Mutational Processes Molding the Genomes of 21 Breast Cancers


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.

DOI: 10.1016/j.cell.2012.04.024

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@inproceedings{NikZainal2012MutationalPM, title={Mutational Processes Molding the Genomes of 21 Breast Cancers}, author={Serena Nik-Zainal and Ludmil B. Alexandrov and David C. Wedge and Peter Van Loo and Christopher D. Greenman and Keiran Raine and David Jones and Jonathan Hinton and John Marshall and Lucy A. Stebbings and Andrew Menzies and Sancha Martin and Kenric Leung and Lina Chen and Catherine Leroy and Manasa Ramakrishna and Richard Rance and King Wai Lau and Laura J. Mudie and Ignacio Varela and David J. McBride and Graham R. Bignell and Susanna L. Cooke and Adam Shlien and John Gamble and Ian Whitmore and Mark Maddison and Patrick S. Tarpey and Helen R. Davies and Elli Papaemmanuil and Philip J. Stephens and Stuart McLaren and Adam P. Butler and Jon W. Teague and G{\"{o}ran J{\"{o}nsson and Judy E. Garber and Daniel Silver and Penelope Miron and Aquila Fatima and Sandrine Boyault and Anita Langer\od and Andrew Tutt and John W.M. Martens and Samuel A.J.R. Aparicio and {\AA}ke Borg and Anne Vincent Salomon and Gilles Thomas and Anne-Lise B\orresen-Dale and Andrea L. Richardson and Michael S. Neuberger and P. Andrew Futreal and Peter J. Campbell and Michael R. Stratton}, booktitle={Cell}, year={2012} }