Abstract
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 (1.43-2.36) 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.
Highlights
Digestive tract cancers, including head and neck, esophageal, stomach, small intestine, and colorectal cancers, account for 27% of all cancer-related deaths worldwide [1, 2], and represent a major public health burden
D, The indirect effect is the contrast between the outcome in those with the ALDH2 Lys allele and the outcome in those with the ALDH2 Lys allele under the counterfactual situation of drinking intensity being the same as what it would be without the ALDH2 Lys allele (Glu/Glu)
Nonsignificant dORs were observed for small intestine cancer and colorectal cancer
Summary
Digestive tract cancers, including head and neck, esophageal, stomach, small intestine, and colorectal cancers, account for 27% of all cancer-related deaths worldwide [1, 2], and represent a major public health burden. Previous epidemiologic studies have shown that the ALDH2 rs671 Lys allele (ALDH2 Lys allele) increases susceptibility to head and neck cancer and esophageal cancer among drinkers due to strong gene– environment interaction between the Lys allele and alcohol drinking [7]. The International Agency for Research on Cancer has classified acetaldehyde associated with the consumption of alcoholic beverages as carcinogenic for head and neck cancer and esophageal cancer [8]. Similar interaction between ALDH2 Lys allele and alcohol drinking is reported in stomach cancer risk [9, 10]. Acetaldehyde's role in colorectal carcinogenesis has not been fully elucidated [11], and no clear evidence for a gene–environment interaction between ALDH2 Lys allele and alcohol drinking in colorectal cancer risk is yet available
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