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Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity

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Abstract

In contrast to the relative morphological uniformity of histone H3 K27-mutant high-grade gliomas, H3 G34-mutant tumors present as a histopathologically heterogeneous group of neoplasms, with microscopic characteristics typical of either glioblastoma (GBM) or central nervous system primitive neuroectodermal tumors (CNS-PNET). In the current study, we performed an integrative clinical, histopathological and molecular analysis of 81 G34-mutant CNS tumors. Routinely prepared tumor tissues were investigated for genomic and epigenomic alterations. Despite their divergent histopathological appearance, CNS tumors with H3.3 G34 mutations displayed uniform epigenetic signatures, suggesting a single biological origin. Comparative cytogenetic analysis with other GBM subtypes disclosed a high frequency and high specificity of 3q and 4q loss across G34-mutant tumors. PDGFRA amplification was more common in cases with GBM than with PNET morphology (36 vs. 5 %, respectively), while CCND2 amplifications showed the opposite trend (5 vs. 27 %). Survival analysis revealed the presence of amplified oncogene(s) and MGMT methylation as independent prognostic markers for poor and favorable outcomes, respectively. No difference in outcome was found between morphological variants (GBM vs. PNET). Thus, different histological variants of G34-mutant CNS tumors likely comprise a single biological entity (high-grade glioma with H3 G34 mutation, HGG_G34), which should be outlined in future diagnostic and therapeutic classifications. Screening for H3.3 G34 mutation should therefore be recommended as a routine diagnostic marker for supratentorial CNS tumors across a broad histological spectrum.

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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, David Capper, David Reuss, Daniel Schrimpf, Jochen Meyer & Andreas von Deimling

  2. Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany

    Andrey Korshunov, David Capper, David Reuss, Daniel Schrimpf, Jochen Meyer & Andreas von Deimling

  3. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Andrey Korshunov, David Capper, David Reuss, Marcel Kool, Peter Lichter, Andreas von Deimling, Stefan M. Pfister & David T. W. Jones

  4. Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia

    Marina Ryzhova

  5. Division of Molecular Genetics (B060), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Volker Hovestadt & Peter Lichter

  6. Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Dominik Sturm, Marcel Kool, Stefan M. Pfister & David T. W. Jones

  7. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany

    Dominik Sturm & Stefan M. Pfister

  8. Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, Sutton, UK

    Chris Jones

  9. Department of Neuro-Oncology, Russian Scientific Center of Radiology, 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 Neuroradiology, NN Burdenko Neurosurgical Institute, Moscow, Russia

    Andrey Golanov

  12. Center of Neuropathology, Lüdwig-Maximilians University, Munich, Germany

    Ulrich Schüller

  13. Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany

    Michel Mittelbronn

  14. Institute of Neuropathology, University Hospital Münster, Münster, Germany

    Martin Hasselblatt

  15. Department of Neuropathology, Institute of Pathology and Neuropathology, University Tübingen, Tübingen, Germany

    Jens Schittenhelm

  16. Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany

    Guido Reifenberger

  17. Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany

    Christel Herold-Mende

Authors
  1. Andrey Korshunov
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  2. David Capper
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  3. David Reuss
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  4. Daniel Schrimpf
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  5. Marina Ryzhova
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  6. Volker Hovestadt
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  7. Dominik Sturm
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  8. Jochen Meyer
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  9. Chris Jones
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  10. Olga Zheludkova
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  12. Andrey Golanov
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  13. Marcel Kool
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  14. Ulrich Schüller
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  15. Michel Mittelbronn
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  16. Martin Hasselblatt
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  17. Jens Schittenhelm
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  18. Guido Reifenberger
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  19. Christel Herold-Mende
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  20. Peter Lichter
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  21. Andreas von Deimling
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  22. Stefan M. Pfister
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  23. David T. W. Jones
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Corresponding author

Correspondence to Andrey Korshunov.

Electronic supplementary material

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401_2015_1493_MOESM1_ESM.pdf

Suppl. Figure 1. Unsupervised hierarchical clustering of DNA methylation of the full cohort of various glioblastoma molecular variants. H3G34, H3K27, IDH1 mutant groups and RTK1 tumors are clearly distinguished (PDF 5003 kb)

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Korshunov, A., Capper, D., Reuss, D. et al. Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity. Acta Neuropathol 131, 137–146 (2016). https://doi.org/10.1007/s00401-015-1493-1

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  • DOI: https://doi.org/10.1007/s00401-015-1493-1

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