APOBEC3A is a prominent cytidine deaminase in breast cancer.

Luis M Cortez,Madeline A Dennis,Tony M Mertz,Steven A Roberts,Christopher D Collins,Alexander J Brown,Amber L Brown,Debra Mitchell,Matthew D Weitzman

doi:10.1371/journal.pgen.1008545

Luis M Cortez, Madeline A Dennis + Show 7 more

Open Access

https://doi.org/10.1371/journal.pgen.1008545

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Abstract

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.

Highlights

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) cytidine deaminases are a major cause of mutation in approximately 15% of sequenced human tumors [1,2,3]
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
Using analysis of mutations from 28 whole exome sequenced breast cancer (BRCA) cell lines and the corresponding expression of APOBEC3 family members determined by qRT-PCR, we show that only A3A expression was elevated in APOBEC-mutated lines compared to non-APOBEC-mutated lines and that the overall abundance of APOBEC-induced mutations linearly correlates with A3A expression

Summary

Introduction

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) cytidine deaminases are a major cause of mutation in approximately 15% of sequenced human tumors [1,2,3]. While these enzymes play diverse physiological roles, including contributing to antibody diversification and restricting viral pathogenesis [4], their off-target activity towards genomic DNA frequently causes oncogenic PIK3CA mutations [5], creates genetic diversity within cancer genomes [6], and contributes to chemotherapeutic resistance [7]. APOBEC-induced mutations in tumors display replication strand bias [13,14,15], high density clustering around DNA translocation sites (termed kataegis) [11, 12], and frequently occur in hairpin forming sequences [16], all of which have been recapitulated in experimental systems exogenously expressing APOBECs [8, 17,18,19,20,21], which further reinforces the consensus that APOBECs are the underlying cause of this distinctive class of tumor-specific genetic instability

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