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

Abstract

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.

EBV‐LMP1 induces APOBEC3s and mitochondrial DNA hypermutation in nasopharyngeal cancer

“…NPC reportedly contains APOBEC signature mutations that associate with A3A or A3B upregulation 7 . Additionally, in gastric and mammary tumors, EBV infection is associated with A3s expression and APOBEC signature mutation 8,9 . Consistently, we found that EBV‐LMP1 increased A3s expression, identifying a viral gene responsible for A3s upregulation (Figure 1).…”

“…7 Additionally, in gastric and mammary tumors, EBV infection is associated with A3s expression and APOBEC signature mutation. 8,9 Consistently, we found that EBV-LMP1 increased A3s expression, identifying a viral gene responsible for A3s upregulation (Figure 1). Nonetheless, our 3D-PCR analysis did not detect increased mutation of nuclear genes, TP53 and PIK3CA, by A3s or LMP1 either in vitro or in vivo (Figures 2A and 3B, and Figs.…”

“…NPC exhibits APOBEC signature mutations, accompanying A3A or A3B upregulation 7 . In addition, EBV infection in gastric and breast cancers is associated with APOBEC3s(A3s) expression and APOBEC signature mutations, 8,9 implying an unidentified mechanism by which EBV induces A3s expression and host gene mutation. Furthermore, an accumulation of mitochondrial DNA (mtDNA) mutations, such as those found in NPC patients, 10 reportedly facilitates metastasis via upregulation of reactive oxygen species 11 …”

Genomics and epidemiology for gastric adenocarcinomas (GE4GAC): a Brazilian initiative to study gastric cancer

“…qPCR EBV-analysis (N = 400) showed 12.7% EBV+ in GC-cases and 2.9% in controls. We recently showed a possible new mechanism of EBV-carcinogenesis where EBV-infection triggers APOBEC3 over-expression and an APOBECmutation signature [7]. ii) Whole exome sequencing (WES) and RNA-Seq:…”

Mutational signatures driven by epigenetic determinants stratify patients for therapeutic interventions in gastric cancer

“…Previous studies [4] have extracted distinct mutational signatures by examining a large set of human cancer genomes and some of these have been reported in the COSMIC database (denoted hereafter as CS). This pan-cancer analysis revealed significant heterogeneity of operational mutational processes, that encompass mutation-triggering events as diverse as the off-target activity AID/APOBEC family of cytidine deaminases, the exposure to ultraviolet light, tobacco-smoking and the defective DNA mismatch repair [5, 6].…”