Cyclooxygenase-2 Gly587Arg variant is associated with differential enzymatic activity and risk of esophageal squamous-cell carcinoma.

Full Abstract

Functional SNPs in the COX-2 promoter region have been associated with susceptibility to esophageal squamous-cell carcinoma (ESCC). In this study, we investigated SNPs in the COX-2 coding region and their impact on risk of ESCC. The coding region of COX-2 in DNAs from 30 Han Chinese individuals was sequenced to identify SNPs. Different coding region variants identified were cloned and expressed in MCE-7 cells for the measurement of COX-2 enzymatic activity. Genotypes were determined by PCR-RFLP in 1026 patients with ESCC and 1270 controls and odds ratios (ORs) and 95% confidence intervals (CI) were computed by logistic regression model. A SNP at exon 10 (1759G>A, rs3218625) was identified, which causes (587)Gly to (587)Arg amino acid substitution. Enzymatic assays using different recombinant COX-2 variants showed that COX-2-(587)Arg had significantly higher activity towards arachidonic acid than COX-2-(587)Gly (13.8 +/- 3.2 U/mg vs. 11.2 +/- 2.4 U/mg; P = 0.012). Case-control analysis showed that 10.2% of ESCC patients carried the 1759A allele whereas only 5.4% of controls had this allele (P < 0.0001). No homozygous 1759AA genotype was presented in controls albeit two patients carrying this genotype. Multivariate logistic regression analysis revealed that subjects with at least one 1759A allele had increased risk for the development of ESCC (OR, 1.91; 95% CI, 1.39-2.62) compared with those with the 1759GG genotype. These results extend our previous findings and indicate that inherited variant in arachidonic acid-metabolizing enzyme, which results in heightened enzymatic activity, may confer susceptibility to ESCC. (c) 2009 Wiley-Liss, Inc.

Author information

Author/s: Zhao, Dan (D); Zhang, Xuemei (X); Guo, Yongli (Y); Tan, Wen (W); Lin, Dongxin (D);

Affiliation: Department of Etiology & Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Journal and publication information

Publication Type: Comparative Study; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't

Journal: Molecular carcinogenesis (Mol Carcinog), published in United States. (Language: eng)

Reference: 2009-Oct; vol 48 (issue 10) : pp 934-41

Dates: Created 2009/09/28; Completed 2009/10/15;

PMID: 19347867, status: MEDLINE (last retrieval date: 10/15/2009, IMS Date: )

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