@article{fbdba88deed64cba910ad40eb09b0e4b,
title = "Glioblastomas with primitive neuronal component harbor a distinct methylation and copy-number profile with inactivation of TP53, PTEN, and RB1",
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.",
keywords = "Classification, DNA methylation, GBM, PNET, Phenotype, Plasticity",
author = "Suwala, {Abigail K.} and Damian Stichel and Daniel Schrimpf and Maas, {Sybren L.N.} and Martin Sill and Hildegard Dohmen and Rouzbeh Banan and Annekathrin Reinhardt and Philipp Sievers and Felix Hinz and Mirjam Blattner-Johnson and Christian Hartmann and Leonille Schweizer and Boldt, {Henning B.} and Kristensen, {Bjarne Winther} and Jens Schittenhelm and Wood, {Matthew D.} and Guillaume Chotard and Rolf Bjergvig and Anirban Das and Uri Tabori and Martin Hasselblatt and Andrey Korshunov and Zied Abdullaev and Martha Quezado and Kenneth Aldape and Harter, {Patrick N.} and Matija Snuderl and J{\"u}rgen Hench and Stephan Frank and Till Acker and Sebastian Brandner and Frank Winkler and Pieter Wesseling and Pfister, {Stefan M.} and Reuss, {David E.} and Wolfgang Wick and {von Deimling}, Andreas and Jones, {David T.W.} and Felix Sahm",
note = "Funding Information: This study was financially supported by the SFB 1389 UNITE by the German research foundation (DFG). AKS is a fellow of the Mildred Scheel Postdoctoral Fellowship Program of the German Cancer Aid. FS is a fellow of the Else Kr{\"o}ner Excellence Program of the Else Kr{\"o}ner-Fresenius Stiftung (EKFS). PS is a fellow of the Hertie Academy of Excellence in Clinical Neuroscience. LS is a fellow of the BIH‐Charit{\'e} Clinical Scientist Program by the Charit{\'e} and BIH and supported by a DKTK Young Investigator grant. Methylation profiling at NYU Langone Health was in part supported by grants from the Friedberg Charitable Foundation, the Making Headway Foundation and the Sohn Foundation (to M.S.). Methylation profiling at UCL/UCLH was partly supported by NIHR funding the UCLH BRC (to SB). We would like to thank Viktoria Zeller, Ulrike Vogel, Sabrina Sprengart, Lisa Kreinbihl, Laura D{\"o}rner, Moritz Schalles, Lea Hofmann, Ulrike Lass and Jochen Meyer for excellent assistance. Funding Information: This study was financially supported by the SFB 1389 UNITE by the German research foundation (DFG). AKS is a fellow of the Mildred Scheel Postdoctoral Fellowship Program of the German Cancer Aid. FS is a fellow of the Else Kr{\"o}ner Excellence Program of the Else Kr{\"o}ner-Fresenius Stiftung (EKFS). PS is a fellow of the Hertie Academy of Excellence in Clinical Neuroscience. LS is a fellow of the BIH‐Charit{\'e} Clinical Scientist Program by the Charit{\'e} and BIH and supported by a DKTK Young Investigator grant. Methylation profiling at NYU Langone Health was in part supported by grants from the Friedberg Charitable Foundation, the Making Headway Foundation and the Sohn Foundation (to M.S.). Methylation profiling at UCL/UCLH was partly supported by NIHR funding the UCLH BRC (to SB). We would like to thank Viktoria Zeller, Ulrike Vogel, Sabrina Sprengart, Lisa Kreinbihl, Laura D{\"o}rner, Moritz Schalles, Lea Hofmann, Ulrike Lass and Jochen Meyer for excellent assistance. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = jul,
doi = "10.1007/s00401-021-02302-6",
language = "English (US)",
volume = "142",
pages = "179--189",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "1",
}