Alcohol dehydrogenase 3 genotype and risk of oral cavity and pharyngeal cancers

Background: The consumption of alcoholic beverages is a strong risk factor for cancers of the oral cavity and pharynx (oral cancers). Alcohol dehydrogenase type 3 (ADH(3)) metabolizes ethanol to acetaldehyde, a carcinogen. We evaluated whether individuals homozygous for the fast-metabolizing ADH(3)(1) allele (ADH(3)(1-1)) have a greater risk of developing oral cancer in the presence of alcoholic beverage consumption than those with the slow-metabolizing ADH(3)(2) allele (ADH(3)(1-2) and ADH(3)(2-2)). Methods: As part of a population-based study of oral cancer conducted in Puerto Rico, the ADH(3) genotypes of 137 patients with histologically confirmed oral cancer and of 146 control subjects (i.e., individuals with no history of oral cancer) were determined by molecular genetic analysis of oral epithelial cell samples. Risks were estimated by use of multiple logistic regression analyses. Results: Compared with nondrinkers with the ADH(3)(1-1) genotype, consumers of at least 57 alcoholic drinks per week with the ADH(3)(1-1), ADH(3)(1-2), and ADH(3)(2-2) genotypes had 40.1-fold (95% confidence interval [CI] = 5.4-296.0), 7.0-fold (95% CI = 1.4-35.0), and 4.4-fold (95% CI = 0.6-33.0) increased risks of oral cancer, respectively; the risk associated with the ADH(3)(1-1) genotype, compared with the ADH(3)(1-2) and ADH(3)(2-2) genotypes combined, was 5.3 (95% CI = 1.0-28.8) among such drinkers. Considering all levels of alcohol consumption. the risk of oral cancer per additional alcoholic drink per week increased 3.6% (95% CI = 1.9%-5.4%) for subjects with the ADH(3)(1-1) genotype and 2.0% (95% CI = 0.9%-3.0%) for subjects with the ADH(3)(1-2) or ADH(3)(2-2) genotype (two-sided P = .04). Conclusions: The ADH(3)(1-1) genotype appears to substantially increase the risk of ethanol-related oral cancer, thus providing further evidence for the carcinogenicity of acetaldehyde.