Polymorphisms in MGMT and DNA repair genes and the risk of esophageal adenocarcinoma
Polymorphisms in MGMT and DNA repair genes and the risk of esophageal adenocarcinoma
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DOI：
10.1002/ijc.23410
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发表时间：
2008-07-01
影响因子：
6.4
通讯作者：
Whiteman, David C.
中科院分区：
文献类型：
--
作者：
Doecke, James;Zhao, Zhen Zhen;Whiteman, David C.
近几十年来，食管腺癌（EAC）和食管胃交界处腺癌（EGJAC）的发病率迅速增加。主要危险因素胃食管酸反流和吸烟通过第六代 N-亚硝基化合物具有潜在的遗传毒性。 DNA 修复蛋白 O-6-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 是细胞抵御烷基化 DNA 损伤的主要防御机制。我们将 EAC (n = 263) 或 EGJAC (n = 303) 患者与匹配人群对照 (n = 1,337) 的 5 个 MGMT 单核苷酸多态性 (SNP)（rs12269324、rs12268840、L84F、I143V、K178R）的频率以及 DNA 修复基因 ERCC1 中的 SNP 频率进行比较(N118N)、XRCC1 (Q399R) 和 XPD (K751Q)。使用多变量逻辑回归估计相对风险。通过协同指数 S 评估潜在的生物相互作用。每个 MGMT SNP 都会增加 EAC 的风险，但不会增加 EGJAC 的风险；发现 2 个变异 MGMT 等位基因 rs12268840 和 I143V 之间的关联性最强（分别为 p = 0.005 和 p < 0.001）。频繁胃酸反流的 MGMT rs12268840 纯合子携带者发生 EAC 的风险显着高于加法模型下的预期（OR 15.5，95% CI 5.8-42），这与生物相互作用一致（S = 33，95% CI 1.1-10）。还观察到与吸烟之间存在适度的、不显着的相互作用。纯合变异 ERCC1 基因型与 EAC 风险降低相关（OR 0.6，95% CI 0.4-1.1），而纯合变异 XRCC1 基因型导致 EGJAC 风险较高（OR 1.6，95% CI 1.1-2.4）。 XPD (rs13181) 未观察到与 EAC 或 EGJAC 的关联。总之，MGMT SNP 与 EAC 风险增加相关。暴露于胃酸反流，以及可能吸烟，会导致纯合变异基因型携带者的风险显着升高。 (C) 2008 Wiley-Liss, Inc.
Rates of adenocarcinoma of the esophagus (EAC) and esophagogastric junction (EGJAC) have increased rapidly in recent decades. The primary risk factors, gastro-esophageal acid reflux and smoking, are potentially genotoxic through the 6 generation of N-nitroso compounds. The DNA repair protein O-6-methylguanine-DNA methyltransferase (MGMT) is the major cellular defense against alkylating DNA damage. We compared patients with EAC (n = 263) or EGJAC (n = 303) with matched population controls (n = 1,337) for the frequency of 5 MGMT single nucleotide polymorphisms (SNPs) (rs12269324, rs12268840, L84F, I143V, K178R), as well as SNPs in DNA repair genes ERCC1 (N118N), XRCC1 (Q399R) and XPD (K751Q). Relative risks were estimated using multivariable logistic regression. Potential biological interaction was assessed through the synergy index S. Each MGMT SNP conferred increased risks of EAC but not EGJAC; strongest associations were found for the 2 variant MGMT alleles rs12268840 and I143V (p = 0.005 and p < 0.001, respectively). Homozygous carriers of MGMT rs12268840 with frequent acid reflux had significantly higher risks of EAC (OR 15.5, 95% CI 5.8-42) than expected under an additive model, consistent with biological interaction (S = 33, 95% CI 1.1-10). Modest, nonsignificant interactions with smoking were also observed. Homozygous variant ERCC1 genotype was associated with reduced risks of EAC (OR 0.6, 95% CI 0.4-1.1), while the homozygous variant XRCC1 genotype conferred higher risks of EGJAC (OR 1.6, 95% CI 1.1-2.4). No associations with EAC or EGJAC were observed with XPD (rs13181). In summary, MGMT SNPs are associated with increased risks of EAC. Exposure to acid reflux, and possibly smoking, confer markedly higher risks among homozygous variant genotype carriers. (C) 2008 Wiley-Liss, Inc.