Alcohol and aldehyde dehydrogenase gene polymorphisms influence susceptibility to esophageal cancer in Japanese alcoholics

Background: Studies have consistently demonstrated that inactive aldehyde d ehydrogenase-2 (ALDH2), encoded by ALDH2*1/2*2, is closely associated with alcohol-related carcinogenesis. Recently, the contributions of alcohol dehy drogenase-2 (ADH2) polymorphism to alcoholism, esophageal cancer, and the f lushing response have also been described. Methods: To determine the effects of ALDH2 and ADH2 genotypes in geneticall y based cancer susceptibility, lymphocyte DNA samples from 648 Japanese alc oholic men more than 40 years of age (91 with and 577 without esophageal ca ncer) were genotyped and the results were expressed as odds ratios (ORs). T his study also tested 82 of the alcoholics with esophageal cancer to determ ine whether cancer susceptibility is associated with patients' responses to simple questions about current or former flushing after drinking a glass o f beer. Results: The frequencies of ADH2*1/2*1 and ALDH2*1/2*2 were significantly h igher in alcoholics with, than in those without, esophageal cancer (0.473 v s. 0.289 and 0.560 vs. 0.099, respectively). After adjustment for drinking and smoking, the analysis showed significantly increased cancer risk for al coholics with either ADH2*1/2*1 (OR = 2.03) or ALDH2*1/2*2 (OR = 12.76). Fo r those having ADH2*1/2*1 combined with ALDH2*1/2*2, the esophageal cancer risk was enhanced in a multiplicative fashion (OR = 27.66). Responses to fl ushing questions showed that only 47.8% of the ALDH2*1/2*2 heterozygotes wi th ADH2*1/2*1, compared with 92.3% of those with ALDH2*1/2*2 and the ADH2*2 allele, reported current or former flushing. Genotyping showed that for al coholics who reported ever flushing, the questionnaire was 71.4% correct in identifying ALDH2*1/2*2 and 87.9% correct in identifying ALDH2*1/2*1. Conclusion: Japanese alcoholics can be divided into cancer susceptibility g roups on the basis of their combined ADH2 and ALDH2 genotypes. The flushing questionnaire can predict high risk ALDH2*1/2*2 fairly accurately in perso ns with ADH2*2 allele, but a reliable screening procedure for the highest r isk gene combination (ADH2*1/2*1 and ALDH2*1/2*2) will require further inve stigation.