title: H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers.
abstract: Pediatric glioblastoma (pedGBM) is an extremely aggressive pediatric brain tumor, accounting for ~6% of all central nervous system neoplasms in children. Approximately half of pedGBM harbor recurrent somatic mutations in histone 3 variants or, infrequently, IDH1/2. The remaining subset of pedGBM is highly heterogeneous, and displays a variety of genomic and epigenetic features. In the current study, we aimed to further stratify an H3-/IDH-wild type (wt) pedGBM cohort assessed through genome-wide molecular profiling. As a result, we identified three molecular subtypes of these tumors, differing in their genomic and epigenetic signatures as well as in their clinical behavior. We designated these subtypes 'pedGBM_MYCN' (enriched for MYCN amplification), 'pedGBM_RTK1' (enriched for PDGFRA amplification) and 'pedGBM_RTK2' (enriched for EGFR amplification). These molecular subtypes were associated with significantly different outcomes, i.e. pedGBM_RTK2 tumors show a significantly longer survival time (median OS 44 months), pedGBM_MYCN display extremely poor outcomes (median OS 14 months), and pedGBM_RTK1 tumors harbor an intermediate prognosis. In addition, the various molecular subtypes of H3-/IDH-wt pedGBM were clearly distinguishable from their adult counterparts, underlining their biological distinctiveness. In conclusion, our study demonstrates significant molecular heterogeneity of H3-/IDH-wt pedGBM in terms of DNA methylation and cytogenetic alterations. The recognition of three molecular subtypes of H3-/IDH-wt pedGBM further revealed close correlations with biological parameters and clinical outcomes and may therefore, be predictive of response to standard treatment protocols, but could also be useful for stratification for novel, molecularly based therapies.
authors.affiliation: Clinical Cooperation Unit Neuropathology (G380), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. andrey.korshunov@med.uni-heidelberg.de.|Department of Neuropathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. andrey.korshunov@med.uni-heidelberg.de.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. andrey.korshunov@med.uni-heidelberg.de.
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.affiliation: Clinical Cooperation Unit Neuropathology (G380), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.|Department of Neuropathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schrimpf
authors.affiliation: Department of Neuropathology and Neuroradiology, NN Burdenko Neurosurgical Institute, 5th Tverskaya-Yamskaya Str. 16, Moscow, Russia.
authors.forename: Marina
authors.initials: M
authors.lastname: Ryzhova
authors.affiliation: Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.|Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Sturm
authors.affiliation: Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Chavez
authors.affiliation: Division of Molecular Genetics (B060), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.affiliation: Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors.forename: Tanvi
authors.initials: T
authors.lastname: Sharma
authors.affiliation: Clinical Cooperation Unit Neuropathology (G380), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.|Department of Neuropathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Habel
authors.affiliation: Division of Molecular Pathology, Institute of Cancer Research, London, SW7 3RP, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Burford
authors.affiliation: Division of Molecular Pathology, Institute of Cancer Research, London, SW7 3RP, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.affiliation: Department of Neuro-Oncology, Russian Scientific Center of Radiology, Profsoyuznaya Str. 36, Moscow, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Zheludkova
authors.affiliation: Department of Neuro-Oncology, Federal Research Clinical Center for Pediatric Hematology, Oncology, Immunology, Moscow, Russia.
authors.forename: Ella
authors.initials: E
authors.lastname: Kumirova
authors.affiliation: Department of Child and Adolescent Health/Division of Pediatric Hematology and Oncology, University Hospital Goettingen, 37075, Goettingen, Germany.
authors.forename: Christof M
authors.initials: CM
authors.lastname: Kramm
authors.affiliation: Department of Neuropathology and Neuroradiology, NN Burdenko Neurosurgical Institute, 5th Tverskaya-Yamskaya Str. 16, Moscow, Russia.
authors.forename: Andrey
authors.initials: A
authors.lastname: Golanov
authors.affiliation: Clinical Cooperation Unit Neuropathology (G380), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.|Department of Neuropathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.affiliation: Clinical Cooperation Unit Neuropathology (G380), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.|Department of Neuropathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.|Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.|Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. david.jones@dkfz.de.|Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. david.jones@dkfz.de.
authors.forename: David T W
authors.initials: DTW
authors.lastname: Jones
mesh_terms: D000293:Adolescent; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic
chemical_list: D006657:Histones; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: Brain tumor; EGFR; Glioblastoma; MYCN; Methylation; PDGFRA; Pediatric; Prognostic; RTK; Subgroup; Survival