Association Between Single Nucleotide Polymorphisms In The Promoter Of COX-2 Gene And Hereditary Susceptibility To Pancreatic Cancer

Background & Aim: Overexpression of cyclooxygenase-2 (COX-2) is implicated in many steps of cancer development. Transcriptional regulation is one of main machnisms of the expression of COX-2, which is regulated by transcriptional factors. It has been shown that the sequence variation in the promoter is an important factor affecting gene transcription by creating or eliminating some binding sites of transcriptional factors. Several single nucleotide polymorphisms (SNPs) have been identified in the COX-2 promoter. But the biological significance of these SNPs is not all known. The previous study had found that SNPs in the COX-2 promoter might contribute to differential COX-2 expression and subsequent interindividual variability in susceptibility to esophogeal cancer. However, the biological significance of these SNPs is not known in pancreatic cancer. This study sought to evaluate the contribution of the SNP in the COX-2 promoter to differential COX-2 expression in the pancreatic cancer cells and the effects of SNPs on the risk of developing pancreatic cancer. Methods: Genotypes of 283 case patients with pancreatic cancer and 566 control subjects were determined by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). The samples of DNA were extracted from the peripheral blood of all subjects. All patients with pancreatic cancer were dignosed by pathology or cytology. ORs and 95% CI were calculated by logistic regression to estimate the associations between different genotypes or haplotypes and the risk of pancreatic cancer, the interaction between different genotypes and smoking in the risk of developing pancreatic cancer. The transcriptional activity of the COX-2 promoter in Aspc-1 transfected with -1195AA or -1195GG genotype was tested by luciferase report gene assay. Results: Three SNPs, -1290A>G, -1195G>A and -765G>C, were identified, with the frequencies of variant alleles being 0.05, 0.54 and 0.05 in patients with pancreatic cancer and 0.04, 0.48, and 0.02 in control, respectively. A case-control analysis revealed a 1.75-fold (95% CI = 1.03-2.33) and 2.53-fold (95% CI = 1.52—4.97) excess risk of developing pancreatic cancer for the -1195AA or -765CG genotype carriers compared with noncarriers, respectively. Compared with A_-1290-G_-1195-G_-765 containing haplotype, a greater risk of developing...