Association of Single-Nucleotide Polymorphisms on FURIN and EPHA2 Genes with the Risk and Prognosis of Undifferentiated Nasopharyngeal Cancer

Abstract

The undifferentiated nasopharyngeal cancer (NPC) is a multifactorial disease mainly due to Epstein-Barr Virus (EBV) infection. The transmembrane tyrosine kinase ‘EphA2’ and the protease ‘Furin’ are implicated in the EBV entry into epithelial cells and other physiological processes. To gain insights into the association of single-nucleotide polymorphisms (SNPs) rs4702 and rs6603883 (FURIN and EPHA2 genes, respectively) with the risk and prognosis of the NPC, the genotypes of 471 individuals (228 cases and 243 controls) were assessed alongside risk cofactors (sex, tobacco, alcohol, occupation, and recurrent Ear, Nose and Throat infections) and prognosis cofactors (Tumor stage, local invasion, lymph node involvement, and metastasis) using multivariable logistic regression. We found that only the rs4702 AG/GG genotypes were statistically significantly associated with a reduced risk of cancer, both in the overall population and in men (approximately 50% reduction). The rs4702 GG genotype was also associated with a low frequency of local tumor invasion in the whole population (OR = 0.382, p = 0.017, co-dominant model, and OR = 0.409, p = 0.02, recessive model), but heterozygous women were associated with a higher lymph node involvement (OR = 3.53, p = 0.031, co-dominant model, and OR = 3.62, p = 0.02, overdominant model). The rs6603883 GG genotype was associated, in the dominant model, with distant metastasis in the whole population (OR = 2.5, p = 0.024), with advanced clinical stage in men (OR = 2.22, p = 0.034), and with advanced clinical stage and distant metastasis in patients under 49 years (OR = 3.13, p = 0.009, and OR = 5.15, p = 0.011, respectively). Additionally, men having the rs6603883 GA genotype were associated with lymph node invasion (OR = 2.22, p = 0.027, overdominant model). Our study is the first to demonstrate that FURIN and EPHA2 germline gene polymorphisms are associated with NPC risk (for rs4702) and prognosis (for both rs4702 and rs6603883), with sex-specific differences. These results need to be replicated and further investigated in other populations.