APOBEC3A mutagenesis

Mutational signatures defined by single base substitution (SBS) patterns in cancer have elucidated potential mutagenic processes that contribute to malignancy. A prevalent mutational pattern in human cancers is attributed to the APOBEC3 cytidine deaminase enzymes. Among the seven human APOBEC3 proteins, APOBEC3A is a potent deaminase and proposed driver of cancer mutagenesis. We sought to prospectively examine genome-wide aberrations caused by APOBEC3A activity. We expressed human APOBEC3A in avian DT40 cells and, using whole-genome sequencing, detected hundreds to thousands of base substitutions per genome. The APOBEC3A mutational signature includes both widespread cytidine mutations and a unique indel signature consisting largely of cytidine deletions. This multi-dimensional APOBEC3A signature is prevalent in cancer genomes. Our data further reveal replication-associated mutations, the rate of clustered mutations, and deamination of methylated cytidines. This comprehensive signature of APOBEC3A mutagenesis provides an essential tool for future studies and a potential biomarker for APOBEC3 activity in cancer.