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

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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.

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Acknowledgements

We thank the Microarray Unit of the German Cancer Research Center (DKFZ) Genomics and Proteomics Core Facility for excellent technical support. This work was principally supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grant #01KU1201A and the e:Med Joint Research Project SYS-GLIO #031A425A). Additional support came from the German Cancer Research Center—Heidelberg Center for Personalized Oncology (DKFZ-HIPO) and the German Cancer Consortium (DKTK). CJ and AB acknowledge NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and the ICR.

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Authors and Affiliations

  1. Clinical Cooperation Unit Neuropathology (G380), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Andrey Korshunov, Daniel Schrimpf, Antje Habel, David Capper & Andreas von Deimling

  2. Department of Neuropathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany

    Andrey Korshunov, Daniel Schrimpf, Antje Habel, David Capper & Andreas von Deimling

  3. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Andrey Korshunov, David Capper, Andreas von Deimling, Stefan M. Pfister & David T. W. Jones

  4. Department of Neuropathology and Neuroradiology, NN Burdenko Neurosurgical Institute, 5th Tverskaya-Yamskaya Str. 16, Moscow, Russia

    Marina Ryzhova & Andrey Golanov

  5. Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Dominik Sturm, Lukas Chavez, Tanvi Sharma, Stefan M. Pfister & David T. W. Jones

  6. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany

    Dominik Sturm & Stefan M. Pfister

  7. Division of Molecular Genetics (B060), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Volker Hovestadt

  8. Division of Molecular Pathology, Institute of Cancer Research, London, SW7 3RP, UK

    Anna Burford & Chris Jones

  9. Department of Neuro-Oncology, Russian Scientific Center of Radiology, Profsoyuznaya Str. 36, Moscow, Russia

    Olga Zheludkova

  10. Department of Neuro-Oncology, Federal Research Clinical Center for Pediatric Hematology, Oncology, Immunology, Moscow, Russia

    Ella Kumirova

  11. Department of Child and Adolescent Health/Division of Pediatric Hematology and Oncology, University Hospital Goettingen, 37075, Goettingen, Germany

    Christof M. Kramm

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  1. Andrey Korshunov
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  2. Daniel Schrimpf
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  3. Marina Ryzhova
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  7. Tanvi Sharma
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  9. Anna Burford
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  10. Chris Jones
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  11. Olga Zheludkova
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  12. Ella Kumirova
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  14. Andrey Golanov
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  15. David Capper
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  16. Andreas von Deimling
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  17. Stefan M. Pfister
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  18. David T. W. Jones
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Correspondence to Andrey Korshunov or David T. W. Jones.

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Korshunov, A., Schrimpf, D., Ryzhova, M. et al. H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers. Acta Neuropathol 134, 507–516 (2017). https://doi.org/10.1007/s00401-017-1710-1

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  • DOI: https://doi.org/10.1007/s00401-017-1710-1

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