Mutational processes molding the genomes of 21 breast cancers

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 VarelaDavid 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 W.M. Martens, Samuel A.J.R. 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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)979-993
Number of pages15
JournalCell
Volume149
Issue number5
DOIs
StatePublished - May 25 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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