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Acta Neuropathologica

, Volume 131, Issue 1, pp 137–146 | Cite as

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

  • Andrey Korshunov
  • David Capper
  • David Reuss
  • Daniel Schrimpf
  • Marina Ryzhova
  • Volker Hovestadt
  • Dominik Sturm
  • Jochen Meyer
  • Chris Jones
  • Olga Zheludkova
  • Ella Kumirova
  • Andrey Golanov
  • Marcel Kool
  • Ulrich Schüller
  • Michel Mittelbronn
  • Martin Hasselblatt
  • Jens Schittenhelm
  • Guido Reifenberger
  • Christel Herold-Mende
  • Peter Lichter
  • Andreas von Deimling
  • Stefan M. Pfister
  • David T. W. Jones
Original Paper

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.

Keywords

Glioblastoma PNET G34 mutation Methylation Prognostic Subgroup Survival 

Supplementary material

401_2015_1493_MOESM1_ESM.pdf (4.9 mb)
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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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Andrey Korshunov
    • 1
    • 2
    • 3
  • David Capper
    • 1
    • 2
    • 3
  • David Reuss
    • 1
    • 2
    • 3
  • Daniel Schrimpf
    • 1
    • 2
  • Marina Ryzhova
    • 4
  • Volker Hovestadt
    • 5
  • Dominik Sturm
    • 6
    • 7
  • Jochen Meyer
    • 1
    • 2
  • Chris Jones
    • 8
  • Olga Zheludkova
    • 9
  • Ella Kumirova
    • 10
  • Andrey Golanov
    • 11
  • Marcel Kool
    • 3
    • 6
  • Ulrich Schüller
    • 12
  • Michel Mittelbronn
    • 13
  • Martin Hasselblatt
    • 14
  • Jens Schittenhelm
    • 15
  • Guido Reifenberger
    • 16
  • Christel Herold-Mende
    • 17
  • Peter Lichter
    • 3
    • 5
  • Andreas von Deimling
    • 1
    • 2
    • 3
  • Stefan M. Pfister
    • 3
    • 6
    • 7
  • David T. W. Jones
    • 3
    • 6
  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 NeuropathologyNN Burdenko Neurosurgical InstituteMoscowRussia
  5. 5.Division of Molecular Genetics (B060)German Cancer Research Center (DKFZ)HeidelbergGermany
  6. 6.Division of Pediatric Neurooncology (B062)German Cancer Research Center (DKFZ)HeidelbergGermany
  7. 7.Department of Pediatric Hematology and OncologyHeidelberg University HospitalHeidelbergGermany
  8. 8.Divisions of Molecular Pathology and Cancer TherapeuticsInstitute of Cancer ResearchSuttonUK
  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 NeuroradiologyNN Burdenko Neurosurgical InstituteMoscowRussia
  12. 12.Center of NeuropathologyLüdwig-Maximilians UniversityMunichGermany
  13. 13.Institute of Neurology (Edinger Institute)Goethe UniversityFrankfurtGermany
  14. 14.Institute of NeuropathologyUniversity Hospital MünsterMünsterGermany
  15. 15.Department of Neuropathology, Institute of Pathology and NeuropathologyUniversity TübingenTübingenGermany
  16. 16.Department of NeuropathologyHeinrich Heine UniversityDüsseldorfGermany
  17. 17.Department of NeurosurgeryHeidelberg University HospitalHeidelbergGermany

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