H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers

  • Andrey Korshunov
  • Daniel Schrimpf
  • Marina Ryzhova
  • Dominik Sturm
  • Lukas Chavez
  • Volker Hovestadt
  • Tanvi Sharma
  • Antje Habel
  • Anna Burford
  • Chris Jones
  • Olga Zheludkova
  • Ella Kumirova
  • Christof M. Kramm
  • Andrey Golanov
  • David Capper
  • Andreas von Deimling
  • Stefan M. Pfister
  • David T. W. Jones
Original Paper

DOI: 10.1007/s00401-017-1710-1

Cite this article as:
Korshunov, A., Schrimpf, D., Ryzhova, M. et al. Acta Neuropathol (2017). doi:10.1007/s00401-017-1710-1

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.

Keywords

Glioblastoma Pediatric Brain tumor Methylation Prognostic Subgroup Survival MYCN PDGFRA EGFR RTK 

Supplementary material

401_2017_1710_MOESM1_ESM.pdf (1.4 mb)
Supplementary material 1 (PDF 1466 kb)
401_2017_1710_MOESM2_ESM.xlsx (18 kb)
Supplementary material 2 (XLSX 17 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Andrey Korshunov
    • 1
    • 2
    • 3
  • Daniel Schrimpf
    • 1
    • 2
  • Marina Ryzhova
    • 4
  • Dominik Sturm
    • 5
    • 6
  • Lukas Chavez
    • 5
  • Volker Hovestadt
    • 7
  • Tanvi Sharma
    • 5
  • Antje Habel
    • 1
    • 2
  • Anna Burford
    • 8
  • Chris Jones
    • 8
  • Olga Zheludkova
    • 9
  • Ella Kumirova
    • 10
  • Christof M. Kramm
    • 11
  • Andrey Golanov
    • 4
  • David Capper
    • 1
    • 2
    • 3
  • Andreas von Deimling
    • 1
    • 2
    • 3
  • Stefan M. Pfister
    • 3
    • 5
    • 6
  • David T. W. Jones
    • 3
    • 5
  1. 1.Clinical Cooperation Unit Neuropathology (G380)German Cancer Research Center (DKFZ)HeidelbergGermany
  2. 2.Department of NeuropathologyHeidelberg University HospitalHeidelbergGermany
  3. 3.German Cancer Consortium (DKTK)German Cancer Research Center (DKFZ)HeidelbergGermany
  4. 4.Department of Neuropathology and NeuroradiologyNN Burdenko Neurosurgical InstituteMoscowRussia
  5. 5.Division of Pediatric Neurooncology (B062)German Cancer Research Center (DKFZ)HeidelbergGermany
  6. 6.Department of Pediatric Hematology and OncologyHeidelberg University HospitalHeidelbergGermany
  7. 7.Division of Molecular Genetics (B060)German Cancer Research Center (DKFZ)HeidelbergGermany
  8. 8.Division of Molecular PathologyInstitute of Cancer ResearchLondonUK
  9. 9.Department of Neuro-OncologyRussian Scientific Center of RadiologyMoscowRussia
  10. 10.Department of Neuro-OncologyFederal Research Clinical Center for Pediatric Hematology, Oncology, ImmunologyMoscowRussia
  11. 11.Department of Child and Adolescent Health/Division of Pediatric Hematology and OncologyUniversity Hospital GoettingenGoettingenGermany

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