Impact of high-risk EBV strains on nasopharyngeal carcinoma gene expression

Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr Virus infection (EBV). Despite ubiquitous EBV infection worldwide, NPC displays a unique geographical distribution in Southern China and Southeast Asia. This observed phenomenon can be attributed to the interplay of different strains of EBV infection with host genetics and environmental factors. Polymorphisms on the EBV BALF2 gene have been shown to influence risk of nasopharyngeal carcinoma (NPC). Notably, two non-synonymous EBV polymorphisms (162476T>C, 163364C>T) account for majority of NPC risk in endemic regions. These polymorphisms confer amino acid changes (I1613V, V317M) within the BALF2 protein. However, their impact on NPC tumor biology is unknown. We evaluated the distribution of BALF2 risk polymorphisms in five independent genomic datasets comprising 351 NPC clinical samples, confirming the high prevalence of high-risk EBV strains in NPC. Importantly, we observed two biologically distinct groups of tumors based on their gene expression profiles when grouped by their EBV risk strains. NPC tumors with the V317M substitution demonstrated increased proliferation processes including cell cycle (NES = 1.71, p = 5.64x10^-24) and keratinization (NES = 2.42, p = 6.95x10^-17). In contrast, NPC tumors without the V317M substitution demonstrated increased immune-related processes, including cell activation (NES = 1.85, p = 8.29x10^-31), myeloid leukocyte activation (NES = 2.16, p = 6.51x10^-24) and leukocyte mediated immunity (NES = 1.99, p = 1.05x10^-23). These findings provide further insight on the influence of BALF2 variants on NPC tumor biology. EBV risk strains may have the potential to define biologically important groups in NPC.