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

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  • A Corrigendum to this article was published on 28 March 2012

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 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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Figure 1: Most frequent mutations in paediatric GBM.
Figure 2: Mutations in H3F3A, ATRX and DAXX distinguish paediatric from adult GBM.
Figure 3: H3F3A mutation variants show distinct expression profiles and are associated with alternative lengthening of telomeres.

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Data deposits

Sequence reads for GBM samples have been deposited in the European Genome Archive under accession number EGAS00001000226.

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Acknowledgements

The authors are indebted to J. Rak, N. Sonenberg and C. Polychronakos for critical reading of this manuscript. D. M. Pearson, A. Wittmann, L. Sieber and L. Senf are acknowledged for technical assistance. This work was supported by the Cole Foundation, and was funded in part by Genome Canada and the Canadian Institute for Health Research (CIHR) with co-funding from Genome BC, Genome Quebec, CIHR-ICR (Institute for Cancer Research) and C17, through the Genome Canada/CIHR joint ATID Competition (project title: The Canadian Paediatric Cancer Genome Consortium: Translating next generation sequencing technologies into improved therapies for high-risk childhood cancer (NJ)), the Hungarian Scientific Research Fund (OTKA) Contract No. T-04639, the National Research and Development Fund (NKFP) Contract No. 1A/002/2004 (P.H., M.G., L.B.), the PedBrain project contributing to the International Cancer Genome Consortium funded by the German Cancer Aid (109252) and the CNS tumour tissue bank within the priority program on tumour tissue banking of the German Cancer Aid (108456), the BMBF, the Samantha Dickson Brain Tumour Trust, a grant from the National Cancer Center Heidelberg (“Paediatric Brain Tumor Preclinical Testing”), and a guest scientist stipend to M.R. from the German Cancer Research Center. X.-Y.L. and A.M.F. are the recipients of studentship awards from CIHR. K.J. is the recipient of a studentship from the Foundation of Stars. S.M.P. is the recipient of the Sybille Assmus Award for Neurooncology in 2009 and N.J. is the recipient of a Chercheur Boursier Award from Fonds de Recherche en Santé du Québec.

Author information

A.K., X.-Y.L., D.T.W.J., E.P., D.-A.K.Q., S.A., M.T., Z.D., P.S., N. Jäger, H.W., T.M., C.Z., U.T., P.C.-B., D.F., P.L. and A.M. performed experimental work. X.-Y.L., J.S., J.M., D.T.W.J., M.K., D.M., V.H., K.J., A.M.F., D.S., A.N., C.K., A.L., A.K., T.R., J.M., J.O.K., T.H., P.L., C.P., S.M.P. and N. Jabado performed data analyses and produced the text and figures. M.R., M.E., M.U.S., W.S., A.P. and M.C.F., W.R., C.K., M.D., J.A., P.H., M.G., L.B., P.P.L., M. Zakrzewska, K.Z., A.E.K., M. Zapatka, A.G., A.K., G.R., J.F., A.v.D., K.I., V.P.C. and O.W. collected data and provided patient materials. J.M., S.M.P. and N. Jabado provided leadership for the project. All authors contributed to the final manuscript.

Correspondence to Jacek Majewski or Stefan M. Pfister or Nada Jabado.

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