Circulating antibodies against Epstein-Barr virus (EBV) and p53 in EBV-positive and -negative gastric cancer

Background: Epstein-Barr virus (EBV)-positive gastric cancers (GC) have clinicopathologic differences from EBV-negative tumors and lack TP53 mutation. Serological profiles may inform viral contribution to carcinogenesis. Methods: We compared humoral responses of EBV-positive (n=67) and -negative (n=137) GC patients from the International EBV-Gastric Cancer Consortium. Serum antibodies against four EBV proteins, nuclear (EBNA), viral capsid (VCA), early-diffuse (EA-D) and Zta replication activator (ZEBRA), and to p53 were assessed by multiplex assays. Odds ratios (OR) of antibody level tertiles (T1-T3) were adjusted by logistic regression. We also conducted a meta-analysis of reported anti-p53 seropositivity in GC. Results: Consistent with EBV9s ubiquity, 99% of patients were seropositive for anti-EBNA and 98% for anti-VCA, without difference by tumor EBV status. Seropositivity varied between patients with EBV-positive and -negative tumors for anti-EA-D (97% vs. 67%, respectively, p<0.001) and anti-ZEBRA (97% vs. 85%, respectively, p=0.009). Adjusted ORs (vs. T1) for patients with EBV-positive vs. -negative tumors were significantly elevated for higher antibodies against EBNA (2.6 for T2 and 13 for T3), VCA (1.8 for T2 and 2.4 for T3), EA-D (6.0 for T2 and 44 for T3), and ZEBRA (4.6 for T2 and 12 for T3). Antibodies to p53 were inversely associated with EBV positivity (3% vs. 15%; adjusted OR=0.16, p=0.021). Anti-p53 prevalence from the literature was 15%. Conclusions: These serological patterns suggest viral reactivation in EBV-positive cancers and identify variation of p53 seropositivity by subtype. Impact: Anti-EBV and anti-p53 antibodies are differentially associated with tumor EBV positivity. Serology may identify EBV-positive GC for targeted therapies.