Across-Site Differences in the Mechanism of Alcohol-Induced Digestive Tract Carcinogenesis: An Evaluation by Mediation Analysis
- 1 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 80 (7), 1601-1610
- https://doi.org/10.1158/0008-5472.can-19-2685
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 (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.Other Versions
Funding Information
- Ministry of Education, Science, Sports, Culture and Technology of Japan (17015018)
- Innovative Areas (221S0001)
- JSPS (JP26253041)
- JSPS (JP15H02524)
- JSPS (JP16H06277)
- JSPS (JP18H03045)
- JSPS (JP19K19425)
This publication has 103 references indexed in Scilit:
- Genetic Variants on 15q25.1, Smoking, and Lung Cancer: An Assessment of Mediation and InteractionAmerican Journal of Epidemiology, 2012
- Preventable Exposures Associated With Human CancersJNCI Journal of the National Cancer Institute, 2011
- Body mass, tobacco smoking, alcohol drinking and risk of cancer of the small intestine—a pooled analysis of over 500 000 subjects in the Asia Cohort ConsortiumAnnals of Oncology, 2011
- A meta-analysis on alcohol drinking and gastric cancer riskAnnals of Oncology, 2011
- Odds Ratios for Mediation Analysis for a Dichotomous OutcomeAmerican Journal of Epidemiology, 2010
- Aldehyde Dehydrogenase 1B1: Molecular Cloning and Characterization of a Novel Mitochondrial Acetaldehyde-Metabolizing EnzymeDrug Metabolism and Disposition, 2010
- Risk of pancreatic cancer by alcohol dose, duration, and pattern of consumption, including binge drinking: a population-based studyCancer Causes & Control, 2010
- Alcohol consumption, cigarette smoking and risk of subtypes of oesophageal and gastric cancer: a prospective cohort studyGut, 2009
- Are there two sides to colorectal cancer?International Journal of Cancer, 2002
- Quantifying heterogeneity in a meta-analysisStatistics in Medicine, 2002