title: Landscape of somatic mutations in 560 breast cancer whole-genome sequences.
abstract: 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.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.|East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.|Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, NM 87545, New Mexico, USA.|Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.
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authors.lastname: Alexandrov
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Young Seok
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authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam 3015CN, The Netherlands.
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authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo 0310, Norway.|K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo 0310, Norway.
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authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo 0310, Norway.|K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo 0310, Norway.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
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authors.affiliation: National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore.|Singapore General Hospital, Outram Road, 169608, Singapore.
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authors.affiliation: The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
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authors.affiliation: Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard., Houston, Texas 77030, USA.
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authors.forename: Alain
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.|Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, Texas 77230, USA.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
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authors.affiliation: The University of Queensland, UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland 4029, Australia.|Pathology Queensland, The Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia.
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authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam 3015CN, The Netherlands.
authors.forename: John W M
authors.initials: JW
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authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo 0310, Norway.|K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo 0310, Norway.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.|Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Andrea L
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authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, South Korea.
authors.forename: Gu
authors.initials: G
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authors.affiliation: Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France.
authors.forename: Gilles
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Michael R
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mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004261:DNA Replication / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006801:Humans; D008297:Male; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D009857:Oncogenes / Q000235:genetics; D059767:Recombinational DNA Repair / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm