Epstein-Barr virus antibodies and risk of non-Hodgkin lymphoma: a pooled analysis of four prospective cohorts.

Non-Hodgkin lymphomas (NHLs) are among the most common cancers in the US, yet their etiology is mostly unknown. Epstein-Barr virus (EBV) is a known driver of rare NHLs, but its role in common subtypes is unclear. We evaluated associations between antibodies to 16 EBV antigens, including 12 emerging markers (anti-: BARF1, BBRF1, BFRF1, BGLF2, BHRF1, BORF1, BPLF1, BRLF1, BXLF1, LF2, LMP1, VCAp40) and NHL risk in prediagnostic blood samples from 2134 case-control sets from 4 prospective cohort studies. Conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Associations across multiple antibodies were summarized using a β‑weighted score (EBVAb score). Eight markers were positively associated with NHL risk. Anti-LMP1 was associated with diffuse large B-cell lymphoma (DLBCL; OR = 2.83, 95% CI: 1.12-7.19) only. Six lytic markers (anti-: BGLF2, VCAp40, BFRF1, BARF1, BHRF1, BXLF1) were associated with a 2-3 times higher risk of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Lytic marker associations for DLBCL and follicular lymphoma (FL) were weaker, with exceptions: anti-BXLF1 and DLBCL: OR = 2.25, 95% CI: 1.33-3.81; anti-BHRF1 and FL: OR = 2.75, 95% CI: 1.22-6.18. Anti-EBV scores > 0 were associated with ~50% higher NHL risk, strongest for CLL/SLL (Tertile 3: OR = 2.43, 95% CI: 1.30-4.55). Select EBV antibodies may serve as markers of common NHL risk.