Exploring the Significance of the APOBEC3B Polymorphism on Cancer Risk

Activity of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like (APOBEC) deaminases on ssDNA have been ascribed to innate and adaptive immunity, restricting replication of viruses, retrotransposons, and triggering antibody diversification in B-cells. However, emerging studies have also shown implication of deregulated APOBEC3 subgroup members, in particular APOBEC3A and APOBEC3B,

in cancer mutagenesis with ~15% of all sequenced tumours displaying C>T or C>G substitutions within TCW (where W = T or A) trinucleotide motif, generating distinctive mutational signatures 2 and 13, respectively. Mechanisms, inducing characteristic off-target activity are yet to be elucidated. Nevertheless, APOBEC3A_B deletion polymorphism, resulting in a loss of entire APOBEC3B coding region, is naturally present in ~22% of global population and breast cancers from APOBEC3A_B carriers harbour a higher mutational load of signatures 2 and 13 than non-carriers. Additionally, recent work has showed that APOBEC3A_B deletion is associated with higher risk of breast cancer. In this study, we aimed to investigate the significance of APOBEC3B polymorphism on cancer risk for different regions by conducting an extensive metaanalysis of all published association studies. The results showed a significant association with breast and ovarian cancers, particularly in Asian cohorts. Moreover, single-cell cloning of novel isogenic model for APOBEC3A_B deletion was performed to identify successful clones, representing homozygous or heterozygous deletion for future studies. Lastly, Western blotting and immunochemical staining revealed APOBEC3B expression and subcellular localisation in the G2 and mitotic phases of the

cell cycle, suggesting a potential novel function during cell division. This work will aid future APOBEC studies for understanding mechanisms driving carcinogenesis in deletion carriers, by firstly elucidating functions of APOBEC3B in healthy versus cancerous cells.