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Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Davies, Helen 
Staaf, Johan 
Ramakrishna, Manasa 
Glodzik, Dominik 

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.

Description

Keywords

Breast Neoplasms, Cohort Studies, DNA Mutational Analysis, DNA Replication, DNA, Neoplasm, Female, Genes, BRCA1, Genes, BRCA2, Genome, Human, Genomics, Humans, Male, Mutagenesis, Mutation, Mutation Rate, Oncogenes, Recombinational DNA Repair

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

534

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research Uk (None)
Cancer Research UK (CB4140)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (60098573)
Cancer Research UK (unknown)
Department of Health (via National Institute for Health Research (NIHR)) (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Cancer Research Uk (None)
Cambridge University Hospitals NHS Foundation Trust (CUH) (RG51913)
European Commission (242006)