Mutational processes molding the genomes of 21 breast cancers
Authors list
Serena Nik-Zainal Ludmil B Alexandrov David C Wedge Peter Van Loo Christopher D Greenman Keiran Raine David Jones Jonathan Hinton John Marshall Lucy A Stebbings Andrew Menzies Sancha Martin Kenric Leung Lina Chen Catherine Leroy Manasa Ramakrishna Richard Rance King Wai Lau Laura J Mudie Ignacio Varela David J McBride Graham R Bignell Susanna L Cooke Adam Shlien John Gamble Ian Whitmore Mark Maddison Patrick S Tarpey Helen R Davies Elli Papaemmanuil Philip J Stephens Stuart McLaren Adam P Butler Jon W Teague Göran Jönsson Judy E Garber Daniel Silver Penelope Miron Aquila Fatima Sandrine Boyault Anita Langerod Andrew Tutt John WM Martens Samuel AJR Aparicio Åke Borg Anne Vincent Salomon Gilles Thomas Anne-Lise Borresen-Dale Andrea L Richardson Michael S Neuberger P Andrew Futreal Peter J Campbell Michael R Stratton Breast Cancer Working Group of the International Cancer Genome Consortium Toggle all authors (54)
Abstract
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.
Full text links
Publisher website (DOI) 10.1016/j.cell.2012.04.024
Europe PubMed Central 22608084
Pubmed 22608084
Keywords
Type of publication