We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
Raw data have been submitted to the European-Genome Phenome Archive under the overarching accession number EGAS00001001178 (please see Supplementary Notes for breakdown by data type). Somatic variants have been deposited at the International Cancer Genome Consortium Data Portal (https://dcc.icgc.org/).
This work has been funded through the ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (BASIS), a European research project funded by the European Community’s Seventh Framework Programme (FP7/2010-2014) under the grant agreement number 242006; the Triple Negative project funded by the Wellcome Trust (grant reference 077012/Z/05/Z) and the HER2+ project funded by Institut National du Cancer (INCa) in France (grant numbers 226-2009, 02-2011, 41-2012, 144-2008, 06-2012). The ICGC Asian Breast Cancer Project was funded through a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A111218-SC01). Personally funded by grants above: F.G.R.-G., S.M., K.R., S.M. were funded by BASIS. Recruitment was performed under the auspices of the ICGC breast cancer projects run by the UK, France and Korea. For contributions towards instruments, specimens and collections: Tayside Tissue Bank (funded by CRUK, University of Dundee, Chief Scientist Office & Breast Cancer Campaign), Asan Bio-Resource Center of the Korea Biobank Network, Seoul, South Korea, OSBREAC consortium, The Icelandic Centre for Research (RANNIS), The Swedish Cancer Society and the Swedish Research Council, and Fondation Jean Dausset-Centre d’Etudes du polymorphisme humain. Icelandic Cancer Registry, The Brisbane Breast Bank (The University of Queensland, The Royal Brisbane and Women’s Hospital and QIMR Berghofer), Breast Cancer Tissue and Data Bank at KCL and NIHR Biomedical Research Centre at Guy’s and St Thomas’s Hospitals. Breakthrough Breast Cancer and Cancer Research UK Experimental Cancer Medicine Centre at KCL. For pathology review: The Mouse Genome Project and Department of Pathology, Cambridge University Hospitals NHS Foundation Trust for microscopes. A. Richardson, A. Ehinger, A. Vincent-Salomon, C. Van Deurzen, C. Purdie, D. Larsimont, D. Giri, D. Grabau, E. Provenzano, G. MacGrogan, G. Van den Eynden, I. Treilleux, J. E. Brock, J. Jacquemier, J. Reis-Filho, L. Arnould, L. Jones, M. van de Vijver, Ø. Garred, R. Salgado, S. Pinder, S. R. Lakhani, T. Sauer, V. Barbashina. Illumina UK Ltd for input on optimization of sequencing throughout this project. Wellcome Trust Sanger Institute Sequencing Core Facility, Core IT Facility and Cancer Genome Project Core IT team and Cancer Genome Project Core Laboratory team for general support. Personal funding: S.N.-Z. is a Wellcome Beit Fellow and personally funded by a Wellcome Trust Intermediate Fellowship (WT100183MA). L.B.A. is supported through a J. Robert Oppenheimer Fellowship at Los Alamos National Laboratory. A.L.R. is partially supported by the Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer (NIH/NCI 5 P50 CA168504-02). D.G. was supported by the EU-FP7-SUPPRESSTEM project. A.S. was supported by Cancer Genomics Netherlands through a grant from the Netherlands Organisation of Scientific research (NWO). M.S. was supported by the EU-FP7-DDR response project. C.S. and C.D. are supported by a grant from the Breast Cancer Research Foundation. E.B. was funded by EMBL. C.S. is funded by FNRS (Fonds National de la Recherche Scientifique). S.J.J. is supported by Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Republic Korea (NRF 2011-0030105). G.K. is supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (NRF 2015R1A2A1A10052578). J.F. received funding from an ERC Advanced grant (no. 322737). For general contribution and administrative support: Fondation Synergie Lyon Cancer in France. J. G. Jonasson, Department of Pathology, University Hospital & Faculty of Medicine, University of Iceland. K. Ferguson, Tissue Bank Manager, Brisbane Breast Bank and The Breast Unit, The Royal Brisbane and Women's Hospital, Brisbane, Australia. The Oslo Breast Cancer Consortium of Norway (OSBREAC). Angelo Paradiso, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari Italy. A. Vines for administratively supporting to identifying the samples, organizing the bank, and sending out the samples. M. Schlooz-Vries, J. Tol, H. van Laarhoven, F. Sweep, P. Bult in Nijmegen for contributions in Nijmegen. This research used resources provided by the Los Alamos National Laboratory Institutional Computing Program, which is supported by the US Department of Energy National Nuclear Security Administration under contract no. DE-AC52-06NA25396. Research performed at Los Alamos National Laboratory was carried out under the auspices of the National Nuclear Security Administration of the United States Department of Energy. N. Miller (in memoriam) for her contribution in setting up the clinical database. Finally, we would like to acknowledge all members of the ICGC Breast Cancer Working Group and ICGC Asian Breast Cancer Project.
Extended data figures
This file zipped contains Supplementary Tables 1-21.