APOBEC3A is a prominent cytidine deaminase in breast cancer

• Published in: PLoS genetics Vol. 15; no. 12; p. e1008545
• Main Authors: Cortez, Luis M, Brown, Amber L, Dennis, Madeline A, Collins, Christopher D, Brown, Alexander J, Mitchell, Debra, Mertz, Tony M, Roberts, Steven A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2019; Public Library of Science (PLoS)
• Subjects: Biology; Biology and Life Sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer; Cell Line, Tumor; Comparative analysis; Cytidine deaminase; Cytidine Deaminase - genetics; Cytidine Deaminase - metabolism; Deamination; Deoxyribonucleic acid; DNA; Enzymes; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomes; Haplotypes; Humans; Localization; Medicine and Health Sciences; Minor Histocompatibility Antigens - genetics; Minor Histocompatibility Antigens - metabolism; Mutagenesis; Mutation; Polymorphism; Proteins; Proteins - genetics; Proteins - metabolism; Research and analysis methods; Ribonucleic acid; RNA; Sequence Analysis, RNA; Tumors; United States > US
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1008545

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.