Carcinogenetic impact of ADH1B and ALDH2 genes on squamous cell carcinoma risk of the esophagus with regard to the consumption of alcohol, tobacco and betel quid

Abstract

The consumption of alcohol, tobacco and betel quid has been found to be an important contributor to esophageal squamous cell carcinoma (ESCC) in Taiwan. The genotoxic effect of the ADH1B and ALDH2 genes modulating an individual's alcohol-metabolizing capacity on ESCC may be linked to drinking behavior, intake pattern and other exogenous factors. To investigate the interplay of these genetic and environmental factors in determining the risk of ESCC, a multicenter case-control study was conducted. Here, 406 patients with pathology-proven ESCC, as well as 656 gender, age and study hospital matched controls were recruited. Genetic polymorphisms of ADH1B and ALDH2 appeared to correlate with the abstinence of alcohol, though not with tobacco and betel quid. Within the same levels of alcohol consumption, carcinoma risks increased along with an increase in the numbers of ADH1B*1 and ALDH2*2 alleles. The inactive ALDH2*1/*2 genotype was found to multiplicatively interact with a low-to-moderate (0.1-30 g/day) and a heavy (>30 g/day) ethanol intake to increase the ESCC risk (the joint aOR 5 14.5 and 102.6, respectively). Among low-tomoderate drinkers, a smoking-dependent carcinogenetic effect for the ADH1B*1/*1 and ALDH2*1/*21*2/*2 genotypes was recognized, with significant risks found in smokers, but not in nonsmokers. Further, a supra-multiplicative combined risk of ESCC for alcohol and tobacco use was identified among carriers of the ADH1B*1/*1 genotype (p for interaction 5 0.042). In conclusion, the interplay of the ADH1B and ALDH2 genotypes, in conjunction with a behaved drinking habit and a practiced drinking pattern, along with continued tobacco consumption, plays an important pathogenic role in modulating ESCC risk. ' 2007 Wiley-Liss, Inc.Key words: alcohol drinking; esophageal neoplasms; genetic polymorphism; tobacco; areca Alcohol consumption has been causally linked to the cancerization of the esophagus in humans. 1 Epidemiological surveys offered ample evidence that esophageal cancer risk due to this agent is not homogeneous across gender and populations, or even socioeconomic classes. 1 Although discrepancies in the characteristics of alcohol intake have clarified parts of this issue, 2 interindividual dissimilarities in regard to the capabilities of alcohol metabolism may be crucial in accounting for the diverse effect of alcohol in populations, since acetaldehyde, the primary intermediate metabolite of ethanol, has been well recognized as a carcinogen in animal models. 3 Though the variant allele of the alcohol dehydrogenase-1B gene (ADH1B*2) that confers the ''fast'' metabolism of ethanol to acetaldehyde, and the mutant allele of the aldehyde dehydrogenase-2 gene (ALDH2*2) that results in a catalytically inactive subunit to oxidize acetaldehyde to acetate, are prevalent in Orientals, they are uncommon in Caucasians. 4 Alcohol flushing syndrome, characterized by a facial flushing accompanied by palpitation, drowsiness, breathlessness or nausea is a condition related to a toxic accumulation of acetaldehyde i...

Genetic modulation of ADH1B and ALDH2 polymorphisms with regard to alcohol and tobacco consumption for younger aged esophageal squamous cell carcinoma diagnosis

“…20 Among drinkers, each additional 5-years of drinking was observed to have a 0.892-fold (12.1% reduction) decreased OR of harboring the ADH1B Arg homozygote, but down to a 0.787-fold (27.1% reduction) reduced OR of carrying the ALDH2 Lys variant. Compatible with epidemiological reports on the stronger ESCC risk for ALDH2 genetic susceptibility, 5,17 this information implies that the carcinogenetic influence of alcohol on the time of ESCC diagnosis is more dependent on the inactive ALDH2 allele than on the slowform ADH1B homozygote.…”

“…11,16 Studies in several populations have found that the risk of esophageal SCC (ESCC) is closely associated with genetic polymorphisms of the two alcohol-metabolizing genes, and this relationship has been suggested to be alcohol amount dependent. [17][18][19] Recently, the mutant ALDH2 Glu487Lys allele in molecular epidemiological studies has been reported to be more prevalent among head and neck carcinoma (HNC) patients of a younger diagnosed age (<66 years). 20 Earlier multiple esophageal dysplasias in HNC patients have also been linked to the presence of this variant allele.…”

Revisit of Field Cancerization in Squamous Cell Carcinoma of Upper Aerodigestive Tract: Better Risk Assessment with Epigenetic Markers

“…Following a negative endoscopy, an efficient risk-assessment method is needed to design surveillance programs for early detection of superficial SCC in the head and neck region and esophagus (2). However, past efforts based on demographic characteristics (5-7), lifestyle risk factors (8,9), genetic susceptibilities (10)(11)(12)(13)(14), serological markers (15)(16)(17)(18), and endoscopic findings (19), alone or in combination (15,20,21), have not produced models efficient enough to be effective.…”

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

“…Acetaldehyde has been established as a carcinogen in experimental animals (8) and is suspected of playing a critical role in cancer development in humans (9). 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).…”