APOBEC3A is a prominent cytidine deaminase in breast cancer

APOBEC cytidine deaminases are the second-most prominent source of mutagenesis in sequenced tumors.Previous studies have proposed that APOBEC3B (A3B) is the major source of mutagenesis in breast cancer (BRCA).We show that APOBEC3A (A3A) is the only APOBEC whose expression correlates with APOBEC-induced mutation load and that A3A expression is responsible for cytidine deamination in multiple BRCA cell lines.Comparative analysis of A3A and A3B expression by qRT-PCR, RSEM-normalized RNA-seq, and unambiguous RNA-seq validated the use of RNA-seq to measure APOBEC expression, which indicates that A3A is the primary correlate with APOBEC-mutation load in primary BRCA tumors.We also demonstrate that A3A has >100-fold more cytidine deamination activity than A3B in the presence of cellular RNA, likely explaining why higher levels of A3B expression contributes less to mutagenesis in BRCA.Our findings identify A3A as a major source of cytidine deaminase activity in breast cancer cells and possibly a prominent contributor to the APOBEC mutation signature. Author summaryAPOBEC-signature mutations are over-represented in ~15% of all sequenced tumors and in many tumors constitute more than 50% of all mutations.Furthermore, APOBEC activity likely contributes to the occurrence of primary driver and late sub-clonal driver mutations, and mutations that contribute to metastasis and resistance to chemotherapeutics in cancer.To clarify the roles of individual APOBEC family members to cancer mutagenesis, we compared the expression of each APOBEC3 gene in a panel of breast cancer cell lines to the corresponding amount of APOBEC-induced mutation, finding that only A3A positively correlated.We found that A3A provides a significant amount of the cell's total cytidine deamination activity in breast cancer cell lines.We also show that unlike other APOBECs, A3A is not inhibited by RNA, which partly explains its disproportionate contribution to cellular APOBEC activity.Further bioinformatics analysis determined that A3A expression is a major correlate with APOBEC-induced mutagenesis in primary