Rare POLN Variants Confer Risk for Familial Nasopharyngeal Carcinoma Through Weaken Epstein-Barr Virus Lytic Infection

摘要: Background: Nasopharyngeal carcinoma (NPC) exhibited significant familial aggregation, but the susceptibility genes were largely unknown.Methods: Whole-exome sequencing was performed in NPC pedigrees with multiple cases. Variations co-segregated with disease status were further validated in a cohort composed of 563 probands of independent families, 2953 sporadic cases and 3175 healthy controls. Experimental studies were used to explore the function of susceptibility gene and its disease-related variants.Findings: Three rare missense variants in POLN gene: p. P577L, p. R303Q and p. F545C were associated with familial NPC risk (5/576 [0.87%] in cases vs. 2/3374 [0.059%] in healthy controls with adjusted OR of 44.84 [95% CI: 3.91-514.34, P= 2.25× 10-3]). POLN was involved in EBV lytic infection, which promoted viral DNA replication, true late genes expression, and progeny viral particles production, and finally resulted in inhibition of cell proliferation. Above three rare POLN variants located in the functional domains and were predicted to alter the protein structure. Indeed, the mutant POLN carrying any of the three rare variants displayed reduced protein expression and thus exerted compromised capacity in Epstein-Barr virus (EBV) lytic infection as well as cell proliferation.Interpretation: We identified a new susceptibility gene POLN for familial NPC and elucidated its new function.