- [Show abstract] [Hide abstract] ABSTRACT: A strong association between inactive aldehyde dehydrogenase-2 (ALDH2) and risk of esophageal cancer has been demonstrated in East Asian drinkers. An alcohol flushing questionnaire asking about past and current tendency for facial flushing to occur after drinking a glass (≈180 mL) of beer predicts the presence of inactive ALDH2 among Japanese aged 40 years or older with a sensitivity and specificity of approximately 90%. We invented a health-risk appraisal (HRA) model that makes it possible to identify Japanese men who are at high risk for esophageal cancer based on their past and current alcohol flushing tendency, drinking, smoking, and intake of vegetables and fruits. Between 2008 and 2009, 2221 Japanese men aged 50 years or older filled out the HRA questionnaire before undergoing a screening examination by upper gastrointestinal endoscopy at five medical facilities. The endoscopic examination resulted in a diagnosis of esophageal cancer in 19 subjects, and 117 (5.27%) subjects had an HRA score ≥11. The proportion of subjects with an HRA score ≥11 was higher in the 50-69 age group (6.11-6.88%) than in 70-89 age group (2.84-2.86%). The esophageal cancer detection rate was 4.27% among the subjects with an HRA score ≥11 and only 0.67% among the other subjects. Based on a receiver operating characteristic curve analysis, when an HRA score of ≥9 was used for subjects aged 50-69 years and of ≥8 for those aged 70-89 years as the cutoff value to select individuals with a high risk for esophageal cancer, its sensitivity and false-positive rate was 52.6% and 15.2%, respectively, and the cancer detection rate was 2.91% in the high-risk group, as opposed to 0.48% in the other group. In conclusion, the high detection rates for esophageal cancer in the high-risk groups encouraged screening based on our HRA model in larger Japanese populations.
- [Show abstract] [Hide abstract] ABSTRACT: Background Many environmental and genetic factors are presumed to be involved in the etiology of esophageal squamous cell carcinoma (ESCC). We developed a health risk appraisal model that includes an alcohol flushing questionnaire (HRA-F) to estimate the ESCC risk. The purpose of this study was to use the HRA-F model to assess regional differences in the ESCC risk between rural and urban regions in Japan. Methods We compared the HRA-F scores for risk of ESCC of 1,043 medical screening examinees (442 men and 601 women) in a rural region of Oita Prefecture and 1,016 medical screening examinees (610 men and 406 women) in a central region of Tokyo, Japan. Results After adjustment for age, there was no difference between the frequencies of current or former facial flushers in the two populations. Oita men consumed more alcohol than Tokyo men, but Oita women consumed less alcohol than Tokyo women. There was no difference between Oita and Tokyo in the suppressive effect of flushing on alcohol consumption. Oita individuals of both genders reported less smoking, lower green and yellow vegetable intake, and lower fruit intake than did Tokyo individuals. The risk of ESCC quantitatively assessed based on the HRA-F scores was higher in Oita men than in Tokyo men, but a higher proportion of women were at high risk in Tokyo than in Oita. Conclusion The HRA-F model was useful for identifying regional differences in ESCC risk and persons at high risk of ESCC in the Japanese population.
- [Show abstract] [Hide abstract] ABSTRACT: To assess the performance of our health risk appraisal (HRA) models for screening individuals at high risk of esophageal/pharyngeal squamous cell carcinoma (EPSCC). Based on the results of our previous case-control study, we invented HRA models that enable screening for EPSCC cases in Japanese men with high sensitivity and specificity based on either their aldehyde dehydrogenase-2 genotype (HRA-G model) or alcohol flushing (HRA-F model) and drinking, smoking, and dietary habits. Follow-up endoscopy combined with esophageal iodine staining (median follow-up period: 5.0 years) was done on 404 Japanese men (50-78 years) who were registered as cancer-free controls in the previous study. The follow-up endoscopy resulted in a diagnosis of 6 esophageal SCC (T(is) in 5 and T(1) in 1), 1 hypopharyngeal SCC (T(2)), and 1 oropharyngeal SCC (T(2)). Seven and 6 of the 8 EPSCC cases were in the top 10% risk group at baseline according to the HRA-G and HRA-F models, respectively. The EPSCC detection rates per 100 person-years in the top 10% risk groups by the HRA-G and HRA-F models were 4.38 (95% confidence interval, 1.76-9.01) and 3.48 (95% confidence interval, 1.28-7.58), respectively. Their age-adjusted relative risk was 95.1- and 26.3-fold, respectively (P < 0.0001), higher than in the bottom 90% risk groups. The high detection rates for EPSCC in the top 10% risk group of this preliminary follow-up study were in good agreement with those predicted by the HRA models and thus encouraged the screening based on our HRA models in larger populations of Japanese men.
- [Show abstract] [Hide abstract] ABSTRACT: Because early squamous cell carcinoma (SCC) of the esophagus is detectable by endoscopic esophageal iodine staining with high accuracy and is easily treated by endoscopic mucosectomy, it is important to develop efficient methods for screening candidates for the endoscopic examination. Inactive aldehyde dehydrogenase-2 (ALDH2) is a very strong risk factor for esophageal SCC in alcohol drinkers and thus may be suitable as a screening tool. To assess the performance of health risk appraisal (HRA) models in screening for esophageal SCC in the Japanese male population. Two types of HRA models were developed based on our previous case-control study, which included assessment of ALDH2 activity and selected risk factors (HRA-G and HRA-F: activities of ALDH2 assessed by genotype and questionnaire for alcohol flushing, respectively). Each individual's risk of esophageal SCC was calculated quantitatively as a risk score. The sensitivity and specificity of the HRA models at various cutoff values of risk score was estimated by a leave-one-out cross-validation. The positive predictive value was estimated assuming the prevalence of esophageal SCC in the whole population to be 0.17% or 0.39% according to literatures. When individuals ranked in the top 10% of the HRA-F risk score was screened, the sensitivity was 57.9% and positive predictive value was 0.93% or 2.12% according to the above assumptions, respectively. The sensitivity was slightly better by the HRA-G model than by the HRA-F model. The HRA models may provide an important approach to early intervention strategies to control esophageal SCC in Japanese men.
- [Show abstract] [Hide abstract] 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.
- [Show abstract] [Hide abstract] ABSTRACT: Aldehyde dehydrogenase-2 (ALDH2) is the key enzyme for elimination of acetaldehyde, an established animal carcinogen produced after drinking. In persons with inactive ALDH2, the body fails to metabolize acetaldehyde rapidly, leading to excessive accumulation of acetaldehyde. Inactive heterozygous ALDH2 enhances the risk of esophageal squamous cell carcinoma (SCC) in Japanese male drinkers. We studied whether this is the case for women. The risk factors of esophageal SCC were examined in 52 Japanese women with esophageal SCC and 412 cancer-free Japanese women. The increasing trend in cancer risk according to the quantity of alcohol consumption was significantly steeper in women with inactive heterozygous ALDH2 than in those with active ALDH2 [adjusted odds ratios (ORs) (95% confidence intervals (CIs)) per +7 U/wk increment of alcohol drinking were 3.91 (2.09-7.31) and 1.39 (0.92-2.09), respectively; p = 0.006 for difference in OR; 1 Ut = 22 g of ethanol]. The results obtained using an alcohol-flushing questionnaire were essentially comparable with those obtained by ALDH2 genotyping [adjusted ORs (95% CIs) per +7 U/wk increment of alcohol drinking were 3.94 (1.87-8.31) and 1.46 (0.96-2.23) in those with and without flushing, respectively; p = 0.021 for difference in OR]. The risk of esophageal cancer was markedly higher in heavy drinkers with ALDH2*1/*2 than in never/rare drinkers with ALDH2*1/*1 [adjusted OR (95% CI) = 59.1 (4.65-750)]. Other independent significant risk factors of esophageal SCC were smoking, a preference for hot food or drinks, and lower intake of green and yellow vegetables. Japanese men and women shared several common risk factors of esophageal SCC, including drinking with inactive heterozygous ALDH2.
- [Show abstract] [Hide abstract] ABSTRACT: Because some of the causes of increased mean corpuscular volume (MCV) and esophageal squamous cell carcinoma (ESCC), including alcoholism, acetaldehyde exposure, smoking, and poor nutrition are common to both, macrocytosis has been used as a predictor of early ESCC in Japanese alcoholics. We examined whether this was also true in the Japanese general population. This study compared the MCV of 522 cancer-free Japanese men with his risk of ESCC as defined using drinking, smoking, dietary habits and aldehyde dehydrogenase-2 (ALDH2) genotype in a previous case-control study of ESCC involving them as control subjects. MCV was significantly correlated with ESCC risk predicted by drinking combined with ALDH2 genotype, smoking, or fruit intake. Men at higher risk of ESCC were more frequent in the groups with higher MCV (p < 0.0001 for trend). The replies to a questionnaire about facial flushing in response to alcohol showed that the trend was more prominent in men with current/former flushing, a surrogate marker for inactive ALDH2, than in men with no flushing (p < 0.0001). In comparison with the mean risk of men with MCV < or = 93 fl (lowest quartile), that of current/former flushing men with MCV > or = 99 fl (highest quartile) was 6.35-fold higher, whereas that of never-flushing men with MCV > or = 99 fl was 2.50-fold higher. The sensitivity and specificity of the combination of moderate-to-heavy drinking and either MCV > or = 99 fl or current/former flushing, either 30+ pack-years or MCV > or = 99 fl or either 30+ pack-years or current/former flushing for detection of high-risk persons ranking in the top 10%, was 85% and 84%, 94% and 76%, or 98% and 77%, respectively. MCV and alcohol flushing might be used to better select candidates to screen this high-mortality-rate cancer not only in alcoholics but also in nonalcoholic Japanese men.
- [Show abstract] [Hide abstract] ABSTRACT: 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.
- [Show abstract] [Hide abstract] 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.
Edo, Tokyo, Japan
- School of Medicine
National Cancer Center, Japan
Edo, Tokyo, Japan
- Endoscopy Division