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

Nik-Zainal S1,2, Davies H1, Staaf J3, Ramakrishna M1, Glodzik D1, Zou X1, Martincorena I1, Alexandrov LB1,4,5, Martin S1, Wedge DC1, Van Loo P1,6, Ju YS1,Smid M7, Brinkman AB8, Morganella S9, Aure MR10,11, Lingjærde OC11,12, Langerød A10,11, Ringnér M3, Ahn SM13, Boyault S14, Brock JE15, Broeks A16,Butler A1, Desmedt C17, Dirix L18, Dronov S1, Fatima A19, Foekens JA7, Gerstung M1, Hooijer GK20, Jang SJ21, Jones DR1, Kim HY22, King TA23,Krishnamurthy S24, Lee HJ21, Lee JY25, Li Y1, McLaren S1, Menzies A1, Mustonen V1, O'Meara S1, Pauporté I26, Pivot X27, Purdie CA28, Raine K1,Ramakrishnan K1, Rodríguez-González FG7, Romieu G29, Sieuwerts AM7, Simpson PT30, Shepherd R1, Stebbings L1, Stefansson OA31, Teague J1, Tommasi S32, Treilleux I33, Van den Eynden GG18,34, Vermeulen P18,34, Vincent-Salomon A35, Yates L1, Caldas C36, Veer LV16, Tutt A37,38, Knappskog S39,40, Tan BK41,42, Jonkers J16, Borg Å3, Ueno NT24, Sotiriou C17, Viari A43,44, Futreal PA1,45, Campbell PJ1, Span PN46, Van Laere S18, Lakhani SR30,47, Eyfjord JE31,Thompson AM28,48, Birney E9, Stunnenberg HG8, van de Vijver MJ20, Martens JW7, Børresen-Dale AL10,11, Richardson AL15,19, Kong G22, Thomas G44,Stratton MR1.

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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.