All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis1, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.
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Genome sequence data have been deposited at the European Genome-phenome Archive under accession number EGAD00001000133. Affymetrix SNP6 data have been deposited under accession number E-MTAB-1110.
This work was supported by the Wellcome Trust (grant reference 077012/Z/05/Z) and Breakthrough Breast Cancer. P.J.C. is personally funded through a Wellcome Trust Senior Clinical Research Fellowship (grant reference WT088340MA). P.V.L. is a postdoctoral researcher at the Research Foundation - Flanders (FWO) and is a visiting scientist at the Wellcome Trust Sanger Institute, supported by a travel grant from the FWO. I.V. is supported by a fellowship from The International Human Frontier Science Program Organization. A.-L.B.-D. and A.L. are funded by the Norwegian Research Council, The Norwegian Cancer Society, The Radium Hospital Foundation and Health Region SØ. A.V.S. was supported by an ‘Interface INSERM’ grant. J.S.R.-F. is funded in part by Breakthrough Breast Cancer and is a recipient of the 2010 CRUK Future Leaders Prize. D.E. is a Principal Research Fellow of Cancer Research UK. A.T. receives financial support from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London, and from King’s College Hospital NHS Foundation Trust in conjunction with The Experimental Cancer Medicine Centre Initiative jointly funded by Cancer Research UK, the National Institute for Health Research, the Welsh Assembly Government, the HSC R&D Office for Northern Ireland and the Chief Scientist Office, Scotland. C.D. and C.S. received partial funding from the MEDIC foundation and the Fonds National de Recherche Scientifique. J.M. and J.F. are funded in part by a research grant from the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research. The INCa-Synergie facility received support from the Institut National du Cancer, the Fondation Synergie-Lyon-Cancer, the Canceropole Lyon Auverge Rhone Alpes and the Centre Leon Berard. A.C.V. is funded by The Ludwig Institute for Cancer Research. L.v.’t.V. and A. Broeks receive funding from the Dutch Genomics Initiative-Cancer Genomics Center. We also acknowledge support for sample collection, banking and processing from the Biological Resource Center of Institut Curie; the Breakthrough Breast Cancer Unit; P. Watson and the BCCA Tumour Tissue Repository; the Centre for Translational Genomics; A. Lane and P. T. Simpson; the Australian Biospecimens Network; the Breast Unit at Royal Brisbane and Women’s Hospital; the Dana-Farber/Harvard SPORE in breast cancer (reference CA089393); A. M. Sieuwerts; and the Singhealth Tissue Repository, Singapore. We are grateful also for the support of T. B. Tean, and acknowledge the input and guidance of P. Spellman and A. Ashworth.
This file contains Supplementary Tables 1-7.