Glioblastomas with primitive neuronal component harbor a distinct methylation and copy-number profile with inactivation of TP53, PTEN, and RB1

Abigail K. Suwala, Damian Stichel, Daniel Schrimpf, Sybren L. N. Maas, Martin Sill, Hildegard Dohmen, Rouzbeh Banan, Annekathrin Reinhardt, Philipp Sievers, Felix Hinz, Mirjam Blattner-Johnson, Christian Hartmann, Leonille Schweizer, Henning B. Boldt, Bjarne Winther Kristensen, Jens Schittenhelm, Matthew D. Wood, Guillaume Chotard, Rolf Bjergvig, Anirban DasUri Tabori, Martin Hasselblatt, Andrey Korshunov, Zied Abdullaev, Martha Quezado, Kenneth Aldape, Patrick N. Harter, Matija Snuderl, J. rgen Hench, Stephan Frank, Till Acker, Sebastian Brandner, Frank Winkler, Pieter Wesseling, Stefan M. Pfister, David E. Reuss, Wolfgang Wick, Andreas von Deimling, David T. W. Jones, Felix Sahm

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Glioblastoma IDH-wildtype presents with a wide histological spectrum. Some features are so distinctive that they are considered as separate histological variants or patterns for the purpose of classification. However, these usually lack defined (epi-)genetic alterations or profiles correlating with this histology. Here, we describe a molecular subtype with overlap to the unique histological pattern of glioblastoma with primitive neuronal component. Our cohort consists of 63 IDH-wildtype glioblastomas that harbor a characteristic DNA methylation profile. Median age at diagnosis was 59.5 years. Copy-number variations and genetic sequencing revealed frequent alterations in TP53, RB1 and PTEN, with fewer gains of chromosome 7 and homozygous CDKN2A/B deletions than usually described for IDH-wildtype glioblastoma. Gains of chromosome 1 were detected in more than half of the cases. A poorly differentiated phenotype with frequent absence of GFAP expression, high proliferation index and strong staining for p53 and TTF1 often caused misleading histological classification as carcinoma metastasis or primitive neuroectodermal tumor. Clinically, many patients presented with leptomeningeal dissemination and spinal metastasis. Outcome was poor with a median overall survival of only 12 months. Overall, we describe a new molecular subtype of IDH-wildtype glioblastoma with a distinct histological appearance and genetic signature.
Original languageEnglish
Pages (from-to)179-189
Number of pages11
JournalActa Neuropathologica
Volume142
Issue number1
DOIs
Publication statusPublished - 1 Jul 2021

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