Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma
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 cases1,2,3,4. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric G...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) Editorial |
| Language: | English |
| Published: |
29 January 2012
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| In: |
Nature
Year: 2012, Volume: 482, Issue: 7384, Pages: 226-231 |
| ISSN: | 1476-4687 |
| DOI: | 10.1038/nature10833 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1038/nature10833 Verlag, Volltext: https://www.nature.com/articles/nature10833 
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| Author Notes: | Jeremy Schwartzentruber, Andrey Korshunov, Xiao-Yang Liu, David T.W. Jones, Elke Pfaff, Karine Jacob, Dominik Sturm, Adam M. Fontebasso, Dong-Anh Khuong Quang, Martje Tönjes, Volker Hovestadt, Steffen Albrecht, Marcel Kool, Andre Nantel, Carolin Konermann, Anders Lindroth, Natalie Jäger, Tobias Rausch, Marina Ryzhova, Jan O. Korbel, Thomas Hielscher, Peter Hauser, Miklos Garami, Almos Klekner, Laszlo Bognar, Martin Ebinger, Martin U. Schuhmann, Wolfram Scheurlen, Arnulf Pekrun, Michael C. Frühwald, Wolfgang Roggendorf, Christoph Kramm, Matthias Dürken, Jeffrey Atkinson, Pierre Lepage, Alexandre Montpetit, Magdalena Zakrzewska, Krzystof Zakrzewski, Pawel P. Liberski, Zhifeng Dong, Peter Siegel, Andreas E. Kulozik, Marc Zapatka, Abhijit Guha, David Malkin, Jörg Felsberg, Guido Reifenberger, Andreas von Deimling, Koichi Ichimura, V. Peter Collins, Hendrik Witt, Till Milde, Olaf Witt, Cindy Zhang, Pedro Castelo-Branco, Peter Lichter, Damien Faury, Uri Tabori, Christoph Plass, Jacek Majewski, Stefan M. Pfister and Nada Jabado |
| Summary: | 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 cases1,2,3,4. 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)5 and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres6,7, 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. |
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| Item Description: | Gesehen am 14.05.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1476-4687 |
| DOI: | 10.1038/nature10833 |