Landscape of somatic mutations in 560 breast cancer whole-genome sequences
Nik-Zainal S., Davies H., Staaf J., Ramakrishna M., Glodzik D., Zou X., Martincorena I., Alexandrov LB., Martin S., Wedge DC., Van Loo P., Ju YS., Smid M., Brinkman AB., Morganella S., Aure MR., Lingjærde OC., Langerød A., Ringnér M., Ahn SM., Boyault S., Brock JE., Broeks A., Butler A., Desmedt C., Dirix L., Dronov S., Fatima A., Foekens JA., Gerstung M., Hooijer GKJ., Jang SJ., Jones DR., Kim HY., King TA., Krishnamurthy S., Lee HJ., Lee JY., Li Y., McLaren S., Menzies A., Mustonen V., O'Meara S., Pauporté I., Pivot X., Purdie CA., Raine K., Ramakrishnan K., Rodríguez-González FG., Romieu G., Sieuwerts AM., Simpson PT., Shepherd R., Stebbings L., Stefansson OA., Teague J., Tommasi S., Treilleux I., Van Den Eynden GG., Vermeulen P., Vincent-Salomon A., Yates L., Caldas C., Veer LVT., Tutt A., Knappskog S., Tan BKT., Jonkers J., Borg Å., Ueno NT., Sotiriou C., Viari A., Futreal PA., Campbell PJ., Span PN., Van Laere S., Lakhani SR., Eyfjord JE., Thompson AM., Birney E., Stunnenberg HG., Van De Vijver MJ., Martens JWM., Børresen-Dale AL., Richardson AL., Kong G., Thomas G., Stratton MR.
© 2016 Macmillan Publishers Limited. All rights reserved. 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.