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

Schwartzentruber, Jeremy and Korshunov, Andrey and Liu, Xiao-Yang and Jones, David T. W. and Pfaff, Elke and Hauser, Péter and Garami, Miklós and Klekner, Álmos and Bognár, László (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature, 484 (7392). p. 130. ISSN 0028-0836

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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 cases1–4. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatricGBMsamples.Somaticmutations 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 inATRX (a-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 (n5784) showedH3F3A mutations to be specific toGBM 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.

Item Type: Article
Subjects: R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia
Depositing User: Dr. Álmos Klekner
Date Deposited: 07 Oct 2014 09:35
Last Modified: 07 Oct 2014 09:35

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