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 LichterAndreas von Deimling, Stefan M. Pfister, David T.W. Jones

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

112 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)137-146
Number of pages10
JournalActa Neuropathologica
Volume131
Issue number1
DOIs
Publication statusPublished - 1 Jan 2016
Externally publishedYes

Keywords

  • G34 mutation
  • Glioblastoma
  • Methylation
  • PNET
  • Prognostic
  • Subgroup
  • Survival

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