Abstract
SummaryAll 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.PaperClip
Highlights
We have relatively limited understanding, of the DNA damage and repair processes that have been operative during the lifetime of the patient and that are responsible for the somatic mutations that underlie the development of all cancers in the first place
These mutations are enriched at CpG dinucleotides and exhibit a transcriptional strand bias reflecting past activity of transcription-coupled nucleotide excision repair (TCR) on bulky adducts of guanine caused by tobacco carcinogens (Hainaut and Pfeifer, 2001)
Sequencing of Breast Cancers We sequenced the complete genomes of 21 primary breast cancers and matched normal DNAs from the same individuals
Summary
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. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. 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. A role for the APOBEC family of cytidine deaminases is proposed
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