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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.

Original publication

DOI

10.1016/j.cell.2012.04.024

Type

Journal article

Journal

Cell

Publication Date

17/05/2012

Volume

149

Pages

979 - 993

Addresses

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.

Keywords

Breast Cancer Working Group of the International Cancer Genome Consortium, Humans, Breast Neoplasms, Cytidine Deaminase, BRCA2 Protein, DNA Mutational Analysis, Mutation, Genes, BRCA1, Female, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, APOBEC-1 Deaminase