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Summary
All cancers carry somatic mutations. The
patterns of mutation in cancer genomes reflect the DNA damage and re
pair
processes to which cancer cells and their
precursors have been ex
posed. To ex
plore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and a
pplied mathematical methods to extract mutational signatures of the underlying
processes. Multi
ple 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. Com
plex relationshi
ps between somatic mutation
prevalence and transcri
ption were detected. A remarkable
phenomenon of localized hy
permutation, termed 鈥渒ataegis,鈥?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 T
pC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the
APOBEC family of cytidine deaminases is
pro
posed.
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