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 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 Langerød, Andrew Tutt, John W M Martens, Samuel A J R Aparicio, Åke Borg, Anne Vincent Salomon, Gilles Thomas, Anne-Lise Børresen-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, 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 Langerød, Andrew Tutt, John W M Martens, Samuel A J R Aparicio, Åke Borg, Anne Vincent Salomon, Gilles Thomas, Anne-Lise Børresen-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
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.
Copyright © 2012 Elsevier Inc. All rights reserved.
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References
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Source: PubMed