Integrative genomic analysis reveals functional diversification of APOBEC gene family in breast cancer

Yanfeng Zhang, Ryan Delahanty, Xingyi Guo, Wei Zheng, Jirong Long

The human APOBEC protein family plays critical but distinct roles in host defense. Recent studies revealed that APOBECs mediate C-to-T mutagenesis in multiple cancers, including breast cancer. It is still unclear whether APOBEC gene family shows functional diversification involved in cancer mutagenesis. We performed an integrated analysis to characterize the functional diversification of APOBEC gene family associated with breast cancer mutagenesis relative to estrogen receptor (ER) status. Among the APOBEC family, we found that both APOBEC3B and APOBEC3C mRNA levels were significantly higher in estrogen receptor negative (ER-) subtype compared with estrogen receptor positive (ER+) subtype (P < 2.2 × 10(-16) and P < 3.1 × 10(-5), respectively). Epigenomic data further reflected the distinct chromatin states of APOBEC3B and APOBEC3C relative to ER status. Notably, we observed the significantly positive correlation between the APOBEC3B-mediated mutagenesis and APOBEC3B expression levels in ER+ cancers but not in ER- cancers. In contrast, we discovered the negative correlation of APOBEC3C mRNA levels with base-substitution mutations in ER- tumors. Meanwhile, we observed that breast cancers in carriers of germline deletion of APOBEC3B gene harbor similar mutation patterns, but higher mutation rates in the TCW motif (W corresponds to A or T) than cancers in non-carriers, indicating additional factors may also induce carcinogenic mutagenesis. These results suggest that functional potential of APOBEC3B and APOBEC3C involved in cancer mutagenesis is associated with ER status.