1. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma
- Author
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Andreas von Deimling, Hendrik Witt, Arnulf Pekrun, André Nantel, Krzystof Zakrzewski, Volker Hovestadt, Wolfram Scheurlen, Andrey Korshunov, Martin Ebinger, Marc Zapatka, Natalie Jäger, Tobias Rausch, Wolfgang Roggendorf, Michael C. Frühwald, Peter Lichter, Almos Klekner, David T.W. Jones, Andreas E. Kulozik, Martin U. Schuhmann, Elke Pfaff, Olaf Witt, Marina Ryzhova, Martje Tönjes, V. Peter Collins, Steffen Albrecht, Cindy Zhang, Koichi Ichimura, Uri Tabori, Damien Faury, Marcel Kool, David Malkin, Peter Hauser, Dong Anh Khuong Quang, Karine Jacob, Pedro Castelo-Branco, Till Milde, Jeremy Schwartzentruber, Jan O. Korbel, Abhijit Guha, Anders Lindroth, Peter M. Siegel, Matthias Dürken, CM Kramm, Guido Reifenberger, Miklós Garami, Jeffrey Atkinson, Jacek Majewski, Adam M. Fontebasso, Pierre Lepage, Nada Jabado, Pawel P. Liberski, Alexandre Montpetit, Jörg Felsberg, Stefan M. Pfister, Thomas Hielscher, Magdalena Zakrzewska, Carolin Konermann, László Bognár, Xiaoyang Liu, Christoph Plass, Dominik Sturm, and Zhifeng Dong
- Subjects
X-linked Nuclear Protein ,DNA Mutational Analysis ,Molecular Sequence Data ,medicine.disease_cause ,Histones ,Histone H3 ,medicine ,Humans ,Exome ,Child ,ATRX ,Pericentric heterochromatin ,Adaptor Proteins, Signal Transducing ,Genetics ,H3 K27M Mutation ,Mutation ,Multidisciplinary ,Base Sequence ,biology ,Gene Expression Profiling ,DNA Helicases ,Nuclear Proteins ,Telomere ,Chromatin Assembly and Disassembly ,Chromatin ,H3F3B ,Histone ,biology.protein ,Tumor Suppressor Protein p53 ,Glioblastoma ,Co-Repressor Proteins ,Molecular Chaperones - Abstract
Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.
- Published
- 2012
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