APOBEC‐mediated DNA alterations: A possible new mechanism of carcinogenesis in EBV‐positive gastric cancer

Mechanisms of viral oncogenesis are diverse and include the off‐target activity of enzymes expressed by the infected cells, which evolved to target viral genomes for controlling their infection. Among these enzymes, the single‐strand DNA editing capability of APOBECs represent a well‐conserved viral infection response that can also cause untoward mutations in the host DNA. Here we show, after evaluating somatic single‐nucleotide variations and transcriptome data in 240 gastric cancer samples, a positive correlation between APOBEC3s mRNA‐expression and the APOBEC‐mutation signature, both increased in EBV+ tumors. The correlation was reinforced by the observation of APOBEC mutations preferentially occurring in the genomic loci of the most active transcripts. This EBV infection and APOBEC3 mutation‐signature axis were confirmed in a validation cohort of 112 gastric cancer patients. Our findings suggest that APOBEC3 upregulation in EBV+ cancer may boost the mutation load, providing further clues to the mechanisms of EBV‐induced gastric carcinogenesis. After further validation, this EBV‐APOBEC axis may prove to be a secondary driving force in the mutational evolution of EBV+ gastric tumors, whose consequences in terms of prognosis and treatment implications should be vetted. What's new? The single‐strand DNA editing properties of the family of APOBEC enzymes is associated with restricting viral genomes but can also lead to unwanted mutations in the host DNA. Here, the authors combined an integrative bioinformatics analysis with experimental evidence to develop a model, in which upregulation of APOBEC3 in gastric cancers harboring Epstein Barr Virus (EBV) may boost the mutation load, contributing a new mechanism to EBV‐induced gastric carcinogenesis.