Functional Genetic Variations In Cyclooxygenase-2 And Their Association With Susceptibility To Gastroesophageal Cancer

Background & Aims: Overexpression of cyclooxygenase-2 (COX-2) has been implicated in the development of many types of human cancer. Single nucleotide polymorphisms (SNPs) in the COX-2 gene might contribute to differential COX-2 expression and enzymatic activity. This study sought to identify SNPs located in the promoter region, coding region, and 3' untranslational region (3'UTR) of COX-2 and evaluated their effects on the biological functions of COX-2 and the risk of developing gastroesophageal cancer.Methods: Thirty individual DNA samples isolated from peripheral blood lymphocytes were sequenced to search for SNPs of the COX-2 gene and the function of the SNPs in vitro were examined by electrophoretic mobility shift assays, luciferase reporter gene assays, chromatin immunoprecipitation assays, and enzymatic assays. The effects of the SNPs on the COX-2 mRNA expression in vivo in esophageal tissues were determined by real-time quantitative PCR. Genotypes and haplotypes were analyzed in 1026 patients with esophageal cancer, 680 patients with gastric cancer, and 1270 controls, and odds ratios and 95% confidence intervals were estimated by logistic regression.Results: Five SNPs were identified in the COX-2 gene, with the minor allelic frequencies being >5%. Among these SNPs, three (-1290A→G, -1195G→A and -765G→C) are located in the promoter region and two are respectively located in the coding region (587Gly→Arg) and 3'UTR (8473T→C). 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 mRNA levels in esophageal tissues compared with the -1195G-containing counterparts. The 587Gly→Arg change had significant impact on COX-2 activity; the COX-2-Arg⁵⁸⁷ isoform showed 1.5-fold elevated enzymatic activity than the COX-2-Gly⁵⁸⁷ isoform in converting arachidonic acid into prostaglandins. The 8473C variant also had significant effect on luciferase gene expression in esophageal cancer cell KYSE150 but not gastric cancer cell MGC803. A case-control analysis showed an excess risk of developing esophageal cancer and gastric cancer for the...