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Summary
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 expos
ed. To explore these mechanisms further, we generat
ed catalogs of somatic mutation from 21 breast cancers and appli
ed 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 exhibit
ed a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detect
ed. A remarkable phenomenon of localiz
ed hypermutation, term
ed 鈥渒ataegis,鈥?was observ
ed. Regions of kataegis differ
ed between cancers but usually colocaliz
ed 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 propos
ed.
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