Geographic variation in EBV genomes predicts variable susceptibility to immune therapy

Epstein-Barr virus (EBV) is a potent carcinogen linked to hematologic and solid malignancies, causing significant global morbidity and mortality. Therapy using allogeneic EBV-specific lymphocytes shows promise in certain populations, but the impact of EBV genome variation on these strategies remains unexplored. To address this, we sequenced EBV genomes from 220 hematologic malignancies in Guatemala, Peru, Malawi, and Taiwan, and analyzed them alongside 1,307 publicly available EBV genomes from cancer, non-malignant diseases, and healthy individuals across Africa, Asia, Europe, North America, and South America. These included the first NK/T-cell lymphoma (NKTCL) EBV genomes reported outside East Asia. Our findings indicate that previously proposed EBV genome variants specific to certain cancer types are more closely tied to geographic origin than cancer histology. This included variants previously reported to be specific to NKTCL but were prevalent in EBV genomes from other cancer types in East Asia. After controlling for geographic region, we did identify multiple NKTCL-specific variants associated with a 7.8-21.9-fold increased risk. We also observed frequent variations in EBV genomes affecting peptide sequences previously reported to bind common MHC alleles. For example, as prior work demonstrated, the LMP-2A peptide CPLTKILL strongly binds to HLA-B*08, but the CLPL(T>S)KILL variant results in weak binding. Finally, we found several non-synonymous mutations across current vaccine targets BALF4, BKRF2, BLLF1, BXLF2, BZLF1, and BZLF2.These results highlight the need to consider geographic variations in EBV genomes when devising strategies for the adaptive immune response against EBV-related cancers, ensuring greater global effectiveness and equity in prevention and treatment