Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S-transferase M1 and drinking, smoking, and diet in Japanese men with esophageal squamous cell carcinoma

Abstract

The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2), alcohol dehydrogenase-2 (ADH2), ADH3, and glutathione S-transferase M1 (GSTM1) influence the metabolism of alcohol and other carcinogens. The ALDH2*1/2*2 genotype, which encodes inactive ALDH2, and ADH2*1/2*1, which encodes the low-activity form of ADH2, enhance the risk for esophageal cancer in East Asian alcoholics. This case-control study of whether the enzyme-related vulnerability for esophageal cancer can be extended to a general population involved 234 Japanese men with esophageal squamous cell carcinoma and 634 cancer-free Japanese men who received annual health checkups. The GSTM1 genotype was not associated with the risk for this cancer. Light drinkers (1-8.9 units/week) with ALDH2*1/2*2 had an esophageal cancer risk 5.82 times that of light drinkers with ALDH2*1/2*1 (reference category), and their risk was similar to that of moderate drinkers (9-17.9 units/week) with ALDH2*1/2*1 (odds ratio = 5.58). The risk for moderate drinkers with ALDH2*1/2*2 (OR = 55.84) exceeded that for heavy drinkers (18+ units/week) with ALDH2*1/2*1 (OR = 10.38). Similar increased risks were observed for those with ADH2*1/2*1. A multiple logistic model including ALDH2, ADH2, and ADH3 genotypes showed that the ADH3 genotype does not significantly affect the risk for esophageal cancer. For individuals with both ALDH2*1/2*2 and ADH2*1/2*1, the risk of esophageal cancer was enhanced in a multiplicative fashion (OR = 30.12), whereas for those with either ALDH2*1/2*2 or ADH2*1/2*1 alone the ORs were 7.36 and 4.11. In comparison with the estimated population-attributable risks for preference for strong alcoholic beverages (30.7%), smoking (53.6%) and for lower intake of green and yellow vegetables (25.7%) and fruit (37.6%), an extraordinarily high proportion of the excessive risk for esophageal cancer in the Japanese males can be attributed to drinking (90.9%), particularly drinking by persons with inactive heterozygous ALDH2 (68.5%). Education regarding these risky conditions in connection with ALDH2 and ADH2 is vitally important in a new strategic approach aimed at preventing esophageal cancer in East Asians.

Health Risk Appraisal Models for Mass Screening of Esophageal Cancer in Japanese Men

“…Acetaldehyde has been established as a carcinogen in experimental animals (8) and is suspected of playing a critical role in cancer development in humans (9). Case-control studies in Japanese (10)(11)(12)(13) and Taiwanese (13)(14)(15)(16) individuals and prospective studies in which esophageal iodine staining has been used in Japanese alcoholics (17)(18)(19) have consistently shown a very strong link between the risk of esophageal SCC and alcohol drinking in people possessing the ALDH2*1/*2 genotype. Alcohol drinking together with the ALDH2*1/*2 genotype has been reported to be a risk factor for multiple cancerization in the upper aerodigestive tract (13,17,(19)(20)(21) and for oropharyngolaryngeal SCC (13,18,20,22,23).…”

“…Based on our previous case-control study of esophageal SCC in Japanese men (12,25), we developed simple health risk appraisal (HRA) models that predicted an individual's risk of developing esophageal cancer based on logistic regression analyses. In addition to drinking habits, smoking habits, and diet, the HRA models included either ALDH2 genotype or the results of a simple questionnaire about alcohol flushing (26).…”

Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo

“…Despite the unpleasant reaction to acetaldehyde accumulation, 17-27% of individuals with ALDH2*1/*2 (heterozygotes) are heavy drinkers (4,12,13). These heterozygotic heavy drinkers (consuming >18 alcoholic drinks/week) have greater than 80-fold increased risk for squamous cell carcinomas in the upper aerodigestive track (UADT; i.e., oral cavity and pharynx, larynx, and esophagus) compared with a ∼fourfold increase in wild-type ALDH2*1/*1 heavy drinkers (4,(13)(14)(15)(16).…”

“…These heterozygotic heavy drinkers (consuming >18 alcoholic drinks/week) have greater than 80-fold increased risk for squamous cell carcinomas in the upper aerodigestive track (UADT; i.e., oral cavity and pharynx, larynx, and esophagus) compared with a ∼fourfold increase in wild-type ALDH2*1/*1 heavy drinkers (4,(13)(14)(15)(16). Further, an elevated risk of hepatocarcinoma and its recurrence occurs among hepatitis C-infected patients with the ALDH2*2 mutation (17).…”

Dietary selenium intake, aldehyde dehydrogenase‐2 and X‐ray repair cross‐complementing 1 genetic polymorphisms, and the risk of esophageal squamous cell carcinoma

“…24 The ALDH2 glutamic acid (Glu)/lysine (Lys) genotype, which encodes inactive ALDH2, enhances the risk for esophageal cancer in East Asian alcoholics. 25 Excessive alcohol consumption among smokers has been associated with an elevated risk of esophageal cancer. 26,27 X-ray repair cross-complementing 1 (XRCC1) is a major gene in the DNA base excision repair (BER) pathway.…”