A polymorphism, which exists intronic lesion of SLC5A10, affects DRG2 expression and survival outcome of early-stage non-small cell lung cancer

RegulomeDB is a new tool that can predict regulatory functions of genetic variants. We investigated the association between putative functional variants selected using RegulomeDB and survival outcome of non-small cell lung cancer (NSCLC) via two independent cohort study. Total 244 variants with category 1a, which have the most confident evidence of variants affecting gene expression using RegulomeDB, were genotyped. Fourteen variants associated with overall survival ( P T) was validated. In a combined analysis, patients with rs2257609 CT or TT genotype exhibited a worse overall survival and disease free survival than those with rs2257609 CC genotype (hazard ratio [HR] = 1.87, 95% confidence interval [CI] = 1.41 – 2.48, P = 2.0 × 10 -5 and HR = 1.44, 95% CI = 1.16 – 1.79, P = 0.001, respectively). DRG2 expression, which was predicted to be affected by rs2257609, was significantly higher in tumor tissues than non-malignant lung tissues ( P = 0.001) and was different according to the rs2257609 genotype ( P trend = 0.03). ). Luciferase assay also revealed higher promoter activity of DRG2 with rs2257609 T allele ( P = 0.03). These results suggest that the rs2257609 Cu003eT may affect DRG2 expression and can be used as prognostic marker in early-stage NSCLC patients.