REVIEW

Alcohol and Aldehyde Dehydrogenase Polymorphisms
and a New Strategy for Prevention and Screening for Cancer
in the Upper Aerodigestive Tract in East Asians
Akira Yokoyama,1 Tai Omori2 and Tetsuji Yokoyama3

National Hospital Organization Kurihama Alcoholism Center, Kanagawa, Japan2
Department of Surgery, Kawasaki Municipal Hospital, Kanagawa, Japan3
Department of Human Resources Development, National Institute of Public Health, Saitama, Japan
1(Received for publication on April 19, 2010)(Revised for publication on May 31, 2010)(Accepted for publication on June 17, 2010)

The ethanol in alcoholic beverages and the acetaldehyde associated with alcohol consumption
are Group 1 human carcinogens (WHO, International Agency for Research on Cancer). The
combination of alcohol consumption, tobacco smoking, the inactive heterozygous aldehyde dehydrogenase-2 genotype (ALDH2*1/*2 ) and the less-active homozygous alcohol dehydrogenase-1B genotype (ADH1B*1/*1 ) increases the risk of squamous cell carcinoma (SCC) in theupper aerodigestive tract (UADT) in a multiplicative fashion in East Asians. In addition to being exposed to locally high levels of ethanol, the UADT is exposed to a very high concentrationof acetaldehyde from a variety of sources, including that as an ingredient of alcoholic beverages per se and that found in tobacco smoke; acetaldehyde is also produced by salivary microorganisms and mucosal enzymes and is present as blood acetaldehyde. The inefficient degradation of acetaldehyde by weakly expressed ALDH2 in the UADT may be critical to the local accumulation of acetaldehyde, especially in ALDH2*1/*2 carriers. ADH1B*1/*1 carriers tend to
experience less intense alcohol flushing and are highly susceptible to heavy drinking and alcoholism. Heavy drinking by persons with the less-active ADH1B*1/*1 leads to longer exposureof the UADT to salivary ethanol and acetaldehyde. The ALDH2*1/*2 genotype is a very strong
predictor of synchronous and metachronous multiple SCCs in the UADT. High red cell mean
corpuscular volume (MCV), esophageal dysplasia, and melanosis in the UADT, all of which arefrequently found in ALDH2*1/*2 drinkers, are useful for identifying high-risk individuals. We
invented a simple flushing questionnaire that enables prediction of the ALDH2 phenotype.
New health appraisal models that include ALDH2 genotype, the simple flushing questionnaire,or MCV are powerful tools for devising a new strategy for prevention and screening for UADT
cancer in East Asians. (Keio J Med 59 (4) : 115－130, December 2010)

Keywords: acetaldehyde, alcohol dehydrogenase, aldehyde dehydrogenase, esophageal cancer, headand neck cancer

Introduction

and these factors synergistically increase the cancer risk.
A large Japanese case-control study demonstrated that a
combination of drinking (≥ 33 g ethanol/day) and heavysmoking (≥ 30 pack-years) posed the highest risk ofesophageal and hypopharyngeal cancer [odds ratio (OR;
95% confidence interval) = 29.9 (10.9–81.9)] in compar-

Alcohol consumption and tobacco smoking are two
major risk factors for squamous cell carcinoma (SCC) of
the upper aerodigestive tract (UADT; the oral cavity,
pharynx, larynx, and esophagus) in developed countries,

Reprint requests to: Akira Yokoyama, MD, National Hospital Organization Kurihama Alcoholism Center, Kanagawa, 5-3-1 Nobi, Yokosuka, Kanagawa
239-0841, Japan, E-mail: a_yokoyama@kurihama1.hosp.go.jp
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ison with the combination of never drinking and neversmoking, whereas the OR was 8.2 (2.4–27.7) for the
combination of drinking (≥ 33 g ethanol/day) and neversmoking and 3.9 (1.3–11.8) for the combination ofheavy smoking and never drinking.1 Adequate intake offruits and vegetables is associated with a reduced risk of
SCC in the UADT. A recent Japanese prospective cohort
study demonstrated that an increase in total fruit andvegetable intake by 100 g/day was associated with an
11% (1%–21%) decrease in the incidence of esophageal
SCC,2 and the protective effect of fruits and vegetables
was greater in heavy drinkers and smokers. Low bodymass index (BMI) is another risk factor for SCC in the
UADT.3 A case-control study4 and a prospective study5
in Japanese alcoholics showed that alcoholics with a
BMI <19.0 (lowest quartile) had a substantially higher
risk of SCC in the UADT than those with a BMI ≥ 23.2–
23.7 [highest quartile; OR = 4.6 (1.8–11.7) for esophageal SCC and hazard ratio (HR; 95% confidence interval) = 3.6 (1.2–11.1) for SCC in the UADT]. Many Japanese alcoholic patients are also heavy smokers, and theirpoor nutritional status and low BMI are largely attributable to poor dietary habits, including a low intake ofgreen and yellow vegetables, and smoking.6
We introduced an endoscopic screening program at
Kurihama Alcoholism Center in 1993,7 and by 2008, initial screening of 5210 Japanese alcoholic men by endoscopy combined with oropharyngolaryngeal inspectionand esophageal iodine staining had detected esophageal
SCC in 206 (4.0%) and oropharyngolaryngeal SCC in 55(1.1%). Recent technical improvements in endoscopes
and a growing understanding of the endoscopic findingsof early SCC in the esophagus7, 8 and pharynx9 have enabled very early detection of SCC in the UADT. Treatment of early esophageal SCC by endoscopic mucosectomy has become widespread in Japan and has succeeded in improving the outcome of this high-mortality cancer1 0, 11; early pharyngeal SCC is also now being treatedby endoscope-guided mucosectomy1 2 with excellent outcomes.1 3 It has thus become even more important to develop preventive strategies and screening programs
based on risk factors.
Genetic Polymorphism of ALDH2 andAlcohol Metabolism
A mutant allele encoding an inactive subunit of aldehyde dehydrogenase-2 (ALDH2; rs671) was carried by
the Han Chinese as they spread throughout East Asia.1 4
Its highest frequency has been found in Southeast China,
and inactive ALDH2 is observed in most areas of China,
Japan, Korea, Mongolia, and Indochina, but is not foundin most other populations. About 40% of Japanese havethe inactive ALDH2*2 allele (e.g., 7% are homozygous
and 35% are heterozygous),1 5 which acts in a dominantmanner. After drinking 0.1 g ethanol/kg body weight,

homozygotes for inactive ALDH2 and heterozygotes forinactive ALDH2 had 18 times higher and 5 times higher
peak blood acetaldehyde concentrations, respectively,
than active ALDH2*1/*1 homozygotes who had consumed 0.8 g ethanol/kg body weight.1 6 An alcohol challenge test showed a 7% slower ethanol elimination rate
among Japanese with the ALDH2*1/*2 genotype thanwith the ALDH2*1/*1 genotype, suggesting product inhibition of ethanol oxidation by high blood acetaldehyde
levels in ALDH2*1/*2 heterozygotes.1 7 After drinking a
relatively small amount of alcohol, people with inactive
ALDH2 tend to experience a flushing response, including facial flushing, palpitations, nausea, and drowsiness,1 8 and they experience a hangover the next morning.1 9 Having inactive ALDH2 generally prevents East
Asians from drinking heavily. Homozygotes for inactive
ALDH2 are usually non-drinkers or occasional drinkers
because of their very intense flushing responses, but
26% of heavy drinkers2 0 and 13% of alcoholics1 5 in Japan have been found to be heterozygous for inactive
ALDH2 in Japan.
ALDH2 and SCC in the UADT
Esophageal SCC in Japan and Taiwan
In 1996, we first reported that the heterozygous inactive ALDH2 genotype is a strong risk factor for esophageal cancer in everyday drinkers and alcoholics.2 1 Since
then, Japanese and Taiwanese case-control studies haveshown that approximately 65%–76% of esophageal cancer patients 2 0 - 2 8 and 53%–63% of alcoholics withesophageal cancer2 1, 2 9- 3 1 had the ALDH2*1/*2 genotype, and the studies have consistently demonstrated
strong associations.3 3 In a study in which alcoholics withno evidence of cancer based on endoscopic screening
served as controls, the OR for detection of esophageal
SCC by screening heterozygote alcoholics with inactive
ALDH2 was 13.5-fold (8.1–22.6) the OR of alcoholics
with active ALDH2.3 1 We conducted a multicenter casecontrol study of 234 esophageal SCC cases and 634 controls2 0 and found that the OR of moderate drinkers (198–
365 g ethanol/week) with the ALDH2*1/*2 genotype
was 55.8 (15.4–202.5) when never/rare drinkers (< 22 gethanol/week) were used as the reference group, and that
far exceeded the OR of 10.4 (2.9–37.8) of heavy drinkers (≥ 396 g ethanol/week) with the ALDH2*1/*1 genotype (Fig. 1A). Estimation of population attributable risk(PAR) revealed that alcohol-drinking ALDH2*1/*2 heterozygotes accounted for 69% of the cancer cases. The
PAR was 31% for preference for drinking strong alcoholic beverages straight, 54% for smoking, 26% for low
intake of green-yellow vegetables, and 38% for low intake of fruits. If ALDH2 heterozygotes who consume
198 g ethanol/week or more consumed less than 198 gethanol/week instead, 53% of esophageal cancers might
be prevented in this population.3 4 The ORs for the devel-

Keio J Med 2010; 59 (4): 115－130

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opment of esophageal cancer of Taiwanese drinkers withinactive heterozygous ALDH2 are also markedly
high.2 6, 2 7 Persons who have the inactive ALDH2*1/*2
genotype and are in the habit of drinking more than 30 gethanol/day have a 103-fold (38–275) greater odds ofdeveloping esophageal cancer than non-drinkers with theactive ALDH2*1/*1 genotype, and a PAR of 58% for alcohol-drinking ALDH2*1/*2 heterozygotes was found.2 7
A meta-analysis showed that ALDH2-related susceptibility to esophageal cancer includes light-to-moderatedrinkers as well as heavy drinkers.3 5 The magnitude of
the ALDH2*1/*2-associated risk was 7.07 (3.67–13.60)
times in heavy drinkers and 2.49 (1.29–4.79) times inlight-to-moderate drinkers.
A Japanese case-control study of women showed amarkedly higher risk [OR = 59.1 (4.65–750)] of esophageal SCC in heavy drinkers (≥ 396 g ethanol/week) with
the ALDH2*1/*2 genotype than in never/rare drinkers
with the ALDH2*1/*1 genotype; this study also showeda somewhat lower risk in women than in men overall,
except among heavy drinkers with the ALDH2*1/*2
genotype. 3 6 The large recent increase in alcohol consumption among women in Japan may have been too recent for the full effects to have materialized. The reported number of years of alcohol consumption among
drinkers was substantially fewer for women than formen, and the women were more health-conscious thanmen in regard to smoking and dietary habits.
The two largest case-control studies, one in Taiwan3 7
and the other in Japan,2 8 showed that the ALDH2*1/*2
genotype increased the risk of esophageal SCC more in
the younger population, suggesting that high acetaldehyde exposure accelerates the development of esophageal SCC at a young age.
Esophageal SCC in Mainland China

Fig. 1 Alcohol drinking by Japanese men and risk of esophageal
squamous cell carcinoma according to (A) ALDH2 genotype,2 0(B) alcohol flushing, 1 0 6 and (C) ADH1B genotype. 2 0 The
subjects were classified as never/rare drinkers, current drinkers
who consumed 1 to 8.9 units/week (light drinkers; 1 unit =22 g ethanol), 9 to 17.9 units/week (moderate drinkers), or
18+ units/week (heavy drinkers), or ex-drinkers. Odds ratios
were adjusted for age, frequency of drinking strong alcoholic
beverages straight, pack-years of smoking, frequency of intake
of green and yellow vegetables, and frequency of fruit intake.
The vertical lines indicate the 95% confidence interval. *p<0.05,**p<0.01, and ***p<0.001.

In high-risk areas for esophageal cancer in mainland
China, there is pronounced heritability of esophageal
cancer risk, and alcohol drinking plays a less importantrole in esophageal carcinogenesis than in Japan and Taiwan. In such a high-risk area, case-control studies haveshown modest to moderate positive associations [ORs =1.67 (1.02–2.72) to 3.12 (1.86–6.58)]3 8-4 1 or no associations4 2 between inactive ALDH2 and esophageal cancer
risk. The ALDH2*1/*2-associated risk in Chinese studies was stronger where the impact of alcohol consumption on esophageal carcinogenesis was stronger, andwhen only male populations were evaluated. Over the
past 40 years, per-capita alcohol consumption has increased by 9 times in China, whereas it has doubled inJapan. Consumption has remained stable in recent years
in Japan, but will probably increase further in China. 4 3
Chinese consumption is still comparable to Japanese
consumption in the 1970s, when the number of heavy
drinkers with inactive heterozygous ALDH2 started toYokoyama A, et al: ADH and ALDH Polymorphisms and Cancer Prevention

118

increase dramatically.4 4 Alcohol-related esophageal cancer in mainland China will be a greater problem in the
future.

respectively].5 0 The impact of the carcinogenesis-inducing effect of acetaldehyde may differ according to anatomical site.

Head and Neck Cancer

Field Cancerization

A meta-analysis of six Japanese case-control studies
showed increased ALDH2*1/*2-related susceptibility tohead and neck cancer in moderate drinkers as well as inheavy drinkers compared to ALDH2*1/*1 genotype,4 5
and the magnitude of the ALDH2*1/*2 effect on headand neck cancer was greater in heavy drinkers [OR =3.57 (1.41–9.05)] than in moderate drinkers [OR = 1.68
(1.27–2.22)]. Japanese studies of the ALDH2*1/*2-associated risk for head and neck cancer have reported different patterns of association according to anatomicalsite and drinking habit. One case-control study of oral
cancer in which alcohol consumption was not a risk factor showed that ALDH2 genotype had no effect,4 6 but
another case-control study of oral cancer in which alcohol consumption was a risk factor reported a relatively
weak but significantly increased risk [OR= 2.9 (1.1–7.8)] associated with ALDH2*1/*2. 4 7 A case-control
study of oral and pharyngeal SCC showed that
ALDH2*1/*2 was a strong risk factor for SCC in the hypopharynx [OR = 10.1 (3.8–26.8)] among men who
were moderate-to-heavy drinkers, but the OR of 1.80
(0.83–3.89) for SCC of the oral cavity and oropharynx
did not reach the level of significance.4 8 We conducted anested case-control study based on the results of the initial endoscopic screening of 3016 Japanese alcoholicmen.4 9 In that study 55 cases of SCC of the oropharyngolarynx were detected, and 275 cancer-free controls
matched for age and initial examination time were randomly selected to provide a case:control ratio of 1:5. The
OR of inactive ALDH2 heterozygotes versus active
ALDH2 homozygotes for SCC in the oropharyngolarynx
as a whole was 4.70 (2.60–8.51), and the OR of inactive
ALDH2 heterozygotes versus active ALDH2 homozygotes for SCC in the oropharynx/hypopharynx/epilarynx
was 6.66 (3.27–13.6). The OR of 1.55 (0.40–5.95) for
SCC in the tongue/gingiva/vocal cord, however, did notreach the level of significance. A prospective study ofcancer-free Japanese alcoholic men showed similarlyhigh HRs of 13.0 (5.2–32.1) and 11.7 (4.7–29.5) for
SCC of the esophagus and oropharyngolarynx in inactive ALDH2 heterozygotes, respectively, but half of theoropharyngolaryngeal SCCs were hypopharyngeal.5 Inactive heterozygous ALDH2 and initial multiplicity of
intra-esophageal SCCs increased the risk of metachronous hypopharyngeal/epilaryngeal SCC in Japanese alcoholic men who had been treated for esophageal SCC[HR = 12.08 (1.52–95.89) and 3.73 (1.22–11.41), respectively], but the positive associations with oralcavity/oropharyngeal SCC did not reach the level of significance [HR = 2.53 (0.82–7.86) and 2.41 (0.96–6.05),

The prevalence of multiple-organ cancer among Japanese esophageal cancer patients in the National Cancer
Center has increased at an alarming rate, from 6% in
1969–80 to 22% in 1981–91 and to 39% in 1992–96. 5 1
The most frequent sites of multiple cancers were thehead, neck and stomach. The SEER Program of the U.S.
National Cancer Institute has reported synchronous andmetachronous multiple cancers in only 2% and 3%, respectively, of esophageal cancer patients between 1973
and 2003.5 2 One reason for the increase in Japan is the
improvement in survival rates, which increases the
chance of developing other primary cancers. Anotherreason is the widespread use of esophageal iodine staining to screen head and neck cancer patients for esophageal cancer; this has yielded a very high esophageal cancer detection rate (e.g., 11.8%).5 3 Yet another reason for
the increase in multiple esophageal cancers in Japan isthe dramatic increase in the proportion of inactive
ALDH2 heterozygotes among Japanese alcoholics in thesame period, from 3% in 1979 to 8% in 1986 and 13% in
1992. 4 4 The proportion of inactive ALDH2 heterozygotes among Han Chinese alcoholics in Taiwan also increased during the 1990s, from 10% to 18%. 5 4 The inhibitory impact of inactive heterozygous ALDH2 onheavy drinking is influenced by sociocultural factors,
such as greater peer pressure and greater social acceptance of drinking in Japanese male culture.
Japanese case-control studies and endoscopic followup studies have consistently demonstrated that
ALDH2*1/*2 is a strong risk factor for multiple cancerization in the UADT.2 9, 3 1, 5 0, 5 5- 5 9 Alcoholics with the
ALDH2*1/*2 genotype and those with synchronous multiple esophageal SCCs at baseline had a markedly increased likelihood of developing metachronous SCC in
the UADT after treatment for esophageal SCC.5 0 Acetaldehyde plays a critical role in multicentric field cancerization throughout the UADT.
The frequency of synchronous and metachronous gastric cancer among esophageal SCC patients is also highin the Japanese population,5 1, 6 0 suggesting the presenceof common background factors underlying the gastricand esophageal cancers. We conducted a case-control
study based on the results of initial endoscopic screeningof 3497 Japanese alcoholic men in which gastric adenocarcinoma was detected at a high rate of 1.4%.6 1 In thegastric cancer cases compared with the controls, there
was a significantly higher age-adjusted prevalence of patients positive for Helicobacter pylori (78% vs. 57%, P= 0.022), of severe chronic atrophic gastritis (CAG) assessed by the serum pepsinogen test (49% vs. 15%, P <Keio J Med 2010; 59 (4): 115－130

0.001), of ALDH2*1/*2 (36% vs. 14%, P < 0.001), ofmean corpuscular volume (MCV) ≥ 106 fl (38% vs.
20%, P = 0.008), and of synchronous SCC in the UADT
(18% vs. 5%, P = 0.004). Even among the gastric-cancer-free controls, the prevalence of severe CAG washigher than generally reported in Japan, and combinations of CAG and ALDH2*1/*2 entailed a higher risk ofgastric cancer [OR = 4.0 (1.1–14), 17.6 (5.3–58), 9.7(2.4–39), 17.1 (3.9–76), and 39.2 (6.4–239) for non-severe CAG alone, severe CAG alone, ALDH2*1/*2
alone, non-severe CAG plus ALDH2*1/*2, and severe
CAG plus ALDH2*1/*2, respectively].
The risk of metachronous gastric cancer in Japanese
men after surgery for esophageal cancer has been reported to be twice that of the general Japanese male population.6 0 The risk of metachronous gastric cancer is especially high in Japanese alcoholic men with esophageal
SCC: the estimated cumulative rate for metachronous
gastric cancer within 5 years was 15% in an alcoholic
study,6 2 as opposed to the 10% within 10 years reported
in a Japanese non-alcoholic study. 6 0 CAG assessed by
the serum pepsinogen test and H. pylori status werecompared in 90 Japanese alcoholic men with esophageal
SCC and 180 age-matched Japanese gastric- and esophageal-cancer-free alcoholic men. 6 2 The results showedmarkedly accelerated progression of H. pylori-related severe CAG in those with esophageal SCC, indicating theexistence of common mechanisms by which both esophageal SCC and severe CAG develop. Endoscopic follow-up in Japanese alcoholic men with esophageal SCC
revealed an age-adjusted HR of 7.87 (1.43–43.46) in patients with severe CAG in comparison with those without CAG. Accelerated development of severe CAG partially explained the very high frequency of developmentof metachronous gastric cancer in this population.
Esophageal Dysplasia
Esophageal dysplasia is rarely detected by endoscopy
in the absence of esophageal iodine staining. We havecollected mucosal biopsy specimens from distinctly iodine-unstained lesions (DIULs) with a greatest dimension of 5 mm or more, but because we often observed
multiple DIULs in alcoholics, especially in those with
ALDH2*1/*2, we were puzzled as to how to prioritize
lesions for biopsy. We noticed that the DIULs changed
color, and that most of the cancerous lesions became
partially or completely tinged light pink about 2 minutes
after staining. We refer to this endoscopic finding as the“pink color sign (PC sign).”6 3 A comparison of 112 dysplasia lesions and 138 very early cancers revealed that
the PC sign was positive in 90% of the cancers but inonly 3% of the dysplasia lesions. Another study demonstrated 92% sensitivity and 94% specificity of the PC
sign as a means of differentiating high-grade intra-epithelial neoplasia or SCC from other non-cancerous le-119

sions when targeted biopsy of 121 DIULs ≥ 5 mm was
performed.6 4 The PC sign is a useful endoscopic finding
for identifying high-risk cancerous lesions during
screening of high-risk drinkers.
In a study in which five deep serial sections were obtained from each biopsy specimen of DIULs ≥ 5 mm detected in alcoholics and stained with hematoxylin andeosin, an expert pathologist in the field of esophageal
neoplasia diagnosed 96% of the non-cancerous DIULs
as esophageal dysplasia. 6 5 The presence of multiple
esophageal iodine-unstained lesions and the presence oflarge esophageal DIULs ≥ 5 mm were correlated withinactive heterozygous ALDH2 5 8, 6 6 - 6 8 and with increased risk of multiple SCCs in the UADT.5, 58, 66, 67, 69, 70
The 6 year cumulative rates of detection of metachronous SCC in the esophagus and oropharyngolarynx were
56% and 35%, respectively, in Japanese alcoholics afterendoscopic mucosectomy of esophageal SCC, as opposed to 31% and 20%, respectively, in those withesophageal dysplasia ≥ 5 mm, and 4% and 4%, respectively, in those without DIULs ≥ 5 mm.7 1 Esophageal
dysplasia ≥ 5 mm is associated with a very high risk of
SCC in the UADT. The presence of multiple esophageal
iodine-unstained lesions is a strong predictor of the development of metachronous SCC in the esophagus6 9 andhead and neck 7 0 in Japanese patients after endoscopic
mucosectomy for esophageal SCC.
Melanosis in the UADT
Melanosis of the palate, pharynx, and esophagus ischaracterized by flat, greenish-black pigmented areas,
and it is frequently (11%, 10%, and 7%, respectively)
detected during endoscopic screening of Japanese alcoholic men.6 5, 6 8 We have shown that the presence of melanosis indicates a high risk of neoplasia in the UADT.
Esophageal dysplasia and SCC in the UADT in alcoholic
men were frequently (25% and 49%, respectively) accompanied by melanosis in the UADT. Inactive ALDH2,
advanced age, and heavy smoking are strongly associated with the presence of melanosis. Some of the causes ofmelanosis and UADT neoplasia are the same, and they
include heavy drinking, inactive ALDH2, acetaldehyde
exposure, heavy smoking, and advanced age. A high detection rate (19%) of esophageal melanosis by endoscopy has been reported in Japanese esophageal SCC patients at a university hospital.7 2 The above findings are
consistent with the results of an earlier pathologicalstudy that found a high frequency and high density ofmelanocytes in surgical specimens obtained from Japanese esophageal cancer patients.7 3 The detection of melanosis in the UADT may encourage endoscopists to use
esophageal iodine staining and to examine the oropharyngolaryngeal sites carefully.

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Carcinogenicity of Acetaldehyde
Acetaldehyde is a mutagen, genotoxin, and DNA-damaging agent,7 4 and sufficient evidence of the carcinogenicity of acetaldehyde has been obtained in experimental
animals.7 5 Acetaldehyde inhalation has been shown toresult in the development of tumors in the respiratory
tract, i.e., adenocarcinomas and SCCs of the nasal mucosa in rats7 6 and laryngeal carcinomas in hamsters7 7; inaddition, acetaldehyde promotes carcinogenesis bybenzo(a)pyrene in hamsters.7 7 We have demonstrated
high blood levels of mutagenic acetaldehyde-DNA adducts in alcoholics with heterozygous inactive
ALDH2.7 8 The formation of DNA adducts may explain
many of the genotoxic effects of acetaldehyde. Other human evidence includes a high frequency of sister chromatid exchanges7 9 and micronuclei8 0 and slower electrophoretic DNA migration8 1 by leukocytes from habitual
drinkers with inactive heterozygous ALDH2. The International Agency for Research on Cancer (IARC) of the
WHO has noted that the substantial mechanistic evidence obtained in ALDH2-deficient humans indicates a
causal role of acetaldehyde in esophageal cancer. 8 2 Itclassified the ethanol in alcoholic beverages as a Group
1 carcinogen in 20078 2 and the acetaldehyde associatedwith alcohol consumption as a Group 1 carcinogen in2009.8 3 Classification as a Group 1 carcinogen means
there is sufficient evidence of carcinogenicity in humans.
Salivary Acetaldehyde
Alcohol challenge tests that monitor blood and salivary acetaldehyde concentrations after a moderate doseof alcohol8 4, 8 5 have shown much higher salivary acetaldehyde concentrations than blood acetaldehyde concentrations in both inactive ALDH2 heterozygotes (e.g., 37–
76 μM vs. 12–25 μM) 8 5 and active ALDH2 homozygotes (e.g., 24–53 μM vs. 2–5 μM). Most experimental
studies on mammalian or human cell cultures haveshown induction of mutations, sister chromatid exchanges, and chromosomal aberrations after exposure to acetaldehyde concentrations ranging from 40 to 1000 μM ina highly dose-dependent manner. 8 6 The acetaldehyde
levels measured in the saliva of healthy persons may besufficient to cause mutagenic damages in the UADT.
Normal oral bacteria and yeasts produce acetaldehyde
from ethanol, and they make a large contribution to thehigh acetaldehyde level in saliva. The in vitro acetaldehyde producing ability of saliva is abolished by sterile
filtration or centrifugation,8 6 and it has been found to becorrelated with both salivary microbial counts and salivary acetaldehyde levels after drinking.8 7, 8 8 The salivary
acetaldehyde levels after drinking were reduced after using an antiseptic mouthwash 8 6 ; 4-methylpyrazole, aweak inhibitor of microbial alcohol dehydrogenase(ADH) but a strong inhibitor of mucosal and hepatic

ADH, decreased the salivary acetaldehyde concentrationof ALDH2*1/*2 subjects but not of ALDH2*1/*1 subjects.8 9 Heavy drinking,8 7, 8 8 smoking,8 7 and poor oral
hygiene,9 0 all of which are common in alcoholics, areassociated with increased salivary acetaldehyde-producing capacity, probably as a result of modification of theoral microflora. Both the oral microbial counts and in vitro salivary acetaldehyde-producing capacity of Japanese
alcoholics decreased after 3 weeks of abstinence, and thedecreases were mutually correlated. 8 8 Many factors in
addition to abstinence, including tooth-brushing behavior and diet, may have changed during the 3-week abstinence period. Overgrowth of oral microorganisms resulting in excessive production of salivary acetaldehyde isanother possible explanation for the very high rate of
UADT cancer in alcoholics.
Acetaldehyde in Alcoholic Beverages
Alcoholic beverages themselves contain high levels of
acetaldehyde.9 1 The French apple brandy Calvados, theJapanese distilled liquor shochu, and other spirits in undiluted form have an acetaldehyde concentration of 1000
μM. 8 5, 9 1 In a randomized cross-over design study inwhich 19 healthy Japanese volunteers ingested 0.6 g
ethanol/kg body weight in the form of 13%-ethanol Calvados, 13%-ethanol shochu, 13%-ethanol red wine, and
5%-ethanol beer under fasting conditions at 3-week intervals,8 5 the acetaldehyde concentration of the beverages consumed was 600 μM, 600 μM, 250 μM, and 140 μM,
respectively. The results showed that the salivary acetaldehyde concentrations immediately after drinking thehigh-acetaldehyde beverages were higher than immediately after drinking the low-acetaldehyde beverages.
Overall trends suggest that consumption of all types ofalcoholic beverages increases the risk for SCC in the
UADT, but Japanese studies have shown stronger associations between SCC in the UADT and a preference fordrinking concentrated alcoholic beverages, such as whiskey and shochu, straight.2 0, 4 8, 9 2 The high level of direct
exposure of the UADT to acetaldehyde as well as to ethanol, at least in part, explains the increased susceptibility
to cancer of the UADT as a result of the preference fordrinking high ethanol/acetaldehyde beverages straight.
Acetaldehyde in Tobacco Smoke
The results of a large genome-wide association study
involving 1070 Japanese esophageal SCC patients and2836 controls demonstrated that four risk factors [i.e.,
inactive heterozygous ALDH2, less-active ADH1B (seebelow), drinking, and smoking] synergistically increase
the risk of esophageal cancer.2 8 The effects of combination of the high-risk genotypes were more prominent insmokers and in heavier drinkers. Interestingly, the increase in risk associated with having the ALDH2*1/*2

Keio J Med 2010; 59 (4): 115－130

genotype was greater in smokers than in non-smokers,
but the increase in risk associated with less-active
ADH1B was similar in smokers and non-smokers. Although alcohol consumption in each drinking category
may have been greater in the smokers than in the nonsmokers, the acetaldehyde in tobacco smoke is anotherpossible explanation for these findings. As one of the
major chemical constituents of tobacco smoke, acetaldehyde dissolves in saliva during active smoking andreaches concentrations as high as 400 μM.9 3 Inefficientdegradation of the acetaldehyde in inactive ALDH2 heterozygotes may lead to accumulation of very high levelsof acetaldehyde in the mucosa of the UADT after highexposure to acetaldehyde during active smoking.
Acetaldehyde Metabolism
in the Mucosa of the UADT
High-Km ADH7 (class IV ADH) is strongly expressedin the UADT and it actively catalyzes conversion of ethanol to acetaldehyde upon exposure to a locally highdose of ethanol.9 4, 9 5 ADH7 activity is higher in esophageal cancer cells than in normal esophageal tissue, suggesting that increased ADH7 activity may be a factor intensifying carcinogenesis through increased mucosal acetaldehyde production.9 6 Chronic alcohol consumption
leads to induction of cytochrome P4502E1, which metabolizes ethanol to acetaldehyde,9 7 and induction of
P4502E1 has been demonstrated in the oropharyngeal
mucosa of alcoholics with oropharyngeal cancer.9 8 The
epithelium of the UADT of alcoholics is exposed to avery high concentration of acetaldehyde from a variety
of sources. ALDH activity is disproportionately lower
than ADH activity in the UADT.9 4, 9 5 The results of immunohistochemical staining of the esophageal mucosa
with ALDH2-antibody in Japanese esophageal cancer
patients have suggested that both inactive and active
forms of ALDH2 are induced in normal esophageal epithelium by heavy drinking,9 9 and this enzyme induction
may widen the difference in mucosal acetaldehyde elimination between ALDH2*1/*1 and ALDH2*1/*2 alcoholics. During exposure to very high levels of acetaldehyde,
the inefficient degradation of acetaldehyde by tissue
ALDH2 in the UADT may be more critical to the difference in local accumulation of acetaldehyde between individuals with ALDH2*1/*1 and ALDH2*1/*2.
The Simple Flushing Questionnaire
ALDH2-associated cancer susceptibility emphasizes
the importance of developing screening tests for inactive
ALDH2 based on alcohol flushing.3 4 The results regarding associations between alcohol flushing and ALDH2
genotype have been found to differ markedly according
to how the question about alcohol flushing is posed.
Without defining the alcohol dose, answers to the ques-121

tion, “Do you currently experience facial flushing after
drinking alcohol?” are unreliable as a means of predicting the presence of inactive ALDH2. Half of active
ALDH2 carriers have been found to be always flushers
or occasional flushers when asked this question, probably because they experienced alcohol flushing when they
drank a substantial amount of alcohol.100 The results of aJapanese cohort study in which this question was asked
showed that 49% of flushers had active ALDH2 and thatthe flushing-associated risk of esophageal cancer wasmodest, but that the hazard risk was greatest for flushers
who were also both heavy drinkers and heavy smokers.101
There have been several important advances in themethods used to predict the presence of inactive ALDH2
based on replies to questionnaires on alcohol flushing responses. Takeshita and Morimoto developed an alcohol
sensitivity screening test based on flushing responses
that had an 89% sensitivity and 90% specificity whenapplied to 424 Japanese male workers.1 0 2 The ethanol
patch test, a cutaneous test for the flushing response, isused in Japan in health education for youths, especiallythose who have never consumed alcohol. The first study
reported a high sensitivity (93%) and specificity (94%)
for identifying inactive ALDH2,1 0 3 but subsequent studi e s f a i l e d t o c o n f i r m s u c h h i g h r e l i a b i l i t y l e vels.1 0 2, 1 0 4, 1 0 5 The sensitivity of 72% and specificity of
71% of the ethanol patch test among men age 50 or older, many of whom had a long history of drinking, were
unsatisfactory,1 0 5 suggesting that aging and acquired tolerance to acetaldehydemia influence the test results.
When the current flushing question, “Do you have atendency to flush in the face immediately after drinking
a glass of beer?” (a glass means about 180 mL, the mostcommon Japanese beer glass size), was used to detect inactive ALDH2, its specificity for detecting active
ALDH2 was very high, but its sensitivity for detecting
inactive ALDH2 was only 74% in cancer-free men, 57%
in men with esophageal cancer, and 8% in alcoholic menwith esophageal cancer.1 0 6, 1 0 7 Alcohol flushing diminishes in intensity as a result of the development of tolerance to acetaldehydemia in higher-risk persons with along or heavy drinking history.
We devised a flushing questionnaire to resolve theabove problems (Fig. 2).1 0 6 The simple flushing questionnaire consists of two questions: (A) Do you have atendency to flush in the face immediately after drinking
a glass (180 mL) of beer? (B) Did you have a tendency
to flush in the face immediately after drinking a glass ofbeer during the first to second year after you started
drinking? We classified the results as current flushing,former flushing, or never flushing. When current flushers and former flushers were assumed to have inactive
ALDH2, the simple flushing questionnaire yielded 90%
sensitivity and 88% specificity among 610 Japanese men
aged 40 years or older1 0 6 and 88% sensitivity and 92%

Yokoyama A, et al: ADH and ALDH Polymorphisms and Cancer Prevention

122

Fig. 2 The simple flushing questionnaire to identify inactive ALDH2. Sensitivity and specificity are both approximately 90% inJapanese subjects 40 years of age and over regardless of gender.36, 106

specificity among 381 Japanese women aged 40 years orolder.3 6 The individuals’ risks of UADT cancer estimated on the basis of the replies to the flushing questionnaire were slightly lower than, but basically comparable
to, those estimated on the basis of ALDH2 genotyping(Fig. 1B).36, 48, 106
Screening for SCC in the UADT
by Means of Health Risk Appraisal Models
Based on the results of a case-control study,2 0 we devised health risk appraisal (HRA) models for esophageal
cancer that include ALDH2 genotype or alcohol flushing.1 0 8 The total risk score is calculated by adding thescores A to E. If the risk score is 11 or more according to
the HRA-flushing model (Fig. 3), that person’s risk ofesophageal cancer is in the top 10% of the study population. A cross-validation study predicted that approximately 60% of the esophageal and hypopharyngeal
SCCs in the entire population could be detected by examining only people whose risk scores were in the top
10% in the HRA models (i.e., sensitivity ≈60% andspecificity ≈90%). The esophageal SCC detection rate
among Japanese men aged 40 years or older whose risk
score was in the top 10% (i.e., positive predictive value,
PPV) was expected to be 1%–2%. Follow-up endoscopy
with esophageal iodine staining (median follow-up period: 5.0 years) was performed on 404 cancer-free controls (aged 50–78 years), and resulted in the diagnosis of
six esophageal SCCs and two pharyngeal SCCs. The risk
scores of six of the eight cancer patients at baseline werein the top 10% according to the HRA-flushing model.1 0 9The cancer detection rate per 100 person-years in the top
10% risk group was 2.3 for esophageal cancer and 3.5
for esophageal or pharyngeal cancer. These figures haveencouraged screening with our questionnaire in larger
populations of Japanese men.
We are now applying this HRA-flushing questionnaire
to mass-screening programs in large Japanese populations. This questionnaire enables many people to identify
their risk of UADT cancer very easily, and public awareness campaigns using the questionnaire will encouragehigh-risk persons to undergo endoscopic screening orconvince them to change their lifestyle to prevent UADT
cancer. The HRA model using ALDH2 genotyping yielded a slightly better PPV1 0 8 and a slightly higher cancer
detection rate1 0 9 than the HRA-flushing model. An initial cost would be necessary to genotype ALDH2 in all
individuals in the target population. However, it shouldbe emphasized that genotyping needs to be performed
only once in a lifetime, that the data are always available, and that the unit cost would be greatly discounted
if a huge number of samples were analyzed.
Screening for SCC in the UADT Basedon Red Cell MCV
A high red cell mean corpuscular volume (MCV) is a
traditional biological marker for alcohol abuse and alcoholism.11 0 Recent epidemiological evidence indicatesthat the MCV of drinkers with ALDH2*1/*2 increases in
response to exposure to acetaldehyde.4, 111-11 5 Smoking,a low BMI, and folate deficiency also increase MCV.113-115
MCV is used as a biomarker for risk of esophageal andKeio J Med 2010; 59 (4): 115－130

123

Fig. 3 Health risk appraisal model for esophageal cancer combined with the simple flushing questionnaire. The risk score is calculated
as the sum of scores A to E. The expected esophageal cancer detection rate of Japanese men 40 years of age and over with a risk scoreof 11 or more who undergo endoscopic screening with esophageal iodine staining is 1%–2%.108, 109

pharyngeal SCC in Japanese alcoholics. 4, 5, 4 9 A high
MCV of 106 fl or more, the ALDH2*1/*2 genotype, and
the ADH1B*1/*1 genotype synergistically increase therisk of esophageal SCC in Japanese alcoholics [OR =320 (27 to >1000)].4 The combination of high MCV andalcohol flushing is associated with a high risk of esophageal SCC, with an OR of 5.5 (2.2–13.8) in alcoholics.
This way of estimating cancer risk can be easily appliedin both public education and screening. An endoscopic
follow-up study in cancer-free Japanese alcoholics revealed that cancer of the UADT developed much more
frequently among alcoholics with a high MCV of 106 fl
or more [HR = 2.52 (1.22–5.22)].5
We have demonstrated that MCV is useful as a marker
for male Japanese drinkers who are at high risk of SCC
in the UADT but who are not alcoholics.1 0 8, 11 3, 11 4 Combining MCV with the traditional risk factors drinking
and smoking had better predictive power for esophageal
and pharyngeal SCC than the combination of drinking
and smoking alone. 1 0 8, 11 4 Approximately 30% of cancer-free Japanese men met the criterion of a combinationof moderate-to-heavy drinking (≥ 198 g ethanol/week)and either 30+ pack-years or an MCV ≥ 99 fl, whereas

approximately 70% of Japanese men with SCC of theesophagus or hypopharynx met the criterion. 1 0 8 MCV
may be used to better select not only alcoholic male Japanese candidates to screen for this high mortality cancer
but non-alcoholic male Japanese candidates as well.
MCV is not a predictor of esophageal cancer in Caucasian heavy drinkers, probably because the main determinant of high MCV is severe acetaldehydemia after heavy
drinking in inactive ALDH2 heterozygotes.116
Genetic Polymorphism of ADH1B,
Alcohol Metabolism, and SCC in the UADT
Alcohol dehydrogenase-1B (ADH1B, previously
called ADH2) also has a functional genetic polymorphism (rs1229984). A small fraction of East Asians havethe less-active ADH1B*1/*1 genotype (e.g., 7% of Japanese)1 5 that is prevalent in Caucasians (present in approximately 90%); this less-active ADH1B is a strongrisk factor for alcoholism in East Asians. Approximately
30% of Japanese and Taiwanese alcoholics have the lessactive ADH1B*1/*1 genotype, 1 5, 5 4 and this genotype
has been found to be more frequent in Japanese and Tai-

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Yokoyama A, et al: ADH and ALDH Polymorphisms and Cancer Prevention

wanese alcoholics with cancer in the UADT3 0, 3 1, 4 9 [e.g.,
OR = 3.46 (1.66–7.22) for oropharyngolaryngeal SCC4 9
and 2.64 (1.62–4.31) for esophageal SCC3 1]. An endoscopic follow-up study in Japanese alcoholics demonstrated that SCC of the UADT was more common
among alcoholics with the less-active ADH1B*1/*1 [HR= 2.07 (1.01–4.26)].5 With the exception of two negative
Japanese studies,2 5, 3 6 the ADH1B*1/*1 genotype has
consistently been demonstrated to be associated with anincreased risk of SCC in the UADT in non-alcoholic
Japanese (Fig. 1C), 2 0, 2 2, 2 8, 4 8, 1 1 7 Chinese, 2 6, 2 7, 3 8 - 4 1
Thai11 8 and Central European populations.11 9 Stratification according to drinking categories has shown that theADH1B*1/*1 genotype increases the risk of UADT cancer in light drinkers2 0, 2 6-2 8, 11 9 as well as in moderate-toheavy drinkers.20, 26-28, 38, 41, 48, 117, 119
The mechanism of the increase in risk of alcoholism
and UADT cancer associated with the ADH1B*1/*1
genotype has remained a puzzle. Alcohol challenge tests
have failed to demonstrate any associations between
ADH1B genotype and the blood ethanol or acetaldehyde
concentration after ingestion of light to moderate dosesof ethanol by Japanese,1 7 Chinese,1 2 0 and Europeans.1 2 1
However, the less-active form of ADH1B encoded by
the ADH1B*1/*1 genotype has an approximately 40
times lower Vmax in vitro than that encoded by
ADH1B*2/*2,122 and an experiment in which a clamping
technique and intravenous alcohol infusion were usedshowed a modestly but significantly lower ethanol elimination rate (11%–18%) among Jews with the less-active
ADH1B*1/*1 genotype than with the ADH1B*2 allele.123 Heavy drinking may amplify the modest effect of
ADH1B*1/*1 on ethanol metabolism and lead to clear
prolongation of the presence of ethanol in the body, including in the UADT. Although ethical considerations
make it impossible to experimentally emulate the dangerously heavy drinking found in alcoholics, many alcoholic patients come to our Alcoholism Center after
drinking the day before, and they have provided an opportunity to measure blood and salivary acetaldehyde
and ethanol levels in that state. When we measured theblood and salivary ethanol and acetaldehyde levels ofJapanese alcoholics in the morning when they first visited our Center after drinking the day before,8 8, 1 2 4 wefound that ethanol and acetaldehyde remained in the
blood and saliva for much longer periods and at muchhigher levels in those with the less-active ADH1B*1/*1
genotype than in those with other genotypes, even after
adjusting for age, body weight, the amount of alcohol
consumed, and interval since the most recent drink. The
blood and salivary ethanol levels were similar, but theacetaldehyde levels in saliva were strikingly higher thanin the blood because of acetaldehyde production by oral
microorganisms (e.g., median salivary acetaldehyde concentration of 47.4 μM in ADH1B*1/*1 carriers vs. 1.6 μM
in ADH1B*2 allele carriers, P = 0.009). 8 8 However,none of the levels differed according to ALDH2 genotype.1 2 4 The ADH1B and ALDH2 genotypes affect the
blood and salivary ethanol and acetaldehyde levels of
non-abstinent alcoholics in a different manner than in
non-alcoholics, and clear effects of ADH1B genotype
and less clear effects of ALDH2 have been observed in
non-abstinent alcoholics. Alterations in alcohol metabolism as a result of alcoholism may modify the gene effects.124
East Asians1 0 6, 1 0 7, 1 2 5- 1 2 7 and Europeans1 2 8 with theless-active ADH1B*1/*1 genotype tend not to report alcohol flushing responses and tend to consume larger
amounts of alcohol than those with the ADH1B*2 allele.
Alcohol-induced flushing is triggered by a steep initialrise in either blood or cutaneous acetaldehyde after
drinking. This dramatic change may not occur in persons
with the less-active ADH1B. The initial phase of acetaldehyde production may be difficult to monitor in conventional alcohol-challenge tests. Less-active
ADH1B*1/*1 markedly masked inactive ALDH2*1/*2-associated alcohol flushing. According to responses
to the simple flushing questionnaire, 53% of alcoholics
with cancer who had the combination of inactive
ALDH2*1/*2 and less-active ADH1B*1/*1 were neverflushers1 0 7; 28% of cancer-free Japanese men with thisgenotype combination reported never flushing, 38% reported former flushing, and only 37% reported current
flushing.1 0 6 The levels of alcohol consumption by inactive ALDH2 heterozygotes were clearly associated with
their alcohol flushing categories.106
The above findings provide a clue as to why less-active ADH1B increases the risk of both alcoholism and
UADT cancer. First, less-active ADH1B diminishes theintensity of alcohol flushing, thereby accounting for thegreater susceptibility to alcoholism associated with it.
Second, heavy drinking by alcoholics amplifies the modest effect of less-active ADH1B on ethanol elimination,
which leads to much longer exposure to ethanol and, inturn, results in smelling of alcohol in the morning. Whenethanol lingers in the body, the UADT is exposed to highlevels of acetaldehyde as a result of acetaldehyde production in saliva, and that creates a condition that increases the risk of UADT cancer (Fig. 4).
The increase in risk of UADT cancer associated with
the inactive ALDH2*1/*2 genotype in Japanese alcoholics is higher than the increase associated with the lessactive ADH1B*1/*1 genotype.5, 3 1, 4 9 Only the inactive
ALDH2*1/*2 genotype, and not the less-active
ADH1B*1/*1 genotype, increases the risk of synchronous and metachronous multiple UADT cancers in Japanese alcoholics.5 0, 5 9 The high tissue accumulation of acetaldehyde in alcoholics with the ALDH2*1/*2 genotype
may affect the risk of SCC in the UADT differently fromthe prolonged exposure of the UADT to ethanol and acetaldehyde in alcoholics with the ADH1B*1/*1 genotype.

Keio J Med 2010; 59 (4): 115－130

125

Fig. 4 Ethanol (ETOH) and acetaldehyde (ACA) exposure and accumulation in the upper aerodigestive tract (UADT) and the effectsof alcohol dehydrogenase-1B*1/*1 (ADH1B*1/*1) and aldehyde dehydrogenase-2*1/*2 (ALDH2*1/*2) genotypes.

Combination of ADH1B and ALDH2 Genotypes
and SCC in the UADT

Genetic Polymorphism of ADH1C,
Alcohol Metabolism, and SCC in the UADTThe risk of SCC in the oropharyngolarynx and esophagus in Japanese alcoholics has been found to be greatly
increased in a multiplicative fashion by the combinationof less-active ADH1B*1/*1 and inactive ALDH2*1/*2[OR = 122 (32–465) and 40 (18–91), respectively].3 1
The PAR due to all combinations of ADH1B and
ALDH2 genotypes in the alcoholic population has beenfound to be 82% for oropharyngolaryngeal SCC and
64% for esophageal SCC. Case-control studies in a general population confirmed a similar multiplicative effectof this genotype combination on the risk of SCC of theesophagus2 0 and hypopharyx4 8 in Japanese subjects andon the risk of SCC of the esophagus in Taiwanese subjects 2 6 [OR = 30.1 (13.2–68.9), 48.9, and 36.8 (9.4–
144.7), respectively]. When the presence of these two
genotypes was combined with consumption of 198–
395 g ethanol/week or ≥ 396 g ethanol/week, the OR for
esophageal SCC was estimated to be 248 and 417, respectively, in Japanese based on the multivariate OR foreach risk factor.2 0 A Taiwanese study also showed a multiplicative effect among the less-active ADH1B, inactive
ALDH2, and drinking of more than 30 g ethanol/day[OR = 382 (47–3085)].2 7 A Japanese genome-wide association study of esophageal SCC showed that individuals
with both high-risk genotypes who smoked and drank>96.5 g ethanol/week had a 189 (95–377) times higher
risk of esophageal SCC than those who had none ofthese risk factors.28

The enzyme encoded by the ADH1C*1 allele (previously called ADH3*1) catalyzes acetaldehyde production twice as fast as the enzyme encoded by the ADH1C*2
allele (rs1693482 and rs698).1 2 2 The ADH1C*2 allele
has been reported to increase the risk of alcoholism inEast Asians1 5, 5 4 and of both UADT cancer2 0, 4 8 and multiple iodine-unstained lesions 5 8 in Japanese drinkers.
However, the associations with ADH1C were explainedby linkage disequilibrium in which the ADH1C*2 allele
and the more influential ADH1B*1 allele are linked; theassociations disappeared after adjustment for the linkage.1 5, 2 0, 4 8, 5 4 A cross-sectional study in 2299 non-alcoholic Japanese subjects showed a significant positive association between the presence of an ADH1C*2 allele
and habitual drinking, regardless of the ADH1B genotype; however, the impact on habitual drinking was weak
(3%–16% increase in OR).129
ADH1C polymorphism may be the rate-limiting factor
in acetaldehyde metabolism in Western populations, inwhich the prevalence of the ALDH2*2 allele and ADH1B*2
allele is very low. Caucasians with the high-activity
ADH1C*1/*1 genotype have been found to have significantly higher salivary acetaldehyde concentrations after
alcohol ingestion than ADH1C*2 allele carriers.1 3 0 Although published studies have not shown a consistentpattern of association,1 3 1 several Western studies haveshown that individuals in heavy drinking populations
who had the ADH1C*1 allele were at greater risk for
UADT cancer.130, 132, 133

Yokoyama A, et al: ADH and ALDH Polymorphisms and Cancer Prevention

126

SCC in the UADT in Ex-drinkers
A recent pooled analysis including 13 studies and over
5000 cases demonstrated that the risk of esophageal cancer and risk of head and neck cancer only started to decline 5 years and 10 years, respectively, after alcohol intake ceased, probably because of the so-called “sickquitter” effect. 1 3 4 Two Japanese case-control studies
showed a very high risk of SCC in ex-drinkers with the
ALDH2*1/*2 or ADH1B*1/*1 genotype.2 0, 4 8 Endoscopic follow-up studies in Japanese alcoholics after treatmentof esophageal SCC failed to detect any effects of drinking cessation on the development of metachronous cancer,5 6, 6 2 suggesting that the molecular changes that predispose patients to metachronous cancer might be at the
point of no return, and that intensive follow-up examinations are essential for cancer prevention in high-risk patients. Further study is needed to evaluate the longerterm effect of drinking cessation on the development of
SCC in the UADT.
Conclusions
The ethanol in alcoholic beverages and the acetaldehyde associated with alcohol consumption are humancarcinogens (Group 1, IARC). The inactive heterozygous ALDH2*1/*2 genotype and the less-active
ADH1B*1/*1 genotype modify ethanol metabolism andgreatly increase the susceptibility of the UADT to SCC
in East Asian drinkers. The simple flushing questionnaire and MCV are useful tools that facilitate the assessment of ALDH2-associated cancer risk. Melanosis in the
UADT and large or multiple esophageal dysplasia areendoscopic evidence of a high risk of developing SCC in
the UADT. New health appraisal models that include the
ALDH2 genotype, the simple flushing questionnaire, or
MCV may provide powerful tools for cancer prevention
and cancer screening in East Asians.
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