| Helicobacter pylori infection is the risk factor most strongly associated with gastric cancer (GC), the second leading cause of cancer-related mortality worldwide. However, presence of the Epstein-Barr virus (EBV) in some gastric tumors suggests that viral co-infection may be a contributing cause. We therefore conducted a multi-phase epidemiologic and molecular investigation of the role of EBV in gastric carcinogenesis.;Pooling individual-level data from international GC case series with consistent laboratory testing, Project 1 addressed the epidemiologic determinants of EBVpositivity. The pooled prevalence of EBV-positivity among 5081 GC cases was 7.7% (95% confidence interval, 6.1 to 9.8%). Multivariable analyses showed significant interactions among age, sex and subsite: the highest probability of EBV positivity was observed among young males with tumors localized to non-antrum subsites. EBV prevalence was also associated with histology (higher in diffuse-type tumors) and geographic origin (higher in Americas).;Considering the predominant location of EBV-positive tumors in the proximal stomach, Project 2 contrasted GC incidence trends by anatomic subsite, using data from the U.S. National Cancer Institute's Surveillance, Epidemiology, and End Results. Age-standardized rates for corpus are rising among Whites and Blacks whereas all other race- and subsite-specific rates are declining. APC analyses identified a significant birth cohort effect centered around 1942 for corpus GC in Whites.;Investigating clinical significance of EBV, Project 3 evaluated the association between EBV presence and long-term progression of gastric premalignant lesions in a high risk cohort in Colombia. Subjects who were EBV positive at baseline were significantly more likely to progress to more advanced lesions after 12-year of follow-up, adjusted for diagnosis at baseline, Helicobacter pylori status, and other covariables.;Histologic and geographic features and age-sex-subsite interactions suggest that EBV-associated GC is a distinct entity. Secular trends for corpus GC indicate a shifting distribution by anatomic subsite, and imply that historic declines in non-cardia GC rates may be expected to reverse. Corpus carcinomas seem to have a distinct epidemiology among other subsites. EBV presence is a risk factor for progression of gastric preneoplastic lesions. These findings implicate EBV as an etiologic agent in GC. |
