Across-Site Differences in the Mechanism of Alcohol-Induced Digestive Tract Carcinogenesis: An Evaluation by Mediation Analysis
Across-Site Differences in the Mechanism of Alcohol-Induced Digestive Tract Carcinogenesis: An Evaluation by Mediation Analysis
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DOI：
10.1158/0008-5472.can-19-2685
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发表时间：
2020-04-01
期刊：
影响因子：
11.2
通讯作者：
Matsuo, Keitaro
中科院分区：
文献类型：
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作者：
Koyanagi, Yuriko N.;Suzuki, Etsuji;Matsuo, Keitaro
乙醛脱氢酶2(ALDH2 rs671，Glu504Lys)的一个基因变异与饮酒后的癌症有关。相反，ALDH2 Lys等位基因还通过减少乙醛相关不良反应引起的酒精消耗量，对酒精诱导的致癌作用产生保护作用。在这里，我们对头颈部、食道癌、胃癌、小肠和结直肠癌的5个病例对照研究进行了中介分析，包括4,099例病例和6,065例对照，通过将ALDH2 Lys等位基因对消化道癌风险的总效应分解为致癌效应(直接效应)和保护效应(饮酒行为介导的间接效应)两种对立效应，探讨了饮酒对消化道癌发生的潜在异质性影响。酒精与大多数消化道癌的风险增加有关，但显著的直接影响仅在上消化道癌症风险中观察到，而且在不同部位有很大差异，头颈部癌的OR值(95%可信区间)为1.83(1.432.36)，食道癌的OR值为21.15(9.11-49.12)，胃癌的OR值为1.65(1.38-1.96)。相反，除了小肠癌外，观察到对所有癌症的风险都有显著的保护性间接效应。这些发现表明，酒精是消化道癌的主要危险因素，但它作为乙醛暴露的替代品的影响似乎因地点而异。同时，ALDH2 Lys等位基因的行为相关效应降低了大多数消化道癌症的风险。意义：这些发现支持遗传避免饮酒是防止酒精诱发癌症的一个因素。
A genetic variant on aldehyde dehydrogenase 2 (ALDH2 rs671, Glu504Lys) contributes to carcinogenesis after alcohol consumption. Somewhat conversely, the ALDH2 Lys allele also confers a protective effect against alcohol-induced carcinogenesis by decreasing alcohol consumption due to acetaldehyde-related adverse effects. Here, we applied a mediation analysis to five case-control studies for head and neck, esophageal, stomach, small intestine, and colorectal cancers, with 4,099 cases and 6,065 controls, and explored the potentially heterogeneous impact of alcohol drinking on digestive tract carcinogenesis by decomposing the total effect of the ALDH2 Lys allele on digestive tract cancer risk into the two opposing effects of the carcinogenic effect (direct effect) and the protective effect (indirect effect mediated by drinking behavior). Alcohol was associated with an increased risk of most digestive tract cancers, but significant direct effects were observed only for upper gastrointestinal tract cancer risk, and varied substantially by site, with ORs (95% confidence interval) of 1.83 (1.432.36) for head and neck cancer, 21.15 (9.11-49.12) for esophageal cancer, and 1.65 (1.38-1.96) for stomach cancer. In contrast, a significant protective indirect effect was observed on risk for all cancers, except small intestine cancer. These findings suggest that alcohol is a major risk factor for digestive tract cancers, but its impact as a surrogate for acetaldehyde exposure appears heterogeneous by site. Meanwhile, the behavior-related effect of the ALDH2 Lys allele results in a decreased risk of most digestive tract cancers.Significance: These findings support that genetic alcohol avoidance is a factor against alcohol-induced cancers.