Signatures of mutational processes in human cancer.
Alexandrov LB., Nik-Zainal S., Wedge DC., Aparicio SA., Behjati S., Biankin AV., Bignell GR., Bolli N., Borg A., Børresen-Dale AL., Boyault S., Burkhardt B., Butler AP., Caldas C., Davies HR., Desmedt C., Eils R., Eyfjörd JE., Foekens JA., Greaves M., Hosoda F., Hutter B., Ilicic T., Imbeaud S., Imielinski M., Jäger N., Jones DT., Jones D., Knappskog S., Kool M., Lakhani SR., López-Otín C., Martin S., Munshi NC., Nakamura H., Northcott PA., Pajic M., Papaemmanuil E., Paradiso A., Pearson JV., Puente XS., Raine K., Ramakrishna M., Richardson AL., Richter J., Rosenstiel P., Schlesner M., Schumacher TN., Span PN., Teague JW., Totoki Y., Tutt AN., Valdés-Mas R., van Buuren MM., van 't Veer L., Vincent-Salomon A., Waddell N., Yates LR., Australian Pancreatic Cancer Genome Initiative None., ICGC Breast Cancer Consortium None., ICGC MMML-Seq Consortium None., ICGC PedBrain None., Zucman-Rossi J., Futreal PA., McDermott U., Lichter P., Meyerson M., Grimmond SM., Siebert R., Campo E., Shibata T., Pfister SM., Campbell PJ., Stratton MR.
All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.