Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma

• Published in: Nature (London) Vol. 482; no. 7384; pp. 226 - 231
• Main Authors: Schwartzentruber, Jeremy, Korshunov, Andrey, Liu, Xiao-Yang, Jones, David T. W., Pfaff, Elke, Jacob, Karine, Sturm, Dominik, Fontebasso, Adam M., Quang, Dong-Anh Khuong, Tönjes, Martje, Hovestadt, Volker, Albrecht, Steffen, Kool, Marcel, Nantel, Andre, Konermann, Carolin, Lindroth, Anders, Jäger, Natalie, Rausch, Tobias, Ryzhova, Marina, Korbel, Jan O., Hielscher, Thomas, Hauser, Peter, Garami, Miklos, Klekner, Almos, Bognar, Laszlo, Ebinger, Martin, Schuhmann, Martin U., Scheurlen, Wolfram, Pekrun, Arnulf, Frühwald, Michael C., Roggendorf, Wolfgang, Kramm, Christoph, Dürken, Matthias, Atkinson, Jeffrey, Lepage, Pierre, Montpetit, Alexandre, Zakrzewska, Magdalena, Zakrzewski, Krzystof, Liberski, Pawel P., Dong, Zhifeng, Siegel, Peter, Kulozik, Andreas E., Zapatka, Marc, Guha, Abhijit, Malkin, David, Felsberg, Jörg, Reifenberger, Guido, von Deimling, Andreas, Ichimura, Koichi, Collins, V. Peter, Witt, Hendrik, Milde, Till, Witt, Olaf, Zhang, Cindy, Castelo-Branco, Pedro, Lichter, Peter, Faury, Damien, Tabori, Uri, Plass, Christoph, Majewski, Jacek, Pfister, Stefan M., Jabado, Nada
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.02.2012; Nature Publishing Group
• Subjects: 631/208/737; 631/337/100/102; 631/45/612/100/2286; 692/699/67/2332; Adaptor Proteins, Signal Transducing - genetics; Amino acids; Base Sequence; Brain cancer; Brain tumors; Child; Chromatin - genetics; Chromatin - metabolism; Chromatin Assembly and Disassembly - genetics; DNA Helicases - genetics; DNA methylation; DNA Mutational Analysis; Epigenetics; Exome - genetics; Gene Expression Profiling; Genomes; Glioblastoma - genetics; Histones - genetics; Histones - metabolism; Humanities and Social Sciences; Humans; letter; Molecular Sequence Data; Mortality; multidisciplinary; Mutation; Mutation - genetics; Nuclear Proteins - genetics; Pathogenesis; Science; Science (multidisciplinary); Telomerase; Telomere - genetics; Tumor Suppressor Protein p53 - genetics; X-linked Nuclear Protein; Young adults
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10833

Recurrent histone mutations are linked to paediatric glioblastoma multiforme, an aggressive type of brain tumour. Drug targets in glioblastoma Exome sequencing of 48 childhood glioblastoma samples has identified somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway in 44% of tumours. Mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were found in 31% of tumours, the first indication that this gene is linked to tumorigenesis. These mutations are shown to be specific to glioblastoma and are highly prevalent in children and young adults, suggesting that defects of the chromatin architecture may underlie the condition. Childhood glioblastoma is fatal and resistant to therapy, so the discovery of potentially disease-relevant drug targets is an important advance. 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 1 , 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 telomeres 6 , 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.