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

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.

Figure 1. The APOBEC3A/3B germline deletion polymorphism is associated with an increased burden of presumptive apobec-related signatures

(A) Signatures 2 and 13 extracted by Non-negative Matrix Factorization share sequence-specific mutation characteristics to members of the AID/APOBEC family of cytidine deaminases. Both signatures are characterized by C>T transitions and/or C>G transversions at a TpCpX sequence context. Signature 2 is dominated by C>T transitions. Signature 13 is dominated by C>G transversions. (B) The APOBEC3A/3B hybrid deletion allele. The genes are in tandem on chromosome 22. The polymorphism involves a deletion of the APOBEC3B coding sequence fusing the 3′UTR of APOBEC3B to the 3′UTR of APOBEC3A.

Figure 2. Additional features of Signatures 2/13 that are similar to mutagenic patterns of APOBECs

(A) Several cancers showed an excess of mutations arising on the same strand or strand-coordinated mutagenesis. For reasons of space only a subset of cancers is depicted here. Odds ratio (OR) of observed strand-coordinated mutations over expected is presented (as a red box) with 95% confidence intervals (grey line). The OR was calculated from the observed number of same strand/different strand mutations divided by the number of expected same strand/different strand mutations (where the expected numbers were corrected for the overall mutation rate of the cancer and the mutation spectra). A higher OR indicates more same strand mutations than expected. Patients highlighted in red have hypermutator breast cancers. (B) A direct correlation is seen between the OR of strand-coordinated mutagenesis and the fractional burden of Signatures 2/13. Patients who are homozygous/heterozygous for the deletion allele are highlighted (red dots) to show the enrichment of deletion carriers amongst breast cancers with a high burden of Signatures 2/13.