Genetic polymorphisms of alcohol and aldehyde dehydrogenases, and drinking, smoking and diet in Japanese men with oral and pharyngeal squamous cell carcinoma

Abstract

The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2), alcohol dehydrogenase-1B (ADH1B, previously called ADH2), and ADH1C (previously called ADH3) affect the metabolism of alcohol. The inactive ALDH2 encoded by ALDH2*1/*2 and the less-active ADH1B encoded by ADH1B*1/*1 increase the risk of esophageal squamous cell carcinoma in East Asian drinkers. This case-control study involved 96 Japanese men with oral and pharyngeal squamous cell carcinoma (hypopharyngeal cancer in 43 patients and oral/oropharyngeal cancer in 53) and 642 cancer-free Japanese men. The risk of the cancers overall and of hypopharyngeal cancer was increased 3.61- and 10.08-fold, respectively, by ALDH2*1/*2 among moderate-to-heavy drinkers (9+ units/week; one unit = 22 g of ethanol), but the risk of oral/oropharyngeal cancer was not significantly affected by the ALDH2 genotype. The results obtained with a simple alcohol flushing questionnaire were essentially comparable with those obtained by ALDH2 genotyping. Among moderate-to-heavy drinkers, men with the less-active ADH1B*1/*1 had a significantly higher risk of the cancers overall, of hypopharyngeal cancer, and of oral/oropharyngeal cancer (OR = 5.56, 7.21 and 4.24, respectively). In view of the linkage disequilibrium between ADH1B and ADH1C, the ADH1C genotype does not significantly affect cancer risk. The significant independent risk factors for oral and pharyngeal cancer overall among moderate-to-heavy drinkers were inactive ALDH2*1/*2, less-active ADH1B*1/*1, frequent drinking of strong alcohol beverages straight, smoking, and lower intake of green-yellow vegetables. Educating these risks for cancer of the upper aerodigestive tract could be a useful new strategic approach to the prevention of these cancers in Japanese.

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

“…A parallel study on oral and pharyngeal SCC conducted in men who came to the same clinics and hospitals showed that hypopharyngeal SCC and esophageal SCC shared several common risk factors including ALDH2 genotype, alcohol flushing, drinking habits, smoking habits, and diet (12,22,25). Figure 5 shows the ROC curves for detecting hypopharyngeal SCC by the HRA models for esophageal SCC.…”

“…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). The IARC has recently concluded that substantial mechanistic evidence in humans with inactive ALDH2 indicates that acetaldehyde derived from the metabolism of ethanol in alcoholic beverages contributes to esophageal cancer (9).…”

“…Because drinking a small amount of alcohol results in acetaldehydemia and unpleasant alcohol flushing responses in persons with inactive ALDH2, the activity of ALDH2 can be assessed by a simple questionnaire that asks about both current and past facial flushing (24,25). This simple questionnaire about flushing as a marker of inactive ALDH2 is a highly reliable means of detecting inactive ALDH2 and predicting the risk of SCC in the upper aerodigestive tract (11,18,22,(25)(26)(27).…”

Prognostic value of p16 expression and alcohol consumption in Japanese patients with oropharyngeal squamous cell carcinoma

“…In Japan, Korea, and China, genomic aldehyde dehydrogenase-2 (ALDH2) polymorphism, a key enzyme for the elimination of acetaldehyde, is associated with esophageal and head and neck cancers. 25,26 This uniquely Asian genetic alteration 27 may render p16-negative OPSCC less responsive to therapy; however, future studies will be needed for further elucidation. Furthermore, because the number of p16-positive patients was relatively small (37 of 124 patients), the risk of smoking nullified the effects of DNA damage-induced cell death because of smoking.…”

Revue systématique des facteurs de risque modifiables des cancers de la muqueuse buccale

“…Deux études ont évalué l'effet du polymorphisme du gène codant pour l'enzyme alcool déshydrogénase : certaines formes sont moins actives (ADH1C et ADH1B) et semblent constituer un facteur de risque chez les grands consommateurs d'alcool (OR variant de 4,3 à 9,3 pour la forme 2 × 2 de l'ADH1C et 4,2 pour la forme 1 × 1 de l'ADH1B) [19,31] [36]. Ce sont les flavonoïdes, métabolites naturellement présents dans les fruits et les légumes de l'alimentation, qui semblent jouer un rôle protecteur vis-à-vis des CCB grâce à leurs propriétés anti-oxydantes (OR de 0,56) [16].…”