Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer.
OBJECTIVE
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.
Zhang
Xuemei
X
Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Miao
Xiaoping
X
Tan
Wen
W
Ning
Baitang
B
Liu
Zhihua
Z
Hong
Yuan
Y
Song
Wenguang
W
Guo
Yongli
Y
Zhang
Xinyu
X
Shen
Yan
Y
Qiang
Boqin
B
Kadlubar
Fred F
FF
Lin
Dongxin
D
D000328:Adult; D000368:Aged; D001483:Base Sequence; D016022:Case-Control Studies; D016001:Confidence Intervals; D051546:Cyclooxygenase 2; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D004945:Esophagoscopy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D008969:Molecular Sequence Data; D009367:Neoplasm Staging; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018570:Risk Assessment; D012494:Sampling Studies
D008565:Membrane Proteins; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases