Mutational processes molding the genomes of 21 breast cancers.
Nik-Zainal S., Alexandrov LB., Wedge DC., Van Loo P., Greenman CD., Raine K., Jones D., Hinton J., Marshall J., Stebbings LA., Menzies A., Martin S., Leung K., Chen L., Leroy C., Ramakrishna M., Rance R., Lau KW., Mudie LJ., Varela I., McBride DJ., Bignell GR., Cooke SL., Shlien A., Gamble J., Whitmore I., Maddison M., Tarpey PS., Davies HR., Papaemmanuil E., Stephens PJ., McLaren S., Butler AP., Teague JW., Jönsson G., Garber JE., Silver D., Miron P., Fatima A., Boyault S., Langerød A., Tutt A., Martens JWM., Aparicio SAJR., Borg Å., Salomon AV., Thomas G., Børresen-Dale A-L., Richardson AL., Neuberger MS., Futreal PA., Campbell PJ., Stratton MR.
All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis," was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed.