Identification of Functional Genetic Variants in and Their Association With Risk of Esophageal Cancer
Identification of Functional Genetic Variants in and Their Association With Risk of Esophageal Cancer
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功能性遗传变异的鉴定及其与食道癌风险的关联
DOI：
10.1016/j.gastro.2005.05.003
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发表时间：
2005
期刊：
影响因子：
29.4
通讯作者：
Yan Shen
中科院分区：
文献类型：
--
作者：
Xiao Zhang;X. Miao;W. Tan;B. Ning;Zhihua Liu;Yuan Hong;Wen;Yong;Yan Shen
背景与目的环氧化酶-2 （COX-2）的过度表达参与了癌症发展的许多步骤。COX-2启动子的单核苷酸多态性（snp）可能导致COX-2的差异表达和随后的癌症易感性的个体间差异。本研究旨在鉴定COX-2启动子的功能snp，并评估其对发生食管鳞状细胞癌（ESCC）风险的影响。方法对30份个体DNA样本进行测序，寻找SNPs，并通过一系列生化检测检测SNPs的功能。分析1026例患者和1270例对照的基因型和单倍型，并通过logistic回归估计优势比和95%置信区间（ci）。结果共鉴定出−1290A→G、−1195G→A和−765G→C三个snp；变异等位基因频率分别为0.04、0.51和0.02。−1195G→A的改变产生了一个c-MYB结合位点，并显示出更高的启动子活性。与含有- 1195g的单倍型相比，含有- 1195a的单倍型在食管组织中荧光素酶的表达和COX-2信使RNA水平显著增加。病例对照分析显示，与非携带者相比，- 1195AA或- 765CC基因型携带者发生ESCC的风险分别高出1.72倍（95% CI, 1.35-2.20）和2.24倍（95% CI, 1.59-3.16）。与含有G - 1195-G - 765的单倍型相比，含有A - 1195-C - 765的单倍型发生ESCC的风险更高，这表明在单倍型背景下，- 1195G→A和- 765G→C多态性之间存在相互作用。结论COX-2基因变异可能在食管癌易感性中起调节作用。
Background & AimsOverexpression 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).MethodsThirty 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.ResultsThree 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.ConclusionsThese findings indicate that genetic variants in COX-2 may play a role in mediating susceptibility to esophageal cancer.