Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities

David E. Reuss, Annekathrin Kratz, Felix Sahm, David Capper, Daniel Schrimpf, Christian Koelsche, Volker Hovestadt, Melanie Bewerunge-Hudler, David T.W. Jones, Jens Schittenhelm, Michel Mittelbronn, Elisabeth Rushing, Matthias Simon, Manfred Westphal, Andreas Unterberg, Michael Platten, Werner Paulus, Guido Reifenberger, Joerg Christian Tonn, Kenneth AldapeStefan M. Pfister, Andrey Korshunov, Michael Weller, Christel Herold-Mende, Wolfgang Wick, Sebastian Brandner, Andreas von Deimling*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

219 Citations (Scopus)

Abstract

IDH wild type (IDHwt) anaplastic astrocytomas WHO grade III (AA III) are associated with poor outcome. To address the possibilities of molecular subsets among astrocytoma or of diagnostic reclassification, we analyzed a series of 160 adult IDHwt tumors comprising 120 AA III and 40 diffuse astrocytomas WHO grade II (A II) for molecular hallmark alterations and established methylation and copy number profiles. Based on molecular profiles and hallmark alterations the tumors could be grouped into four major sets. 124/160 (78 %) tumors were diagnosed as the molecular equivalent of conventional glioblastoma (GBM), and 15/160 (9 %) as GBM-H3F3A mutated (GBM-H3). 13/160 (8 %) exhibited a distinct methylation profile that was most similar to GBM-H3-K27, however, lacked the H3F3A mutation. This group was enriched for tumors of infratentorial and midline localization and showed a trend towards a more favorable prognosis. All but one of the 120 IDHwt AA III could be assigned to these three groups. 7 tumors recruited from the 40 A II, comprised a variety of molecular signatures and all but one were reclassified into distinct WHO entities of lower grades. Interestingly, TERT mutations were exclusively restricted to the molecular GBM (78 %) and associated with poor clinical outcome. However, the GBM-H3 group lacking TERT mutations appeared to fare even worse. Our data demonstrate that most of the tumors diagnosed as IDHwt astrocytomas can be allocated to other tumor entities on a molecular basis. The diagnosis of IDHwt diffuse astrocytoma or anaplastic astrocytoma should be used with caution.

Original languageEnglish
Pages (from-to)407-417
Number of pages11
JournalActa Neuropathologica
Volume130
Issue number3
DOIs
Publication statusPublished - 21 Sept 2015
Externally publishedYes

Keywords

  • Astrocytoma
  • Classification
  • Glioblastoma
  • H3F3A
  • IDH1
  • IDH2
  • TERT

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