Clarke, M.
Mackay, A.
Ismer, B.
Pickles, J.C.
Tatevossian, R.G.
Newman, S.
Bale, T.A.
Stoler, I.
Izquierdo, E.
Temelso, S.
Carvalho, D.M.
Molinari, V.
Burford, A.
Howell, L.
Virasami, A.
Fairchild, A.R.
Avery, A.
Chalker, J.
Kristiansen, M.
Haupfear, K.
Dalton, J.D.
Orisme, W.
Wen, J.
Hubank, M.
Kurian, K.M.
Rowe, C.
Maybury, M.
Crosier, S.
Knipstein, J.
Schüller, U.
Kordes, U.
Kram, D.E.
Snuderl, M.
Bridges, L.
Martin, A.J.
Doey, L.J.
Al-Sarraj, S.
Chandler, C.
Zebian, B.
Cairns, C.
Natrajan, R.
Boult, J.K.
Robinson, S.P.
Sill, M.
Dunkel, I.J.
Gilheeney, S.W.
Rosenblum, M.K.
Hughes, D.
Proszek, P.Z.
Macdonald, T.J.
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Haberler, C.
Slavc, I.
Packer, R.
Ng, H.-.
Caspi, S.
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Faganel Kotnik, B.
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Baird, L.
Davare, M.A.
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Capra, M.
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Kerl, K.
Hettmer, S.
Pietsch, T.
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Driever, P.H.
Korshunov, A.
Hiddingh, L.
Worst, B.C.
Sturm, D.
Zuckermann, M.
Witt, O.
Bloom, T.
Mitchell, C.
Miele, E.
Colafati, G.S.
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Bailey, S.
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Hassall, T.E.
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von Deimling, A.
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Pfister, S.M.
Sahm, F.
Baker, S.J.
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Jones, C.
(2020). Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes. Cancer discov,
Vol.10
(7),
pp. 942-963.
show abstract
full text
Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890..
Vinci, M.
Burford, A.
Molinari, V.
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Popov, S.
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Pemberton, H.N.
Lord, C.J.
Gutteridge, A.
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Moore, A.S.
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H'mida-Ben Brahim, D.
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de Torres, C.
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Mackay, A.
Jones, C.
(2018). Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells. Nat med,
Vol.24
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pp. 1204-1215.
show abstract
full text
The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments..
Mackay, A.
Burford, A.
Molinari, V.
Jones, D.T.
Izquierdo, E.
Brouwer-Visser, J.
Giangaspero, F.
Haberler, C.
Pietsch, T.
Jacques, T.S.
Figarella-Branger, D.
Rodriguez, D.
Morgan, P.S.
Raman, P.
Waanders, A.J.
Resnick, A.C.
Massimino, M.
Garrè, M.L.
Smith, H.
Capper, D.
Pfister, S.M.
Würdinger, T.
Tam, R.
Garcia, J.
Thakur, M.D.
Vassal, G.
Grill, J.
Jaspan, T.
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Jones, C.
(2018). Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial. Cancer cell,
Vol.33
(5),
pp. 829-842.e5.
show abstract
full text
The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8+ tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term "HGG" in the pediatric population..
Mackay, A.
Burford, A.
Carvalho, D.
Izquierdo, E.
Fazal-Salom, J.
Taylor, K.R.
Bjerke, L.
Clarke, M.
Vinci, M.
Nandhabalan, M.
Temelso, S.
Popov, S.
Molinari, V.
Raman, P.
Waanders, A.J.
Han, H.J.
Gupta, S.
Marshall, L.
Zacharoulis, S.
Vaidya, S.
Mandeville, H.C.
Bridges, L.R.
Martin, A.J.
Al-Sarraj, S.
Chandler, C.
Ng, H.-.
Li, X.
Mu, K.
Trabelsi, S.
Brahim, D.H.
Kisljakov, A.N.
Konovalov, D.M.
Moore, A.S.
Carcaboso, A.M.
Sunol, M.
de Torres, C.
Cruz, O.
Mora, J.
Shats, L.I.
Stavale, J.N.
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Reis, R.M.
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Monje, M.
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Fouladi, M.
von Bueren, A.O.
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Jones, C.
(2017). Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. Cancer cell,
Vol.32
(4),
pp. 520-537.e5.
show abstract
full text
We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification..
Taylor, K.R.
Mackay, A.
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Philippe, C.
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Vol.46
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pp. 457-461.
full text