Background
Epstein-Barr virus (EBV) is a widespread persistent human pathogen implicated in several cancers, yet its broader contribution to overall cancer risk remains unclear. Prior prospective evidence on antibody markers and cancer risk, especially beyond well-established EBV-associated cancers, is limited, creating the need for large-scale longitudinal evaluation in high-incidence regions.
Objectives
This study aimed to assess the association between seropositivity for EBV viral capsid antigen IgA (VCA-IgA) and subsequent risk of total and site-specific cancers in adults from Southern China, thereby quantifying the cancer burden attributable to EBV-associated immune responses.
Methods
We analysed two large prospective cohorts from Southern China comprising 73,939 adults followed for approximately 8–10 years. Baseline VCA-IgA serostatus was measured, and incident cancer cases were identified through follow-up. Age-standardised incidence rates were calculated, and multivariable Cox proportional hazards regression models estimated hazard ratios (HRs) for total and site-specific cancers in relation to antibody seropositivity, adjusting for demographic and behavioural covariates. The population-attributable risk percentage was calculated to estimate EBV’s contribution to cancer burden.
Results
VCA-IgA seropositivity was associated with significantly higher age-standardised incidence rates of total cancer in both cohorts. Pooled analyses showed that seropositive individuals had elevated risks of total cancer (HR 4.88, 95% CI: 2.84–8.37), lung cancer (HR 1.76, 95% CI: 1.23–2.54), liver cancer (HR 1.70, 95% CI: 1.10–2.63), nasopharyngeal carcinoma (HR 26.05, 95% CI: 11.77–57.65), and lymphoma (HR 3.20, 95% CI: 1.46–6.99) compared to seronegative individuals. Positive dose–response relationships between VCA-IgA levels and overall cancer risk were observed, persisting up to ten years before diagnosis. Estimated population-attributable risk for total cancers due to EBV seropositivity was approximately 7.8%, indicating a substantial attributable cancer burden.
Conclusions
In these large Southern Chinese cohorts, elevated EBV VCA-IgA antibodies were prospectively associated with increased risks of multiple major cancers, extending beyond traditionally recognised EBV-related malignancies. The findings provide robust epidemiological evidence that EBV seropositivity contributes to cancer risk and highlight the potential value of EBV-related biomarkers in cancer risk stratification and prevention strategies.