https://www.gastrojournal.org/article/S0016-5085(09)01425-5/pdf

Functional Variants in ADH1B and ALDH2 Coupled With Alcohol and Smoking Synergistically Enhance Esophageal Cancer Risk

Quantification of the association between alcohol drinking and risk of esophageal squamous cell carcinoma (ESCC) is an open issue, particularly among light alcohol drinkers, never-smokers, and Asian populations, in which some high-risk polymorphisms in alcohol metabolizing genes are more prevalent. To address these issues, we conducted a systematic review and meta-analysis using 40 case-control and 13 cohort studies that reported on the risk associated with alcohol drinking for at least three levels of consumption. In studies adjusted for age, sex, and tobacco smoking, the relative risk (RR) and 95% confidence interval (CI) for the association between light alcohol drinking (≤12.5 g/d) and risk of ESCC was 1.38 (1.14–1.67). The association was slightly stronger in Asian countries than in other populations. The adjusted RRs (95% CIs) were 2.62 (2.07–3.31) for moderate drinking (>12.5–<50 g/d) and 5.54 (3.92–7.28) for high alcohol intake (≥50 g/d); the RRs were slightly higher in non-Asian populations. In prospective studies, the RR (95% CI) was 1.35 (0.92–1.98) for light, 2.15 (1.55–2.98) for moderate, and 3.35 (2.06–5.46) for high alcohol intakes; light drinking showed an association with ESCC in Asia (five studies) but not in other regions (three studies). Among never-smokers (nine studies), the RR (95% CI) was 0.74 (0.47–1.16) for light, 1.54 (1.09–2.17) for moderate, and 3.09 (1.75–5.46) for high intakes. This meta-analysis further corroborates the association of moderate and high alcohol intake with risk of ESCC and provides risk estimates based on multiple prospective studies. Light alcohol intake appears to be associated to ESCC mainly in studies in Asia, which suggests a possible role of genetic susceptibility factors.

Alcohol drinking and esophageal squamous cell carcinoma with focus on light-drinkers and never-smokers: a systematic review and meta-analysis.

Background 
Alcohol consumption is increasing worldwide and is associated with numerous cancers. This systematic review examined the role of alcohol in the incidence of cancer in the Chinese population.


Methods 
Medline/PubMed, EMBASE, CNKI and VIP were searched to identify relevant studies. Cohort and case-control studies on the effect of alcohol use on cancers in Chinese were included. Study quality was evaluated using the Newcastle-Ottawa Scale. Data were independently abstracted by two reviewers. Odds ratios (OR) or relative risks (RR) were pooled using RevMan 5.0. Heterogeneity was evaluated using the Q test and I-squared statistic. P<.01 was considered statistically significant.


Results 
Pooled results from cohort studies indicated that alcohol consumption was not associated with gastric cancer, esophageal cancers (EC) or lung cancer. Meta-analysis of case-control studies showed that alcohol consumption was a significant risk factor for five cancers; the pooled ORs were 1.79 (99% CI, 1.47–2.17) EC, 1.40 (99% CI, 1.19–1.64) gastric cancer, 1.56 (99% CI, 1.16–2.09) hepatocellular carcinoma, 1.21 (99% CI, 1.00–1.46) nasopharyngeal cancer and 1.71 (99% CI, 1.20–2.44) oral cancer. Pooled ORs of the case-control studies showed that alcohol consumption was protective for female breast cancer and gallbladder cancer: OR 0.76 (99% CI, 0.60–0.97) and 0.70 (99% CI, 0.49–1.00) respectively. There was no significant correlation between alcohol consumption and lung cancer, colorectal cancer, pancreatic cancer, cancer of the ampulla of Vater, prostate cancer or extrahepatic cholangiocarcinoma. Combined results of case-control and cohort studies showed that alcohol consumption was associated with 1.78- and 1.40-fold higher risks of EC and gastric cancer but was not significantly associated with lung cancer.


Conclusions 
Health programs focused on limiting alcohol intake may be important for cancer control in China. Further studies are needed to examine the interaction between alcohol consumption and other risk factors for cancers in Chinese and other populations.

Association between Alcohol Consumption and Cancers in the Chinese Population—A Systematic Review and Meta-Analysis

Alcohol consumption dates back to the Neolithic period, and alcohol dependence contributes substantially to the current global burden of disease Despite this, optimal therapies and preventive strategies are lacking Formal genetic studies of alcohol dependence have shown that genetic factors play as large a role in disease etiology as environmental factors Molecular genetic studies may identify causal factors and facilitate the development of novel preventive and therapeutic approaches Whereas earlier studies involved the use of linkage- and candidate-gene approaches, recent years have witnessed the introduction of genome-wide association studies (GWAS) The present review provides a brief overview of the findings of formal genetic studies, summarizes the results of earlier molecular-genetic investigations, and presents a detailed overview of all published GWAS in the field of alcohol dependence research To date, few genome-wide significant findings have been reported However, through the polygenic approach, GWAS have both confirmed the existence of a multitude of novel risk genes and indicated interesting new candidates

The genetics of alcohol dependence.

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 the upper 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 concentration of 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 cri! tical 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 exposure of 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 are frequently 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.

/pdf/alcohol-and-aldehyde-dehydrogenase-polymorphisms-and-a-new-fx43kkzcvn.pdf

Alcohol and aldehyde dehydrogenase polymorphisms and a new strategy for prevention and screening for cancer in the upper aerodigestive tract in East Asians

Genetic polymorphisms in cytochrome P4502E1, alcohol and aldehyde dehydrogenases and the risk of esophageal squamous cell carcinoma in Gansu Chinese males

Genetic polymorphisms in cytochrome P4502E1, alcohol and aldehyde dehydrogenases and the risk of esophageal squamous cell carcinoma in Gansu Chinese males.

Huei-Min Chen

Papers

Genetic polymorphisms in cytochrome P4502E1, alcohol and aldehyde dehydrogenases and the risk of esophageal squamous cell carcinoma in Gansu Chinese males.