Association Study On Genetic Variations And Esophageal Squamous-Cell Carcinoma And T-cell Lymphoma

Accumulating evidence has suggested that individual genetic variations play important role in the development and progression of human cancer. This study sought to identify single nucleotide polymorphisms (SNPs) that associated with susceptibility to esophageal squamous-cell carcinoma (ESCC) and survival of T-cell lymphoma (TCL).We conducted a multi-stage genome-wide association study (GWAS) and genome-wide gene-environment interaction analysis of esophageal squamous-cell carcinoma (ESCC) that included2,031cases and2,044controls in stage one followed by a second stage (8,092cases and8,620controls). We identified nine new susceptibility loci, of which seven at chromosomes4q23,16q12.1,17q21,22q12,3q27,17p13and18p11displayed significant marginal effect (P=1.78×10-39to2.49×10-11) and two (2q22and13q33) displayed significant association only in gene-alcohol drinking interaction (PGxE=4.39×10-11and PGxE=4.80×10-8). Loci at4q23harboring the ADH gene cluster displayed significant interaction with alcohol drinking (Pgxe=2.54x10-7to3.23×10-2). We confirmed the association for12q24(ALDH2) and the joint analysis showed that drinkers with both risk ADH1B and ALDH2alleles had a4-fold increased risk compared to those with non-risk alleles.Genetic polymorphism (rs9514828C>T) in the promoter region of BAFF, which encoding BAFF, a potent cytokine that plays important roles in the activation and survival of B and T cells, and survival of TCL were analyzed in the discovery group including150patients, and the results were replicated in an independent validation group of120patients. Kaplan-Meier analysis was performed to compare survival among different genotypes. Cox proportional hazard models were used to identify independent significant variables. Luciferase reporter gene assays were conducted to examine the function of rs9514828variant. We found that BAFF rs9514828polymorphism was significantly associated with TCL survival. In pooled analysis of two independent groups, the favorable rs9514828TC and TT genotypes had significantly better5-year survival rates compared with the CC genotype (47%and53%versus22%, P=2.27×10-5for log-rank test). Multivariate Cox regression analysis showed that rs9514828was an independent prognostic factor, with hazard ratios [HR] for patient death being0.48(95%confidence interval [CI],0.32-0.71) for the CT and0.47(95%CI,0.23-0.93) for the TT genotypes. Reporter gene assays indicated that the rs9514828T allele had significantly higher promoter activity than the rs9514828C counterpart.These findings underscore the contribution of genetic variants to susceptibility to ESCC directly and through interaction with alcohol consumption, a known risk factor for ESCC, and prognosis of TCL. These results may have potential implication in the prediction of ESCC and clinical care of TCL.