The landscape of cancer genes and mutational processes in breast cancer.
Stephens PJ., Tarpey PS., Davies H., Van Loo P., Greenman C., Wedge DC., Nik-Zainal S., Martin S., Varela I., Bignell GR., Yates LR., Papaemmanuil E., Beare D., Butler A., Cheverton A., Gamble J., Hinton J., Jia M., Jayakumar A., Jones D., Latimer C., Lau KW., McLaren S., McBride DJ., Menzies A., Mudie L., Raine K., Rad R., Chapman MS., Teague J., Easton D., Langerød A., Oslo Breast Cancer Consortium (OSBREAC) None., Lee MT., Shen CY., Tee BT., Huimin BW., Broeks A., Vargas AC., Turashvili G., Martens J., Fatima A., Miron P., Chin SF., Thomas G., Boyault S., Mariani O., Lakhani SR., van de Vijver M., van 't Veer L., Foekens J., Desmedt C., Sotiriou C., Tutt A., Caldas C., Reis-Filho JS., Aparicio SA., Salomon AV., Børresen-Dale AL., Richardson AL., Campbell PJ., Futreal PA., Stratton MR.
All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.