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Nat Genet. 2014 May;46(5):487-91. doi: 10.1038/ng.2955. Epub 2014 Apr 13.

Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer.

Author information

1
1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. [2] Department of Medical Genetics, Addenbrooke's Hospital National Health Service (NHS) Trust, Cambridge, UK.
2
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
3
1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. [2] Department of Haematology, University of Cambridge, Cambridge, UK.
4
1] Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway. [2] Department of Oncology, Haukeland University Hospital, Bergen, Norway.
5
1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. [2] Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
6
Regional Genetics Laboratories, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.

Abstract

The somatic mutations in a cancer genome are the aggregate outcome of one or more mutational processes operative through the lifetime of the individual with cancer. Each mutational process leaves a characteristic mutational signature determined by the mechanisms of DNA damage and repair that constitute it. A role was recently proposed for the APOBEC family of cytidine deaminases in generating particular genome-wide mutational signatures and a signature of localized hypermutation called kataegis. A germline copy number polymorphism involving APOBEC3A and APOBEC3B, which effectively deletes APOBEC3B, has been associated with modestly increased risk of breast cancer. Here we show that breast cancers in carriers of the deletion show more mutations of the putative APOBEC-dependent genome-wide signatures than cancers in non-carriers. The results suggest that the APOBEC3A-APOBEC3B germline deletion allele confers cancer susceptibility through increased activity of APOBEC-dependent mutational processes, although the mechanism by which this increase in activity occurs remains unknown.

PMID:
24728294
PMCID:
PMC4137149
DOI:
10.1038/ng.2955
[Indexed for MEDLINE]
Free PMC Article

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