Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer

(Background & Aims) under bar: Overexpression of cyclooxygenase-2 (COX-2) is implicated in many steps of cancer development. Single nucleotide polymorphisms (SNIPS) in the COX-2 promoter might contribute to differential COX-2 expression and subsequent interindividual variability in susceptibility to cancer. This study sought to identify functional SNPs in the COX-2 promoter and evaluated their effects on the risk of developing esophageal squamous cell carcinoma (ESCC). (Methods) under bar: Thirty individual DNA samples were sequenced to search for SNPs, and the function of the SNIPS was examined by a set of biochemical assays. Genotypes and haplotypes were analyzed in :1026 patients and 1270 controls, and odds ratios and 95% confidence intervals (Cls) were estimated by logistic regression. (Results: ) under bar Three SNPs, -1290A -> G, -1195G -> A, and -765G -> C, were identified; the frequencies of variant alleles were 0.04, 0.51, and 0.02, respectively. The -1195G -> A change creates a c-MYB binding site and displays a higher promoter activity. The -1195A-containing haplotypes had significantly increased luciferase expression and COX-2 messenger RNA levels in esophageal tissues compared with the -1195G-containing counterparts. A case-control analysis showed a 1.72-fold (95% Cl, 1.35-2.20) and 2.24-fold (95% Cl, 1.59-3.16) excess risk of developing ESCC for the -1195AA or -765CC genotype carriers compared with noncarriers. A greater risk of developing ESCC was observed for A(-1195)-C-765- containing haplotypes compared with G(-1195)-G(-765)- containing haplotypes, suggesting an interaction between the -1195G -> A and -765G -> C polymorphisms in the context of haplotype. (Conclusions) under bar: These findings indicate that genetic variants in COX-2 may play a role in mediating susceptibility to esophageal cancer.