Across-site differences in the mechanism of alcohol-induced digestive tract carcinogenesis: an evaluation by mediation analysis

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 (HNC), esophageal (EC), stomach (SC), small intestine (SIC), and colorectal cancers (CRC), 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 odds ratios (95% confidence interval) of 1.83 (1.43-2.36) for HNC, 21.15 (9.11-49.12) for EC, and 1.65 (1.38-1.96) for SC. In contrast, a significant protective indirect effect was observed on risk for all cancers, except SIC. 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.