Journal
NATURE
Volume 482, Issue 7384, Pages 226-U119Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature10833
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Funding
- Cole Foundation
- Genome Canada
- Canadian Institute for Health Research (CIHR)
- Genome BC
- Genome Quebec
- CIHR-ICR (Institute for Cancer Research)
- C17, through the Genome Canada/CIHR
- Hungarian Scientific Research Fund(OTKA) [T-04639]
- National Research and Development Fund (NKFP) [1A/002/2004]
- German Cancer Aid [109252]
- CNS tumour tissue bank [108456]
- BMBF
- Samantha Dickson Brain Tumour Trust
- National Cancer Center Heidelberg
- German Cancer Research Center
- Foundation of Stars
- Sybille Assmus Award for Neurooncology
- Fonds de Recherche en Sante du Quebec
- The Brain Tumour Charity [10/106] Funding Source: researchfish
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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 cases(1-4). 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 (alpha-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.
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