A proteome-wide analysis unveils a core Epstein–Barr virus antibody signature of classic Hodgkin lymphoma across ethnically diverse populations

Epstein–Barr virus (EBV) is an oncogenic virus associated with various malignancies, including classical Hodgkin lymphoma (cHL). Despite its known association, the specific role of humoral immune response to EBV remains poorly characterized in cHL. To address this, we conducted a study using a custom protein microarray to measure the antibody responses in cHL patients and matched healthy controls recruited from an East-Asian hospital-based case–control study. We identified 16 IgG antibodies significantly elevated in EBV-positive cHL compared with controls, defining an “East-Asian antibody signature of EBV-positive cHL.” We evaluated responses against these 16 antibodies in a distinct European population, leveraging data from our previous European cHL case–control study from the UK, Denmark, and Sweden. A subset of antibodies (14/16, 87.5%) from the “East-Asian antibody signature of EBV-positive cHL” exhibited significant associations with cHL in the European population. Conversely, we assessed the “European antibody signature of EBV-positive cHL” identified in our prior study which consisted of 18 EBV antibodies (2 IgA, 16 IgG), in the East-Asian population. A subset of these antibodies (15/18, 83.3%) maintained significant associations with cHL in the East-Asian population. This cross-comparison of antibody signatures underscores the robust generalizability of EBV antibodies across populations. Five anti-EBV IgG antibodies (LMP-1, TK, BALF2, BDLF3, and BBLF1), found in both population-specific antibody signatures, represent a “core signature of EBV-positive cHL.” Our findings suggest that the antibody responses targeting these core EBV proteins reflect a specific EBV gene expression pattern, serving as potential biomarkers for EBV-positive cHL independent of population-specific factors.