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

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.

Alcohol flushing, alcohol and aldehyde dehydrogenase genotypes, and risk for esophageal squamous cell carcinoma in Japanese men.

Alcohol flushing after light drinking is triggered mainly by severe acetaldehydemia in individuals possessing inactive aldehyde dehydrogenase (ALDH)-2. Inactive ALDH2 encoded by ALDH2*1/2*2 and the low-activity form of alcohol dehydrogenase (ADH)-2 encoded by ADH2*1/2*1 enhance the risk for esophageal cancer in Japanese light to heavy drinkers, a significant association that emphasizes the importance of screening tests for inactive ALDH2 based on alcohol flushing. The objectives of the present report were (a). to evaluate the reliability of a simple questionnaire that asks about both current and past flushing for detecting inactive ALDH2 and (b). to predict cancer risk based on flushing in a case-control manner. The study subjects consisted of 233 Japanese men with esophageal squamous cell carcinoma and 610 cancer-free Japanese men. When current or former flushing individuals were considered to have inactive ALDH2, the sensitivity and specificity of the test were 84.8% and 82.3%, respectively, for the cases and 90.1% and 88.0%, respectively, for the controls. To clarify the characteristics of men who had genetically inactive ALDH2 but did not report alcohol flushing, we analyzed individuals possessing the ALDH2*1/2*2 genotype and found that those who also had ADH2*1/2*1 (both cases and controls) tended not to report current flushing, and those who did not report current flushing (controls only) tended to be heavier drinkers. As compared with overall never or rare drinking, the cancer risks for light (1-8.9 units/week; 1 unit = 22 g of ethanol), moderate (9-17.9 units/week), and heavy (18+ units/week) drinkers with current or former flushing (odds ratio = 6.69, 42.66, and 72.86, respectively) significantly exceeded the risks for those who had never flushed (odds ratio = 1.27, 10.12, and 15.61, respectively), even after adjustment for age, smoking, and diet. The flushing questionnaire may be used in large-scale epidemiological studies as a surrogate marker of ALDH2 genotype to predict individual cancer risk.

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.

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.

Multiple cancers associated with esophageal and oropharyngolaryngeal squamous cell carcinoma and the aldehyde dehydrogenase-2 genotype in male Japanese drinkers.

Aldehyde dehydrogenase-2 (ALDH2) is a key enzyme for the elimination of acetaldehyde, an established animal carcinogen generated by alcohol metabolism. In the presence of ALDH2*2, a mutant allele that is prevalent in East Asians, this enzyme is inactive, leading to excessive accumulation of acetaldehyde. Only among Japanese alcoholic patients has the positive association between this inactive form of ALDH2 and multiple-field cancerization in the upper aerodigestive tract been demonstrated. Whether this finding could be extended to multiple-cancer patients in general is of great interest, because the prevalence of esophageal cancer with other organ cancers has increased dramatically during recent decades in Japan. This study compared the ALDH2 genotypes of groups of male Japanese drinkers who had either esophageal squamous cell carcinomas (SCCs) with (n = 26) or without (n = 48) multiplicity or oropharyngolaryngeal SCCs with (n = 17) or without (n = 29) multiplicity. After adjustments for age and drinking and smoking habits, logistic regression analysis showed significantly increased risk for each multiplicity associated with either esophageal or oropharyngolaryngeal SCCs in the presence of the ALDH2*2 allele (odds ratio, 5.26; 95% confidence interval, 1.08-51.06 and odds ratio, 7.36; 95% confidence interval, 1.29-80.70, respectively). This study is the first to strongly link inactive ALDH2 with the multiple cancer susceptibility of male Japanese drinkers with either esophageal or oropharyngolaryngeal cancers. A simple questionnaire about both current and past facial flushing after drinking a glass of beer was highly sensitive (95.6%) in detecting inactive ALDH2 in these patients and may be useful for identifying high-risk patients.

Velopharyngeal function after microsurgical reconstruction of lateral and superior oropharyngeal defects.

OBJECTIVES/HYPOTHESIS: Defects of the lateral and superior oropharyngeal wall are difficult to reconstruct because of their complicated anatomy and the possibility of causing velopharyngeal incompetence. The objective was to investigate problems of reconstruction and postoperative velopharyngeal function. STUDY DESIGN: Defects were classified into three types (I, II, and III) according to their extent. Four operative procedures were performed: the Patch, Jump, Denude, and Gehanno methods, which include a lateral-posterior pharyngeal advancement flap. Speech intelligibility, velopharyngeal function, and wound dehiscence between the flap and the remaining soft palate were evaluated. METHODS: Forty patients who had undergone resection of the lateral and superior oropharyngeal walls and subsequent reconstruction were reviewed. RESULTS: Most patients with type I or II defects had satisfactory velopharyngeal function. However, in patients with type III defects, speech function was worse and severe velopharyngeal incompetence was more common. The type of defect and the presence of wound dehiscence were related to postoperative function. The rates of wound dehiscence were lower with the Patch and Gehanno methods. CONCLUSIONS: Postoperative function in patients with type III defects can be affected by various factors. We suggest that the Gehanno method be the treatment of choice for reconstruction of extensive defects of the oropharynx. However, patients in whom more than two-thirds of the superior and posterior oropharyngeal walls has been resected are poor candidates for reconstruction because of the difficulty of maintaining both nasal airway patency and velopharyngeal function.