APOBEC3A induces cancer-specific mutational signatures in human genomes

Cancer genomics suggest a link between infection- and inflammation-induced antiviral APOBEC3 cytidine deaminases and mutational signatures in tumors, but a functional proof in cells of higher organisms is still missing. Inducible expression of five human APOBEC-3 in human HEK293 cells showed decreased cell viability and genome integrity for isoforms -A, -C, -F, and -G. Cells expressing wild-type but not inactive APOBEC3A contain two prominent mutational signatures proposed to be mediated by APOBEC3 family members. Analyses of human tumor databases revealed that the validated APOBEC3A-type mutations contribute to up to two thirds of the mutational load in epithelial cancers, notably bladder and cervical cancer. APOBEC3A-type mutations induced gain of function changes in cancer drivers and truncations in tumor suppressor genes.