Landscape of somatic mutations in 560 breast cancer whole genome sequences

By S. Nik-Zainal, H. Davies, J. Staaf, Manasa Ramakrishna, D. Głodzik, Xueqing Zou, Iñigo Martincorena, Ludmil B. Alexandrov, Sancha Martin, David C. Wedge and 78 more. Nature, 2016

2,045 citations recorded by the source corpus.

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. Whole-genome sequencing of tumours from 560 breast cancer cases provides a comprehensive genome-wide view of recurrent somatic mutations and mutation frequencies across both protein coding and non-coding regions; several mutational signatures in these cancer genomes are associated with BRCA1 or BRCA2 function and defective homologous-recombination-based DNA repair. This study reports whole-genome sequencing of tumours and normal tissue from 560 breast cancer cases, providing a comprehensive genome-wide view of recurrent somatic mutations and mutation frequencies across both protein coding and non-coding regions. The authors analyse mutational signatures in these cancer genomes, including a new investigation of rearrangement mutational processes, and find several that are associated with BRCA1 or BRCA2 function and defective homologous-recombination-based DNA repair. They also find mutational signatures showing distinct DNA replication strand biases.

Subfields: Cancer Research, Genetics, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/abb27e35f11dcd60325f42f270b7811a4e852852

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Citations in the corpus

A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity. (2018, neutral): “Driver as well as passenger mutations arise through diverse mutational processes resulting in distinct mutational signatures, at least 12 of which are found in BC (Alexandrov et al., 2013; Nik-Zainal et al., 2012, 2016).”
Universal Patterns of Selection in Cancer and Somatic Tissues (2018, neutral): “S4A ) (Nik-Zainal et al., 2016).”
The BioGRID interaction database: 2017 update (2016, background): “Extensive network contexts now provide a basis for the rationalization of perturbations caused by disease-associated mutations (10– 12) and have helped deconvolve complex mutational profiles generated by genome-wide association studies (GWAS) and next-generation sequencing-based approaches for analy”
Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer. (2018, positive): “In addition, previous studies have demonstrated that SVs may define subtypes of ovarian, pancreatic, and breast cancers (Nik-Zainal et al., 2016; Patch et al., 2015; Waddell et al., 2015; Wang et al., 2017).”
Awareness and current knowledge of breast cancer (2017, background): “Since mutational inactivation of gene activity is reserved to cancer cells in these contexts, cancer gene modification techniques may give an opening for selective targeting without major hazards of normal, noncancer cells [244, 245].”