Mutational processes molding the genomes of 21 breast cancers

Nik-Zainal, Serena, Alexandrov, Ludmil B., Wedge, David C., Van Loo, Peter, Greenman, Christopher D., Raine, Keiran, Jones, David, Hinton, Jonathan, Marshall, John, Stebbings, Lucy A., Menzies, Andrew, Martin, Sancha, Leung, Kenric, Chen, Lina, Leroy, Catherine, Ramakrishna, Manasa, Rance, Richard, Lau, King Wai, Mudie, Laura J., Varela, Ignacio, McBride, David J., Bignell, Graham R., Cooke, Susanna L., Shlien, Adam, Gamble, John, Whitmore, Ian, Maddison, Mark, Tarpey, Patrick S., Davies, Helen R., Papaemmanuil, Elli, Stephens, Philip J., McLaren, Stuart, Butler, Adam P., Teague, Jon W., Jönsson, Göran, Garber, Judy E., Silver, Daniel, Miron, Penelope, Fatima, Aquila, Boyault, Sandrine, Langerød, Anita, Tutt, Andrew, Martens, John W. M., Aparicio, Samuel A. J. R., Borg, Åke, Vincent Salomon, Anne, Thomas, Gilles, Børresen-Dale, Anne-Lise, Richardson, Andrea L., Neuberger, Michael S., Futreal, P. Andrew, Campbell, Peter J. and Stratton, Michael R. (2012) Mutational processes molding the genomes of 21 breast cancers. Cell, 149 (5). pp. 979-993. ISSN 0092-8674

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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.

Item Type: Article
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Science > School of Computing Sciences
Depositing User: Pure Connector
Date Deposited: 07 Jul 2014 13:08
Last Modified: 24 Oct 2022 06:23
DOI: 10.1016/j.cell.2012.04.024

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