Abstract
(Cancer Sci 2010; 101: 2497–2498)
Dear Editor,
In a recent article in Cancer Science( 1 ) Oze et al. reported that current facial flushing after a small dose of alcohol is unreliable as a predictor of inactive aldehyde dehydrogenase‐2 (ALDH2) and of increased risk of upper aerodigestive tract (UAT) cancer. Epidemiological studies have shown a strong association between inactive heterozygous ALDH2 (ALDH2*1/*2) and risk of UAT cancer in East Asian drinkers, and “acetaldehyde associated with alcohol consumption” has been classified as a Group 1 human carcinogen by the International Agency for Research on Cancer of the World Health Organization.( 2 )
In earlier papers, we highlighted the importance of developing a simple screening test for inactive ALDH2 based on alcohol flushing as a tool for public education, mass screening, and epidemiological studies.( 3 ) The results regarding associations between alcohol flushing and ALDH2 genotype differ markedly according to how the question about alcohol flushing is posed. When Japanese subjects are asked, “Do you currently experience facial flushing after drinking alcohol?”, without specifying the alcohol dose, half of those with active ALDH2 are occasional or usual flushers, because they experience facial flushing after drinking a substantial amount of alcohol.( 4 ) A Japanese cohort study in which subjects were asked this question showed that 49% of the flushers had active ALDH2, and the flushing‐associated risk of esophageal cancer did not reach the level of significance.( 5 )
The questionnaire used by Oze et al. asked about the current occurrence of facial flushing after drinking a glass of beer, and classified occasional or usual flushers as flushers. Alcohol flushing diminishes in intensity due to the development of tolerance to acetaldehydemia by higher‐risk persons with a long or heavy drinking history. That explains the low facial flushing positive rates in the inactive ALDH2 heterozygotes, 57.1% in the case and 83.7% in the controls, and 42.4% in the heavy drinking cases and 67.9% in the heavy drinking controls in their study. Furthermore, the inclusion of occasional flushers among the flushers caused the slightly high positive rates of facial flushing (14.1–18.3%) in active ALDH2 carriers. These misclassifications are responsible for the failure to find any associations between facial flushing and UAT cancer in their study.
We have devised a questionnaire that prevents these problems: (A) Do you have a tendency to develop facial flushing immediately after drinking a glass (about 180 mL) of beer? (B) Did you have the tendency in the first one or 2 years after you started drinking?( 6 ) We classified the results as current, former, or never flushing. When only current flushers were assumed to have inactive ALDH2, the questionnaire’s sensitivity for detecting inactive ALDH2 was 74.3% in cancer‐free men,( 6 ) 54.9–56.7% in men with UAT cancer,( 6 , 7 ) and 12.5–18.9% in alcoholics( 8 , 9 ) (Table 1), and these results were consistent with the results reported by Oze et al. When current or former flushers were assumed to have inactive ALDH2, however, its sensitivity increased to 90.1%, 82.4–84.8%, and 73.8–75.7%, respectively, and its specificity was also high. The odds ratios (ORs) for UAT cancer in drinkers increased stepwise in the order of current flushers, current/former flushers, and inactive ALDH2 carriers (e.g. ORs for esophageal squamous cell carcinoma of 4.13, 5.44, and 8.98, respectively; Table 2). In alcoholics, however, neither the OR nor the hazard ratio (HR) in the current flushers reached a significant level. The OR and HR associated with current/former flushing were significantly high in the alcoholics (3.31 and 2.36, respectively), but substantially lower than the respective risks associated with inactive ALDH2 (7.65 and 6.78, respectively). In addition, higher proportions of men with UAT cancer (19.8–21.9%) and alcoholics (26.6–56.9%) than of cancer‐free men (5.1%) have the less‐active alcohol dehydrogenase‐1B (ADH1B*1/*1), and the presence of ADH1B*1/*1 substantially reduces the sensitivity of current/former flushing for detecting inactive ALDH2 (Table 1).
Table 1.
Sensitivity and specificity of a simple flushing questionnaire as a marker for inactive aldehyde dehydrogenase‐2 (ALDH2) in Japanese men aged 40 years or older
| Inactive ALDH2† | Active ALDH2 | Current flushing | Current or former flushing | |||
|---|---|---|---|---|---|---|
| n | n | Sensitivity (%) | Specificity (%) | Sensitivity (%) | Specificity (%) | |
| All ADH1B genotypes | ||||||
| Case–control study 1 [ref 6, 7] | ||||||
| Cancer‐free men | 284 | 326 | 74.3 | 95.1 | 90.1 | 88.0 |
| Men with esophageal SCC | 171 | 62 | 56.7 | 88.7 | 84.8 | 82.3 |
| Men with head and neck SCC | 51 | 45 | 54.9 | 91.1 | 82.4 | 84.4 |
| Case–control study 2 [ref 8] | ||||||
| Cancer‐free alcoholic men | 32 | 174 | 12.5 | 97.7 | 75.0 | 90.2 |
| Alcoholic men with esophageal SCC | 37 | 28 | 18.9 | 100.0 | 75.7 | 92.9 |
| Follow‐up study [ref 9] | ||||||
| Cancer‐free alcoholic men | 80 | 461 | 16.3 | 98.3 | 73.8 | 92.0 |
| ADH1B*1/*1 genotype | ||||||
| Case–control study 1 [ref 6, 7] | ||||||
| Cancer‐free men | 20 | 11 | 40.0 | 90.9 | 70.0 | 81.8 |
| Men with esophageal SCC | 45 | 6 | 35.6 | 83.3 | 60.0 | 66.7 |
| Men with head and neck SCC | 13 | 6 | 30.8 | 100.0 | 53.9 | 83.3 |
| Case–control study 2 [ref 8] | ||||||
| Cancer‐free alcoholic men | 9 | 50 | 0.0 | 100.0 | 33.3 | 100.0 |
| Alcoholic men with esophageal SCC | 21 | 16 | 19.1 | 100.0 | 57.1 | 100.0 |
| Follow‐up study [ref 9] | ||||||
| Cancer‐free alcoholic men | 12 | 132 | 15.4 | 98.6 | 53.9 | 92.5 |
†With the exception of 42 cancer‐free men and two men with esophageal squamous cell carcinoma (SCC) who were inactive ALDH2 homozygotes, all the inactive ALDH2 carriers were inactive ALDH2 heterozygotes. ADH, alcohol dehydrogenase.
Table 2.
Odds ratios (OR) and hazard ratios (HR) for squamous cell carcimoma (SCC) in the upper aerodigestive tract (UAT) based on results of the simple flushing questionnaire and aldehyde dehydrogenase‐2 (ALDH2) genotyping in Japanese men aged 40 years or older
| Current flushing | Current or former flushing | Inactive ALDH2† | ||||
|---|---|---|---|---|---|---|
| OR‡ | (95% CI) | OR‡ | (95% CI) | OR‡ | (95% CI) | |
| Case–control study 1 [ref 6, 7] | ||||||
| (Light‐ to heavy‐drinking men) | ||||||
| Esophageal SCC | 4.13 | (2.70–6.32) | 5.44 | (3.63–8.15) | 8.98 | (5.81–13.87) |
| Head and neck SCC | 2.04 | (1.13–3.69) | 2.26 | (1.34–3.79) | 2.58 | (1.53–4.34) |
| Case–control study 2 [ref 8] | ||||||
| (Alcoholic men) | ||||||
| Esophageal SCC | 2.65 | (0.90–7.83) | 3.31 | (1.81–6.06) | 7.65 | (4.02–14.56) |
| HR‡ | (95% CI) | HR‡ | (95% CI) | HR‡ | (95% CI) | |
| Follow‐up study [ref 9] | ||||||
| (Alcoholic men) | ||||||
| Event: SCC in the UAT | 1.31 | (0.52–3.31) | 2.36 | (1.39–4.00) | 6.78 | (4.04–11.40) |
†With the exception of two cancer‐free light‐drinking men, all the inactive ALDH2 carriers were inactive ALDH2 heterozygotes. ‡OR (HR) of inactive ALDH2 for the risk of cancer. ORs (HRs) were adjusted for age and amount of alcohol drinking. CI, confidence interval.
We have developed health risk appraisal models for non‐alcoholic populations, including data on alcohol flushing or ALDH2 genotype as well as drinking, smoking, and diet.( 10 ) The health risk appraisal model, including the flushing questionnaire, enables many people to determine their risk of UAT cancer very easily. However, it should be emphasized that genotyping needs to be carried out just once in a lifetime, and that the unit‐cost would be greatly discounted if a huge number of samples are analyzed.
References
- 1. Oze I, Matsuo K, Hosono S et al. Comparison between self‐reported facial flushing after alcohol consumption and ALDH2 Glu504Lys polymorphisms for risk of upper aerodigestive tract cancer in a Japanese population. Cancer Sci 2010; 101: 1875–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Secretan B, Straif K, Baan R et al. A review of human carcinogens‐Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol 2009; 10: 1033–4. [DOI] [PubMed] [Google Scholar]
- 3. Brooks PJ, Enoch MA, Doldman D, Li TK, Yokoyama A. The alcohol flushing response: an unrecognized risk factor of esophageal cancer from alcohol consumption. PLoS Med 2009; 6: e50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Higuchi S, Muramatsu T, Shigemori K et al. The relationship between low Km aldehyde dehydrogenase phenotype and drinking behavior in Japanese. J Stud Alcohol 1992; 53: 170–5. [DOI] [PubMed] [Google Scholar]
- 5. Ishiguro S, Sasazuki S, Inoue M et al. Effect of alcohol consumption, cigarette smoking and flushing response on esophageal cancer risk: a population‐based cohort study (JPHC study). Cancer Lett 2009; 275: 240–6. [DOI] [PubMed] [Google Scholar]
- 6. Yokoyama T, Yokoyama A, Kato H et al. Alcohol flushing, alcohol and aldehyde dehydrogenase genotypes, and risk for esophageal squamous cell carcinoma in Japanese men. Cancer Epidemiol Biomarkers Prev 2003; 12: 1227–33. [PubMed] [Google Scholar]
- 7. Asakage T, Yokoyama A, Haneda T et al. Genetic polymorphisms of alcohol and aldehyde dehydrogenases and drinking, smoking, and diet in Japanese men with oral and pharyngeal squamous cell carcinoma. Carcinogenesis 2007; 28: 865–74. [DOI] [PubMed] [Google Scholar]
- 8. Yokoyama A, Yokoyama T, Muramatsu T et al. Macrocytosis, a new predictor for esophageal squamous cell carcinoma in Japanese men. Carcinogenesis 2003; 24: 1773–8. [DOI] [PubMed] [Google Scholar]
- 9. Yokoyama A, Omori T, Yokoyama T et al. Risk of squamous cell carcinoma of the upper aerodigestive tract in cancer‐free alcoholic Japanese men: an endoscopic follow‐up study. Cancer Epidemiol Biomarkers Prev 2006; 15: 2209–15. [DOI] [PubMed] [Google Scholar]
- 10. Yokoyama T, Yokoyama A, Kumagai Y et al. Health risk appraisal models for mass screening of esophageal cancer in japanese men. Cancer Epidemiol Biomarkers Prev 2008; 17: 2846–54. [DOI] [PubMed] [Google Scholar]