Alan Kwok Shing Chiang, Kwok Wai Lo, Musheng Zeng
This chapter focuses on Epstein-Barr virus (EBV)-mediated tumorigenesis in nasopharyngeal carcinoma (NPC). EBV-mediated epithelial cell transformation is a crucial early event in the development of NPC. NPC and other EBV-associated lymphoepithelioma-like carcinoma have latency II program and a genomic landscape characterized by NF-κB pathway activating mutations, implicating the presence of viral latency program-specific oncogenesis. After the establishment of persistent EBV infection in nasopharyngeal epithelial cells, latency II viral genes (such as EBNA1, LMP1) are expressed to drive malignant transformation and reshape tumor microenvironment. During clonal expansion of EBV-infected NPC cells, various somatic genetic and epigenetic alterations are acquired to prevent virus-induced stress, evade immune surveillance, enhance genomic instability, reprogram metabolism mechanism, and promote NPC progression. Pathogenic variant of EBV characterized by EBER2 polymorphism is highly concentrated in NPC of Southern Chinese population. The interaction between this variant and host HLA haplotype may create a high viral set point to predispose risk individuals in the same population to develop NPC. Effective screening program of risk individuals in endemic populations will allow detection of early-stage NPC that is more amenable to cure utilizing treatment regimen with reduced toxicity while targeting EBV's pathogenic mechanism in NPC will enable the development of novel therapeutic strategy against metastatic and recurrent disease.