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

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

doi:10.1007/s00401-021-02302-6

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.

Highlights

Glioblastoma is the most common malignant brain tumor among adults
Almost all samples were obtained at first surgery for the brain tumor; whereas, one sample was diagnosed as a recurrence of an Isocitrate dehydrogenase (IDH)-wildtype glioblastoma
We present a new molecular type that is linked to a specific histological pattern of IDH-wildtype glioblastoma

Summary

Introduction

Median overall survival after standard of care treatment, which includes resection followed by radio- and chemotherapy, is only 15 months [15]. This tumor type is predominantly found in the elderly, with a peak of incidence at 75–84 years [23]. Presence of microvascular proliferation and/or necrosis, often accompanied by perinecrotic palisades, are mandatory for the histological diagnosis of glioblastoma. Irrespective of these characteristics, glioblastoma may harbor histological patterns of small cells, primitive neuronal cells, oligodendroglial components,

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Conclusion