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Summary
All cancers carry so
matic
mutations. The patterns of
mutation in cancer geno
mes reflect the DNA da
mage and repair processes to which cancer cells and their precursors have been exposed. To explore these
mechanis
ms further, we generated catalogs of so
matic
mutation fro
m 21 breast cancers and applied
mathe
matical
methods to extract
mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with
m>BRCA1m> or
m>BRCA2m>
mutations exhibited a characteristic co
mbination of substitution
mutation signatures and a distinctive profile of deletions. Co
mplex relationships between so
matic
mutation prevalence and transcription were detected. A re
markable pheno
menon of localized hyper
mutation, ter
med 鈥渒ataegis,鈥?was observed. Regions of kataegis differed between cancers but usually colocalized with so
matic rearrange
ments. Base substitutions in these regions were al
most exclusively of cytosine at TpC dinucleotides. The
mechanis
ms underlying
most of these
mutational signatures are unknown. However, a role for the
m>APOBECm> fa
mily of cytidine dea
minases is proposed.
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