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

Gastroenterology. 2005 Aug;129(2):565-76. doi: 10.1016/j.gastro.2005.05.003.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Base Sequence
  • Case-Control Studies
  • Confidence Intervals
  • Cyclooxygenase 2
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / pathology
  • Esophagoscopy
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease*
  • Genotype
  • Haplotypes / genetics*
  • Humans
  • Male
  • Membrane Proteins
  • Middle Aged
  • Molecular Sequence Data
  • Neoplasm Staging
  • Odds Ratio
  • Polymorphism, Genetic*
  • Prognosis
  • Promoter Regions, Genetic
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Risk Assessment
  • Sampling Studies


  • Membrane Proteins
  • RNA, Messenger
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases