochemical positivity with four antibodies to the p53 protein. Positive staining was also seen in scattered nuclei of morphologically normal epidermal keratinocytes and pilosebaceous cells, but not in lymphocytes or other morphologically normal cells from the index case. However, a similar staining pattern in apparently normal tissue was also observed in 13/48 sections from other individuals with various skin conditions (melanocytic naevi, psoriasis and normal skin adjacent to malignant melanoma and fibrous histiocytomas), suggesting that this pattern of p53 staining may not be unique to individuals with constitutional p53 mutations..
Eeles, R.A.
Fisher, C.
A'Hern, R.P.
Robinson, M.
Rhys-Evans, P.
Henk, J.M.
Archer, D.
Harmer, C.L.
(1993). Head and neck sarcomas: prognostic factors and implications for treatment. Br j cancer,
Vol.68
(1),
pp. 201-207.
show abstract
full text
One hundred and thirty patients with soft tissue sarcoma of the head and neck were treated at the Royal Marsden Hospital between 1944 and 1988. Pathological review was possible in 103 of these cases; only pathologically reviewed cases have been analysed. The median age at presentation was 36 years, and 53% were male. Four had neurofibromatosis type I, and one previous bilateral retinoblastoma. Six had undergone previous radiotherapy, 12 to 45 years prior to developing sarcoma. The tumours were < or = 5 cm in 78% of cases and high grade in 48%. Only one patient presented with lymph node metastases and only one with distant metastases (to lung). Malignant fibrous histiocytoma was the commonest histological type, occurring in 30 cases. The overall 5 year survival was 50% (95% CI 39-60). Local tumour was the cause of death in 63% of cases and 5 year local control was only 47% (95% CI 36-58) with local recurrence occurring as late as 15 years after treatment. The only favourable independent prognostic factor for survival was the ability to perform surgery (other than biopsy), with or without radiotherapy, as opposed to radiotherapy alone (hazard ratio 0.39; P = 0.003). Only one patient had a biopsy with no further treatment. Favourable independent prognostic factors for local control at 5 years were site (tumours of the head as opposed to the neck, hazard ratio 0.42; P = 0.02) and modality of treatment (combined surgery and radiotherapy compared to either alone, hazard ratio 0.31; P = 0.002). Patients in the combined modality and single treatment modality groups were well balanced for T stage, grade and tumour site. The patients in the combined treatment group had less extensive surgery, yet their local recurrence-free survival was longer. Unlike soft tissue sarcomas at other sites, those in the head and neck region more often cause death by local recurrence. The addition of radiotherapy to surgery may result in longer local recurrence-free survival..
PRICE, A.
CHAMBERLAIN, J.
MELIA, J.
SHEARER, R.J.
EELES, R.
MUIR, G.
STRATTON, M.
JARMAN, M.
DEARNALEY, D.P.
(1993). PROSTATE-CANCER. Lancet,
Vol.342
(8876),
pp. 901-5.
Tait, D.M.
Eeles, R.A.
Carter, R.
Ashley, S.
Ormerod, M.G.
(1993). Ploidy and proliferative index in medulloblastoma: useful prognostic factors?. Eur j cancer,
Vol.29A
(10),
pp. 1383-1387.
show abstract
Paraffin sections from 32 patients with primary medulloblastoma were analysed by flow cytometry for DNA ploidy and proliferative index to assess the value of these measurements in determining prognosis. Twenty-seven samples were informative. Of these 27 patients, 8 had had a total resection. The tumors were diploid in 13 patients and aneuploid in 14. Neither ploidy nor S-phase fraction were prognostic factors for survival, even when considered in conjunction with the type of surgery performed. This is in contrast to other published data, emphasising the need for large multicentre studies of biological prognostic factors in this rare tumour..
Brada, M.
Eeles, R.
Ashley, S.
Nichols, J.
Horwich, A.
(1992). Salvage radiotherapy in recurrent Hodgkin's disease. Ann oncol,
Vol.3
(2),
pp. 131-135.
show abstract
Forty-four patients with Hodgkin's disease (HD) which relapsed after chemotherapy were treated with salvage radiotherapy (S-RT) with curative intent. Patients were aged 7 to 80 years (median 32 years) at the time of S-RT and the median follow-up from S-RT was 5 years (1-15). Nine patients had recurrent HD following first-line chemotherapy and thirty five patients had refractory HD. Salvage therapy consisted of radiotherapy alone in 25 and combined chemotherapy and radiotherapy in 19 patients. The overall CR rate of salvage therapy was 66%. The overall median survival of 44 patients was 4.6 years from S-RT with 46% 5 year and 40% 10 year survivals. Age (greater than 40 years) and progression free interval (less than or equal to 1 year) were adverse independent prognostic factors for survival on multivariate analysis. The 5 and 10 year progression free survivals were 38% and 23% respectively. Adverse independent prognostic factors for progression-free survival were extranodal site of recurrence and short progression free interval (less than or equal to 1 year). We conclude that radiotherapy with or without chemotherapy has a role in the salvage of patients failing chemotherapy, particularly in those with nodal disease and progression-free interval greater than 1 year..
Leatham, E.W.
Eeles, R.
Sheppard, M.
Moskovic, E.
Williams, M.P.
Horwich, A.
Mitchell, D.N.
(1992). The association of germ cell tumours of the testis with sarcoid-like processes. Clin oncol (r coll radiol),
Vol.4
(2),
pp. 89-95.
show abstract
Sarcoid-type pulmonary lymphadenopathy associated with testicular cancer is a rare condition which has been previously reported in only 14 cases. Earlier case reports have failed to distinguish between generalized sarcoidosis as opposed to a local granulomatous reaction to tumour. We describe a further 8 cases of the association and provide strong supportive evidence for systemic sarcoidosis in 5 of our patients. In 3 of our patients with systemic sarcoidosis there was coexisting testicular cancer requiring additional treatment. We therefore advise caution in the interpretation of the clinical and histological findings in these patients, and recommend thorough investigation of all such cases..
Warren, W.
Eeles, R.A.
Ponder, B.A.
Easton, D.F.
Averill, D.
Ponder, M.A.
Anderson, K.
Evans, A.M.
DeMars, R.
Love, R.
(1992). No evidence for germline mutations in exons 5-9 of the p53 gene in 25 breast cancer families. Oncogene,
Vol.7
(5),
pp. 1043-1046.
show abstract
Recent studies have demonstrated that families with the Li-Fraumeni syndrome carry inherited point mutations of the p53 gene. In the present study 25 families with strong histories of breast cancer were screened for the presence of such mutations. Polymerase chain reaction products of exons 5-9 of the p53 gene were examined by single-stranded conformational polymorphism analysis and, in addition, exon 7 was further screened by direct sequencing. No mutations were detected in constitutive DNA by either method. These results indicate that familial breast cancer does not usually result from germline point mutations in the p53 gene..
Wooster, R.
Mangion, J.
Eeles, R.
Smith, S.
Dowsett, M.
Averill, D.
Barrett-Lee, P.
Easton, D.F.
Ponder, B.A.
Stratton, M.R.
(1992). A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome. Nat genet,
Vol.2
(2),
pp. 132-134.
show abstract
Breast cancer in men is rare--among the risk factors that have been identified are a family history of breast cancer and evidence of androgen insufficiency. We report a family in which two brothers who both developed breast cancer had clinical and endocrinological evidence of androgen resistance. Sequence analysis revealed a mutation in the androgen receptor gene on the X chromosome, within the region encoding the DNA binding domain. This is the first report of a germline mutation in a member of the steroid/thyroid hormone receptor superfamily associated with the development of cancer..
Eeles, R.A.
O'Brien, P.
Horwich, A.
Brada, M.
(1991). Non-Hodgkin's lymphoma presenting with extradural spinal cord compression: functional outcome and survival. Br j cancer,
Vol.63
(1),
pp. 126-129.
show abstract
full text
Between 1971 and 1988, 20 patients with previously undiagnosed non-Hodgkin's lymphoma (NHL), of intermediate or high grade histology presented with extradural spinal cord compression. All had decompressive surgery. The first treatment after surgery was chemotherapy in nine and radiotherapy in 11 patients. At presentation 15% were ambulant and this improved to 55% after surgery; urinary continence improved from 30 to 80%. Mobility and sphincter control remained unchanged, regardless of subsequent therapy. Chemotherapy as the initial treatment modality after surgery, either alone or in combination with radiotherapy, did not jeopardise functional outcome. Mobility after surgery was an independent prognostic factor for survival, when corrected for age and stage at presentation (P = 0.04). The treatment of intermediate and high grade NHL presenting with spinal cord compression should be based on histology, extent of disease and age, as with other sites of presentation, but should also take into consideration the prognostic importance of post-surgical mobility..
Eeles, R.A.
Tan, S.
Wiltshaw, E.
Fryatt, I.
A'Hern, R.P.
Shepherd, J.H.
Harmer, C.L.
Blake, P.R.
Chilvers, C.E.
(1991). Hormone replacement therapy and survival after surgery for ovarian cancer. Bmj,
Vol.302
(6771),
pp. 259-262.
show abstract
OBJECTIVE: To evaluate whether hormone replacement therapy affects survival in women who have undergone bilateral salphingo-oophorectomy because of epithelial ovarian cancer. DESIGN: Retrospective analysis by review of patients' notes and questionnaires completed by general practitioners to compare the overall survival and disease free survival in patients with ovarian cancer who did or did not receive hormone replacement therapy after diagnosis. Data were analysed by Cox regression, with hormone replacement therapy as a time dependent covariate because patients who received hormone replacement did so at different times after diagnosis. SETTING: Gynaecological oncology unit of Royal Marsden Hospital. PATIENTS: 373 patients aged 50 years or younger who attended the hospital from 1972 to 1988. All of the women had undergone bilateral salpingoophorectomy for epithelial ovarian cancer. In all, 78 had received hormone replacement therapy, starting at a median of four months after diagnosis. INTERVENTION: A questionnaire was sent to the general practitioners of all patients who were not recorded as having received hormone replacement therapy. MAIN OUTCOME MEASURES: Overall survival and disease free survival. RESULTS: There was no significant difference in survival between women receiving hormone replacement therapy and those not receiving it after accounting for the effects of other known prognostic factors (stage of cancer, differentiation of tumour, histological results, and time to relapse). The relative risk of dying in those who received hormone replacement therapy was 0.73 (95% confidence interval 0.44 to 1.20). In addition, there was no significant difference in disease free survival (relative risk in those receiving hormone replacement therapy was 0.90; 95% confidence interval 0.52 to 1.54). CONCLUSIONS: This study shows that hormone replacement therapy is unlikely to have a detrimental effect on the prognosis of patients with ovarian cancer, but this would be shown conclusively only by a randomised controlled trial..
Robinson, M.H.
Spruce, L.
Eeles, R.
Fryatt, I.
Harmer, C.L.
Thomas, J.M.
Westbury, G.
(1991). Limb function following conservation treatment of adult soft tissue sarcoma. Eur j cancer,
Vol.27
(12),
pp. 1567-1574.
show abstract
Quality of life and limb function were studied in 54 patients who were disease-free 2 or more years after limb-conserving treatment for soft tissue sarcoma of the leg or pelvic girdle. Tumours of the thigh predominated (25 patients) and the mean tumour size was 9.9 cm. 41 patients had been treated with a combination of surgery and radiotherapy (29 with conventional and 12 with high dose), 12 with surgery alone and one with irradiation and intra-arterial doxorubicin. Only 15 patients had a normal range of movement in all lower limb joints and only 12 had normal power in all muscle groups; tumours of the lower leg were particularly unfavourable in this respect. Gait was normal in 42 patients but 8 required a walking aid and 4 a joint support. 16 had detectable lymphoedema but only 2 needed to wear compression hosiery. 35 patients still experienced pain at some time but only 6 required analgesia. However, when assessed by questionnaire for locomotion, grooming and home/leisure/vocational activities, 37 patients (68%) reported excellent function, and only 2 had moderate impairment. Function loss was most marked in leisure (25 patients) and vocational (8) activities, but was mild in 66% of cases. Multivariate analysis was carried out to determine the prognostic factors for poor limb function. The results suggested that overall functional score was predominantly determined by gait (P less than 0.001), muscle power or range of movement (P less than 0.001), with increasing age, female sex and the use of radiotherapy poor prognostic factors. Reduced muscle power or range of movement were the major factors determining gait (P less than 0.02) with the use of radiotherapy the significant prognostic factor for both in the conventionally treated group. Doses in excess of 60 Gy resulted in increased fibrosis and a worse functional outcome. Extent of surgery was not an independent prognostic factor for limb function, although univariate analysis suggested an association with range of movement in the conventionally treated group (P less than 0.025). Despite significant objective loss of range of movement and muscle power patients retain excellent limb function and quality of life following limb conserving treatment. For optimal function, radiotherapy should be given with small fractions to a dose not exceeding 60 Gy..
Olliff, J.F.
Eeles, R.
Williams, M.P.
(1990). Mimics of metastases from testicular tumours. Clin radiol,
Vol.41
(6),
pp. 395-399.
show abstract
This paper presents 10 patients with a diagnosis of testicular tumour in whom computed tomography (CT) at staging or follow-up demonstrated abnormalities which mimic the appearance of metastatic testicular tumour. The entities mimicking metastases were sarcoidosis, mushroom worker's lung, lymphoma and phaeochromocytoma. Representative examples of these lesions are illustrated and features which may enable the radiologist to differentiate them from metastatic testicular tumour are discussed..
Newell, D.R.
Eeles, R.A.
Gumbrell, L.A.
Boxall, F.E.
Horwich, A.
Calvert, A.H.
(1989). Carboplatin and etoposide pharmacokinetics in patients with testicular teratoma. Cancer chemother pharmacol,
Vol.23
(6),
pp. 367-372.
show abstract
The pharmacokinetics of carboplatin and etoposide were studied in four testicular teratoma patients receiving four courses each of combination chemotherapy consisting of etoposide (120 mg/m2 daily x 3); bleomycin (30 mg weekly) and carboplatin. The carboplatin dose was calculated so as to achieve a constant area under the plasma concentration vs time curve (AUC) of 4.5 mg carboplatin/ml x min by using the formula: dose = 4.5 x (GFR + 25), where GFR is the absolute glomerular filtration rate measured by 51Cr-EDTA clearance. Carboplatin was given on either day 1 or day 2 of each course and pharmacokinetic studies were carried out in each patient on two courses. Etoposide pharmacokinetics were also studied on two separate courses in each patient on the day on which carboplatin was given and on a day when etoposide was given alone. The pharmacokinetics of carboplatin were the same on both the first and second courses, on which studies were carried out with overall mean +/- SD values (n = 8) of 4.8 +/- 0.6 mg/ml x min, 94 +/- 21 min, 129 +/- 21 min, 20.1 +/- 5.41, 155 +/- 33 ml/min and 102 +/- 24 ml/min for the AUC, beta-phase half-life (t 1/2 beta), mean residence time (MRT), volume of distribution (Vd) and total body (TCLR) and renal clearances (RCLR), respectively. The renal clearance of carboplatin was not significantly different from the GFR (132 +/- 32 ml/min). Etoposide pharmacokinetics were also the same on the two courses studied, with overall mean values +/- SD (n = 8) of: AUC = 5.1 +/- 0.9 mg/ml x min, t 1/2 alpha = 40 +/- 9 min, t 1/2 beta = 257 +/- 21 min, MRT = 292 +/- 25 min, Vd = 13.3 +/- 1.31, TCLR = 46 +/- 9 ml/min and RCLR = 17.6 +/- 6.3 ml/min when the drug was given alone and AUC = 5.3 +/- 0.6 mg/ml x min, t 1/2 alpha = 34 +/- 6 min, t 1/2 beta = 242 +/- 25 min, MRT = 292 +/- 25 min, Vd = 12.5 +/- 1.81, TCLR = 43 +/- 6 ml/min and RCLR = 13.4 +/- 3.5 ml/min when it was given in combination with carboplatin. Thus, the equation used to determine the carboplatin accurately predicted the AUC observed and the pharmacokinetics of etoposide were not altered by concurrent carboplatin administration. The therapeutic efficacy and toxicity of the carboplatin-etoposide-bleomycin combination will be compared to those of cisplatin, etoposide and bleomycin in a randomised trial..
EELES, R.
TAIT, D.M.
PECKHAM, M.J.
(1986). LHERMITTE SIGN AS A COMPLICATION OF CISPLATIN-CONTAINING CHEMOTHERAPY FOR TESTICULAR CANCER. Cancer treatment reports,
Vol.70
(7),
pp. 905-3.
Stoker, M.
Perryman, M.
Eeles, R.
(1982). Clonal analysis of morphological phenotype in cultured mammary epithelial cells from human milk. Proc r soc lond b biol sci,
Vol.215
(1199),
pp. 231-240.
show abstract
Three main types of colony forming epithelial cell, termed elongated, cuboidal and open, are found in cultures of human milk. Subculture of identified colonies, and cloning from single cells shows that each cell type can maintain its morphological phenotype, but in addition the cuboidal and open cell types can give rise to the elongated type. The results, which suggest a differentiation pathway starting with open cell types, are discussed in relation to differentiation studies on mammary cancer cells..
Turnbull, C.A.
Ruark, E.
Seal, S.
McDonald, H.
Zhang, F.
Elliot, A.
Lau, K.
Perdeaux, E.
Rapley, E.
Eeles, R.
Peto, J.
Kote-Jarai, Z.
Muir, K.
Nsengimana, J.
Shipley, J.
UKTCC,
Bishop, D.T.
Stratton, M.
Easton, D.F.
Huddart, R.
Rahman, N.
Identification of nine new loci for testicular cancer, including variants located near DAZL and PRDM14, genes involved in germ cell development. Nature genetics,
.
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full text
Testicular germ cell tumor (TGCT) is the most common cancer in young men and is notable for its high familial risks. To date, six loci associated with TGCT have been reported. From GWAS analysis of 307,291 SNPs in 986 cases and 4,946 controls, we selected for follow-up 694 SNPs, which we genotyped in a further 1,064 TGCT cases and 10,082 controls from the UK. We identified SNPs at nine new loci showing association with TGCT (P<5x10-8), at 1q22, 1q24.1, 3p24.3, 4q24, 5q31.1, 8q13.3, 16q12.1, 17q22 and 21q22.3, which together account for an additional 4-6% of the familial risk of TGCT. The loci include genes plausibly related to TGCT development. PRDM14, at 8q13.3, is essential for early germ cell specification whilst DAZL, at 3p24.3, is required for regulation of germ cell developmen. Furthermore, PITX1, at 5q31.1 regulates TERT expression, and is the third TGCT locus implicated in telomerase regulation..