Identification of Functional Genetic Variants in Cyclooxygenase-2 and Their Association With Risk of Esophageal Cancer

Background & Aims: Overexpression of cyclooxygenase-2 (COX-2) is implicated in many steps of cancer development. Single nucleotide polymorphisms (SNPs) 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: Thirty individual DNA samples were sequenced to search for SNPs, and the function of the SNPs 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 (CIs) were estimated by logistic regression. Results: 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% CI, 1.35-2.20) and 2.24-fold (95% CI, 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: These findings indicate that genetic variants in COX-2 may play a role in mediating susceptibility to esophageal cancer.