ADH1B

Gene Summary

Gene:ADH1B; alcohol dehydrogenase 1B (class I), beta polypeptide
Aliases: ADH2, HEL-S-117
Location:4q23
Summary:The protein encoded by this gene is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. This encoded protein, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation and plays a major role in ethanol catabolism. Three genes encoding alpha, beta and gamma subunits are tandemly organized in a genomic segment as a gene cluster. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:alcohol dehydrogenase 1B
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ADH1B (cancer-related)

Gupta MK, Behara SK, Vadde R
In silico analysis of differential gene expressions in biliary stricture and hepatic carcinoma.
Gene. 2017; 597:49-58 [PubMed] Related Publications
In-silico attempt was made to identify the key hub genes which get differentially expressed in biliary stricture and hepatic carcinoma. Gene expression data, GSE34166, was downloaded from the GEO database, which contains 10 biliary stricture samples (4 benign control and 6 malignant carcinoma), for screening of key hub genes associated with the disease. R packages scripts were identified 85 differentially expressed genes. Further these genes were uploaded in WebGestalt database and identified nine key genes. Using STRING database and Gephi software, the protein-protein interaction networks were constructed and also studied gene ontology through WebGestalt. Finally, we identified four key genes (CXCR4, ADH1C, ABCB1 and ADH1A) are associated with liver carcinoma and further cross-validated with Liverome, Protein Atlas database and bibliography. In addition, transcription factors and their binding sites also studied. These identified hub genes and their transcription factors are the probable potential targets for possible future drug design.

Zhong Q, Wu RR, Zeng ZM
Association of ADH1B Arg47His and ALDH2 Glu487Lys polymorphisms with risk of colorectal cancer and their interaction with environmental factors in a Chinese population.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
Human colorectal cancer (CRC) is a major worldwide health concern, and its development has been shown to be associated with alcohol intake. We carried out a study to investigate the effect of the ADH1B Arg47His and ALDH2 Glu487Lys genetic polymorphisms and their interaction with alcohol consumption on development of CRC. Between March 2013 and May 2015, a total of 274 CRC patients and 358 healthy controls were recruited. Genotyping of sequence variations was performed using the polymerase chain reaction-restriction fragment length polymorphism method. Under a co-dominant model, individuals with the ADH1B Arg47His AA genotype showed increased CRC risk compared to those carrying the GG genotype, with an adjusted odds ratio (and 95% confidence interval) of 3.37 (2.00-5.70). Moreover, under dominant and recessive models, ADH1B Arg47His variant genotypes were associated with greater susceptibility to CRC when compared with the wild-type sequence. Both polymorphisms examined were positively associated with alcohol consumption in a Spearman correlation analysis of CRC risk. In conclusion, our study suggests that the ADH1B Arg47His polymorphism, but not the ALDH2 Glu487Lys variation, may influence development of CRC in the Chinese population.

Masaoka H, Ito H, Soga N, et al.
Aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) polymorphisms exacerbate bladder cancer risk associated with alcohol drinking: gene-environment interaction.
Carcinogenesis. 2016; 37(6):583-8 [PubMed] Related Publications
Although a range of chemical exposures (cigarette smoking and occupational exposure) are recognized risk factors for the development of bladder cancer (BCa), many epidemiological studies have demonstrated that alcohol drinking is not associated with BCa risk. Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms impact the accumulation of acetaldehyde, resulting in an increased risk of various cancers. To date, however, no studies evaluating the association between BCa risk and alcohol drinking have considered these polymorphisms. Here, we conducted a matched case-control study to investigate whether ALDH2 and ADH1B polymorphisms influence BCa risk associated with alcohol drinking. Cases were 74 BCa patients and controls were 740 first-visit outpatients without cancer at Aichi Cancer Center Hospital between January 2001 and December 2005. Odds ratio (OR), 95% confidence interval (CI) and gene-environment interaction were assessed by conditional logistic regression analysis with adjustment for potential confounders. Results showed that ALDH2 Glu/Lys was associated with a significantly increased risk of BCa compared with Glu/Glu (OR 2.03, 95% CI 1.14-3.62, P = 0.017). In contrast, ALDH2 Glu/Lys showed no increase in risk among the stratum of never drinkers compared with Glu/Glu, indicating a gene-environment interaction. ADH1B His/Arg had an OR of 1.98 (1.20-3.24, P = 0.007) compared with His/His. ADH1B Arg+ showed a similar OR and 95% CI. Individuals with ALDH2 Glu/Lys and ADH1B Arg+ had the highest risk of BCa compared with ALDH2 Glu/Glu and ADH1B His/His [OR 4.00 (1.81-8.87), P = 0.001].

Nakao T, Iwata T, Hotchi M, et al.
Prediction of response to preoperative chemoradiotherapy and establishment of individualized therapy in advanced rectal cancer.
Oncol Rep. 2015; 34(4):1961-7 [PubMed] Related Publications
Preoperative chemoradiotherapy (CRT) has become the standard treatment for patients with locally advanced rectal cancer. However, no specific biomarker has been identified to predict a response to preoperative CRT. The aim of the present study was to assess the gene expression patterns of patients with advanced rectal cancer to predict their responses to preoperative CRT. Fifty-nine rectal cancer patients were subjected to preoperative CRT. Patients were randomly assigned to receive CRT with tegafur/gimeracil/oteracil (S-1 group, n=30) or tegafur-uracil (UFT group, n=29). Gene expression changes were studied with cDNA and miRNA microarray. The association between gene expression and response to CRT was evaluated. cDNA microarray showed that 184 genes were significantly differentially expressed between the responders and the non‑responders in the S-1 group. Comparatively, 193 genes were significantly differentially expressed in the responders in the UFT group. TBX18 upregulation was common to both groups whereas BTNL8, LOC375010, ADH1B, HRASLS2, LOC284232, GCNT3 and ALDH1A2 were significantly differentially lower in both groups when compared with the non-responders. Using miRNA microarray, we found that 7 and 16 genes were significantly differentially expressed between the responders and non-responders in the S-1 and UFT groups, respectively. miR-223 was significantly higher in the responders in the S-1 group and tended to be higher in the responders in the UFT group. The present study identified several genes likely to be useful for establishing individualized therapies for patients with rectal cancer.

Liu X, Gao Y, Zhao B, et al.
Discovery of microarray-identified genes associated with ovarian cancer progression.
Int J Oncol. 2015; 46(6):2467-78 [PubMed] Related Publications
Ovarian cancer is the most lethal cancer of female reproductive system. There is a consistent and urgent need to better understand its mechanism. In this study, we retrieved 186 genes that were dysregulated by at least 4-fold in 594 ovarian serous cystadenocarcinomas in comparison with eight normal ovaries, according to The Cancer Genome Atlas Ovarian Statistics data deposited in Oncomine database. DAVID analysis of these genes enriched two biological processes indicating that the cell cycle and microtubules might play critical roles in ovarian cancer progression. Among these 186 genes, 46 were dysregulated by at least 10-fold and their expression was further confirmed by the Bonome Ovarian Statistics data deposited in Oncomine, which covered 185 cases of ovarian carcinomas and 10 cases of normal ovarian surface epithelium. Six genes, including aldehyde dehydrogenase 1 family, member A2 (ALDH1A2), alcohol dehydrogenase 1B (class I), β polypeptide (ADH1B), NEL-like 2 (chicken) (NELL2), hemoglobin, β (HBB), ATP-binding cassette, sub-family A (ABC1), member 8 (ABCA8) and hemoglobin, α1 (HBA1) were identified to be downregulated by at least 10-fold in 779 ovarian cancers compared with 18 normal controls. Using mRNA expression profiles retrieved from microarrays deposited in the Gene Expression Omnibus Profiles database, RT-qPCR measurement and bioinformatics analysis, we further indicated that high expression of HBB might predict a poorer 5-year survival, high expression of ALDH1A2 and ABCA8 might predict a poor outcome; while ALDH1A2, ADH1B, HBB and ABCA8, in particular the former two genes, might be associated with drug resistance, and ALDH1A2 and NELL2 might contribute to invasiveness and metastasis in ovarian cancer. This study thus contributes to our understanding of the mechanism of ovarian cancer progression and development, and the six identified genes may be potential therapeutic targets and biomarkers for diagnosis and prognosis.

Ji YB, Lee SH, Kim KR, et al.
Association between ADH1B and ADH1C polymorphisms and the risk of head and neck squamous cell carcinoma.
Tumour Biol. 2015; 36(6):4387-96 [PubMed] Related Publications
Alcohol consumption is one of the major risk factors for head and neck squamous cell carcinoma (HNSCC), and the alcohol dehydrogenase (ADH) family proteins are key enzymes in ethanol metabolism. We examined the associations between single nucleotide polymorphisms (SNPs) of ADH1B and ADH1C and the risk of HNSCC. We analyzed six SNPS of ADH1B, namely -992C > G, -957C > A, +3170A>G, +3377G>T, +3491G>A, and +13543A>G, and five SNPs of ADH1C, namely -1064C>T, -325G>C, +5702A>G, +7462T>C, and +13044A>G, in 260 Korean HNSCC patients and 330 controls, using single base extension and the TaqMan assay. The odds ratios (ORs) and 95 % confidence intervals (95 % CIs) of the CG and GG genotypes of ADH1B -992C>G, the AA genotype of -957C>A, the GG genotype of +3170A>G, the GA genotype of +3491G>A, and +13543A>G were 0.51 (0.32-0.82), 0.63 (0.42-0.94), 1.84 (1.13-2.99), 1.77 (1.15-2.73), 2.34 (1.44-3.79), and 2.21 (1.23-3.95), respectively. The ORs of ADH1C +13044A>G were 1.94 (1.01-3.71) and 1.97 (1.05-3.71) in the dominant and co-dominant models, respectively. The ORs of the GC genotype of ADH1C -325G>C and the AG genotype of +5702A>G were 2.52 (1.51-4.21) and 2.43 (1.36-4.32), respectively. ADH1B +3170A>G and ADH1C +13044A>G were in strong linkage disequilibrium with the other SNPs of ADH1B and ADH1C, respectively. There were gene-environment interactions between ADH1B +3170A>G and ADH1C +13044A>G and alcohol consumption and smoking. ADH1B +3170A>G and ADH1C +13044A>G SNPs are associated with an increased risk of HNSCC, and they could be used as biomarkers for the high-risk group of HNSCC in Koreans.

Ra SH, Su A, Li X, et al.
Keratoacanthoma and squamous cell carcinoma are distinct from a molecular perspective.
Mod Pathol. 2015; 28(6):799-806 [PubMed] Related Publications
Keratoacanthoma is a controversial entity. Some consider keratoacanthoma as a variant of squamous cell carcinoma, whereas others see it as a distinct self-resolving squamoproliferative lesion. Our objective is to examine the relationship of keratoacanthoma with squamous cell carcinoma and normal skin by using DNA microarrays. DNA microarray studies were performed on formalin-fixed and paraffin-embedded blocks from ten cases of actinic keratoacanthoma utilizing the U133plus2.0 array. These results were compared with our previously developed microarray database of ten squamous cell carcinoma and ten normal skin samples. Keratoacanthoma demonstrated 1449 differentially expressed genes in comparison with squamous cell carcinoma (>5-fold change: P<0.01) with 908 genes upregulated and 541 genes downregulated. Keratoacanthoma showed 2435 differentially expressed genes in comparison with normal skin (>5-fold change: P<0.01) with 1085 genes upregulated and 1350 genes downregulated. The most upregulated genes, comparing keratoacanthoma with normal skin included MALAT1, S100A8, CDR1, TPM4, and CALM1. The most downregulated genes included SCGB2A2, DCD, THRSP, ADIPOQ, adiponectin, and ADH1B. The molecular biological pathway analysis comparing keratoacanthoma with normal skin showed that cellular development, cellular growth and proliferation, cell death/apoptosis, and cell cycle pathways are prominently involved in the pathogenesis of keratoacanthoma. The most enriched canonical pathways were clathrin-mediated endocytosis signaling, molecular mechanisms of cancer and integrin signaling. The distinctive gene expression profile of keratoacanthoma reveals that it is molecularly distinct from squamous cell carcinoma. The molecular pathways and genes differentially expressed in comparing keratoacanthoma with normal skin suggest that keratoacanthoma is a neoplasm that can regress due to upregulation of the cell death/apoptosis pathway.

Bediaga NG, Marichalar-Mendia X, Rey-Barja N, et al.
Polymorphisms in alcohol and tobacco metabolism genes in head and neck cancer in the Basque Country.
J Oral Pathol Med. 2015; 44(10):769-75 [PubMed] Related Publications
BACKGROUND: The Basque Country has one of the highest rates of head and neck squamous cell carcinoma (HNSCC) in Europe, although tobacco and alcohol consumption are not high when compared to other European countries where HNSCC incidence is lower. Our aim was to determine the role of genetic variation with regard to the metabolism of alcohol and carcinogens from tobacco smoke in the Basque Country.
METHODS: Fourteen polymorphisms in alcohol or tobacco metabolism genes were genotyped in 84 HNSCC patients and 242 healthy individuals from the Basque Country.
RESULTS: ADH1B histidine allele (rs1229984), CYP2E1 rs3813867 heterozygous genotype, and GSTT1 deletion conferred protection against HNSCC (OR: 0.318 [0.04-0.75], OR: 0.13 [0.02-0.94], and OR: 0.12 [0.02-0.60], respectively) while GSTP1 (rs1695) Val/Val genotype was related to an increased risk (OR: 4.12 [1.11-15.31]). Regarding alcohol and tobacco habits, GSTT1 deletion was associated with tobacco usage, while the 3 polymorphisms tested in ALDH2 were associated with alcohol consumption. However, genotypic distributions of these 7 SNPs did not differ from those observed for other Caucasian populations where HNSCC incidence is lower.
CONCLUSIONS: The identified genotypic variations in alcohol and tobacco metabolizing genes only by themselves do not seem to be responsible for the higher incidence of HNSCC observed in the Basque Country.

Hidaka A, Sasazuki S, Matsuo K, et al.
Genetic polymorphisms of ADH1B, ADH1C and ALDH2, alcohol consumption, and the risk of gastric cancer: the Japan Public Health Center-based prospective study.
Carcinogenesis. 2015; 36(2):223-31 [PubMed] Related Publications
The association between alcohol consumption, genetic polymorphisms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) and gastric cancer risk is not completely understood. We investigated the association between ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms, alcohol consumption and the risk of gastric cancer among Japanese subjects in a population-based, nested, case-control study (1990-2004). Among 36 745 subjects who answered the baseline questionnaire and provided blood samples, 457 new gastric cancer cases matched to 457 controls were used in the analysis. The odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated using logistic regression models. No association was observed between alcohol consumption, ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms and gastric cancer risk. However, considering gene-environmental interaction, ADH1C G allele carriers who drink ≥150 g/week of ethanol had a 2.5-fold increased risk of gastric cancer (OR = 2.54, 95% CI = 1.05-6.17) relative to AA genotype carriers who drink 0 to <150 g/week (P for interaction = 0.02). ALDH2 A allele carriers who drink ≥150 g/week also had an increased risk (OR = 2.08, 95% CI = 1.05-4.12) relative to GG genotype carriers who drink 0 to < 150 g/week (P for interaction = 0.08). To find the relation between alcohol consumption and gastric cancer risk, it is important to consider both alcohol consumption level and ADH1C and ALDH2 polymorphisms.

Zhang Y, Gu N, Miao L, et al.
Alcohol dehydrogenase-1B Arg47His polymorphism is associated with head and neck cancer risk in Asian: a meta-analysis.
Tumour Biol. 2015; 36(2):1023-7 [PubMed] Related Publications
Head and neck cancers (HNCs) include cancers which arise in oral cavity, pharynx, and larynx. Recent studies have demonstrated that alcohol drinking is an established risk factor for HNC. The alcohol dehydrogenase-1B (ADH1B) plays a major role in the oxidized process of alcohol. To investigate the association of ADH1B Arg47His with HNC in Asian populations, we combined all available studies into a meta-analysis. A total of 2186 cases and 4488 controls were analyzed for this meta-analysis. We used odds ratios (ORs) to assess the strength of the association and 95% confidence intervals (CIs) to give a sense of the precision of the estimate. The ADH1B*47Arg allele was found to be associated with increased risk of HNC in Asians, with the pooled odds ratios (ORs) (Arg/Arg vs. Arg/His + His/His: OR = 2.35, 95% CI = 1.56-3.55, P < 0.0001) in all eight studies. In the subgroup analysis by alcohol consumption, the Arg/Arg vs. Arg/His + His/His genotype was found to be interacted with alcohol consumption, with the OR = 2.44, 95% CI = 1.85-3.20 among ever drinkers. Besides, no significant association was found in non-drinkers. This meta-analysis revealed that ADH1B Arg47His (rs1229984) polymorphism could increase the risk of HNC in Asians significantly.

Bakri MM, Cannon RD, Holmes AR, Rich AM
Detection of Candida albicans ADH1 and ADH2 mRNAs in human archival oral biopsy samples.
J Oral Pathol Med. 2014; 43(9):704-10 [PubMed] Related Publications
OBJECTIVES: The aim of this study was to investigate the relationship between expression of Candida albicans alcohol dehydrogenases (ADH) genes in archival formalin-fixed paraffin-embedded (FFPE) samples from biopsies of leukoplakia.
MATERIALS AND METHODS: Archival FFPE samples were obtained from four sample groups: normal oral mucosa, non-dysplastic leukoplakia, chronic hyperplastic candidosis (CHC), and non-CHC dysplastic leukoplakia. The presence of C. albicans was determined by periodic acid Schiff staining and by immunocytochemistry. C. albicans ADH1 and ADH2 mRNAs were detected using reverse transcription PCR.
RESULTS: Candida albicans was detected in FFPE samples diagnosed as CHC (the histological diagnoses had been made by specialist oral pathologists, using uniform criteria), but not in any other sample group, including the non-dysplastic leukoplakias. RT-PCR confirmed a significant correlation between the expression of CaADH1 mRNA (P = 0.000), but not for CaADH2 mRNA (P = 0.056) in archival FFPE samples (n = 31) from biopsies of leukoplakia.
CONCLUSIONS: Candida albicans was the predominant species in the lesions diagnosed as CHC, and the presence of C. albicans in CHC lesions was associated with a high expression of C. albicans ADH1 mRNA. There was no association between the presence of Candida and malignant transformation in the cases examined; however, the number of cases was limited and further studies are needed to further elucidate the role of C. albicans ADH1 in the pathogenesis of oral squamous cell carcinoma.

Tucker SL, Gharpure K, Herbrich SM, et al.
Molecular biomarkers of residual disease after surgical debulking of high-grade serous ovarian cancer.
Clin Cancer Res. 2014; 20(12):3280-8 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Residual disease following primary cytoreduction is associated with adverse overall survival in patients with epithelial ovarian cancer. Accurate identification of patients at high risk of residual disease has been elusive, lacking external validity and prompting many to undergo unnecessary surgical exploration. Our goal was to identify and validate molecular markers associated with high rates of residual disease.
METHODS: We interrogated two publicly available datasets from chemonaïve primary high-grade serous ovarian tumors for genes overexpressed in patients with residual disease and significant at a 10% false discovery rate (FDR) in both datasets. We selected genes with wide dynamic range for validation in an independent cohort using quantitative RT-PCR to assay gene expression, followed by blinded prediction of a patient subset at high risk for residual disease. Predictive success was evaluated using a one-sided Fisher exact test.
RESULTS: Forty-seven probe sets met the 10% FDR criterion in both datasets. These included FABP4 and ADH1B, which tracked tightly, showed dynamic ranges >16-fold and had high expression levels associated with increased incidence of residual disease. In the validation cohort (n = 139), FABP4 and ADH1B were again highly correlated. Using the top quartile of FABP4 PCR values as a prespecified threshold, we found 30 of 35 cases of residual disease in the predicted high-risk group (positive predictive value = 86%) and 54 of 104 among the remaining patients (P = 0.0002; OR, 5.5).
CONCLUSION: High FABP4 and ADH1B expression is associated with significantly higher risk of residual disease in high-grade serous ovarian cancer. Patients with high tumoral levels of these genes may be candidates for neoadjuvant chemotherapy.

Wang J, Wei J, Xu X, et al.
Replication study of ESCC susceptibility genetic polymorphisms locating in the ADH1B-ADH1C-ADH7 cluster identified by GWAS.
PLoS One. 2014; 9(4):e94096 [PubMed] Free Access to Full Article Related Publications
China was one of the countries with highest esophageal squamous cell carcinoma (ESCC) incidence and mortality worldwide. Alcohol drinking has been identified as a major environmental risk-factor related to ESCC. The alcohol dehydrogenase (ADH) family are major enzymes involved in the alcohol-metabolizing pathways, including alcohol dehydrogenase 1B (ADH1B) and ADH1C. Interestingly, ADH1B and ADH1C genes locate tandemly with ADH7 in a genomic segment as a gene cluster, and are all polymorphic. Several ESCC susceptibility single nucleotide polymorphisms (SNPs) of the ADH1B-ADH1C-ADH7 cluster have been identified previously through a genome-wide association study (GWAS). In the study, we examined the association between five ADH1B-ADH1C-ADH7 cluster SNPs (rs1042026, rs17033, rs1614972, rs1789903 and rs17028973) and risk of developing ESCC. Genotypes were determined in two independent case-control sets from two regions of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. Our data demonstrated that these ADH1B-ADH1C-ADH7 cluster SNPs confer susceptibility to ESCC in these two case-control sets, which were consistent to results of the previous GWAS.

Tsai ST, Wong TY, Ou CY, et al.
The interplay between alcohol consumption, oral hygiene, ALDH2 and ADH1B in the risk of head and neck cancer.
Int J Cancer. 2014; 135(10):2424-36 [PubMed] Related Publications
Alcohol consumption is an established risk factor for head and neck cancer (HNC). The major carcinogen from alcohol is acetaldehyde, which may be produced by humans or by oral microorganisms through the metabolism of ethanol. To account for the different sources of acetaldehyde production, the current study examined the interplay between alcohol consumption, oral hygiene (as a proxy measure for the growth of oral microorganisms), and alcohol-metabolizing genes (ADH1B and ALDH2) in the risk of HNC. We found that both the fast (*2/*2) and the slow (*1/*1+ *1/*2) ADH1B genotypes increased the risk of HNC due to alcohol consumption, and this association differed according to the slow/non-functional ALDH2 genotypes (*1/*2+ *2/*2) or poor oral hygiene. In persons with the fast ADH1B genotype, the HNC risk associated with alcohol drinking was increased for those with the slow/non-functional ALDH2 genotypes. For those with the slow ADH1B genotypes, oral hygiene appeared to play an important role; the highest magnitude of an increased HNC risk in alcohol drinkers occurred among those with the worst oral hygiene. This is the first study to show that the association between alcohol drinking and HNC risk may be modified by the interplay between genetic polymorphisms of ADH1B and ALDH2 and oral hygiene. Although it is important to promote abstinence from or reduction of alcohol drinking to decrease the occurrence of HNC, improving oral hygiene practices may provide additional benefit.

Ahrens W, Pohlabeln H, Foraita R, et al.
Oral health, dental care and mouthwash associated with upper aerodigestive tract cancer risk in Europe: the ARCAGE study.
Oral Oncol. 2014; 50(6):616-25 [PubMed] Related Publications
OBJECTIVE: We aimed to assess the association of oral health (OH), dental care (DC) and mouthwash with upper-aerodigestive tract (UADT) cancer risk, and to examine the extent that enzymes involved in the metabolism of alcohol modify the effect of mouthwash.
MATERIALS AND METHODS: The study included 1963 patients with incident cancer of the oral cavity, oropharynx, hypopharynx, larynx or esophagus and 1993 controls. Subjects were interviewed about their oral health and dental care behaviors (which were converted to scores of OH and DC respectively), as well as smoking, alcohol drinking, diet, occupations, medical conditions and socio-economic status. Blood samples were taken for genetic analyses. Mouthwash use was analyzed in relation to the presence of polymorphisms of alcohol-metabolizing genes known to be associated with UADT. Adjusted odds ratios (ORs) and 95%-confidence intervals [CI] were estimated with multiple logistic regression models adjusting for multiple confounders.
RESULTS: Fully adjusted ORs of low versus high scores of DC and OH were 2.36[CI=1.51-3.67] and 2.22[CI=1.45-3.41], respectively, for all UADT sites combined. The OR for frequent use of mouthwash use (3 or more times/day) was 3.23[CI=1.68-6.19]. The OR for the rare variant ADH7 (coding for fast ethanol metabolism) was lower in mouthwash-users (OR=0.53[CI=0.35-0.81]) as compared to never-users (OR=0.97[CI=0.73-1.29]) indicating effect modification (pheterogeneity=0.065) while no relevant differences were observed between users and non-users for the variant alleles of ADH1B, ADH1C or ALDH2.
CONCLUSIONS: Poor OH and DC seem to be independent risk factors for UADT because corresponding risk estimates remain substantially elevated after detailed adjustment for multiple confounders. Whether mouthwash use may entail some risk through the alcohol content in most formulations on the market remains to be fully clarified.

Wang HL, Zhou PY, Liu P, Zhang Y
ALDH2 and ADH1 genetic polymorphisms may contribute to the risk of gastric cancer: a meta-analysis.
PLoS One. 2014; 9(3):e88779 [PubMed] Free Access to Full Article Related Publications
AIM: We conducted a meta-analysis of case-control studies to determine whether ALDH2, ADH1 and ADH2 genetic polymorphisms contribute to the pathogenesis of gastric cancer.
METHODS: The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before November 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. We calculated crude odds ratios (ORs) with their 95% confidence intervals (95%CI) to evaluate their relationships under five genetic models. Seven case-control studies with a total of 2,563 gastric cancer patients and 4,192 healthy controls met the inclusion criteria. Nine common polymorphisms were evaluated, including rs671, rs16941667 and rs886205 in the ALDH2 gene, rs1230025, rs13123099, rs698 and rs1693482 in the ADH1 gene, and rs1229984 and rs17033 in the ADH2 gene.
RESULTS: The results of our meta-analysis suggested that ALDH2 genetic polymorphisms might be strongly correlated with an increased risk of gastric cancer (allele model: OR = 1.21, 95%CI: 1.11 ∼ 1.32, P<0.001; dominant model: OR = 1.23, 95%CI: 1.09 ∼ 1.39, P = 0.001; respectively), especially for rs671 polymorphism. Furthermore, we observed significant associations between ADH1 genetic polymorphisms and an increased risk of gastric cancer (allele model: OR = 1.21, 95%CI: 1.08 ∼ 1.36, P = 0.001; dominant model: OR = 10.52, 95%CI: 3.04 ∼ 36.41, P<0.001; respectively), especially for rs1230025 polymorphism. Nevertheless, no positive relationships were found between ADH2 genetic polymorphisms and gastric cancer risk (all P>0.05).
CONCLUSION: The current meta-analysis suggests that ALDH2 and ADH1 genetic polymorphisms may play crucial roles in the pathogenesis of gastric cancer. However, ADH2 genetic polymorphisms may not be important dominants of susceptibility to gastric cancer.

Kropotova ES, Zinovieva OL, Zyryanova AF, et al.
Altered expression of multiple genes involved in retinoic acid biosynthesis in human colorectal cancer.
Pathol Oncol Res. 2014; 20(3):707-17 [PubMed] Related Publications
All-trans-retinoic acid (atRA), the oxidized form of vitamin A (retinol), regulates a wide variety of biological processes, such as cell proliferation and differentiation. Multiple alcohol, retinol and retinaldehyde dehydrogenases (ADHs, RDHs, RALDHs) as well as aldo-keto reductases (AKRs) catalyze atRA production. The reduced atRA biosynthesis has been observed in several human tumors, including colorectal cancer. However, subsets of atRA-synthesizing enzymes have not been determined in colorectal tumors. We investigated the expression patterns of genes involved in atRA biosynthesis in normal human colorectal tissues, primary carcinomas and cancer cell lines by RT-PCR. These genes were identified using transcriptomic data analysis (expressed sequence tags, RNA-sequencing, microarrays). Our results indicate that each step of the atRA biosynthesis pathway is dysregulated in colorectal cancer. Frequent and significant decreases in the mRNA levels of the ADH1B, ADH1C, RDHL, RDH5 and AKR1B10 genes were observed in a majority of colorectal carcinomas. The expression levels of the RALDH1 gene were reduced, and the expression levels of the cytochrome CYP26A1 gene increased. The human colon cancer cell lines showed a similar pattern of changes in the mRNA levels of these genes. A dramatic reduction in the expression of genes encoding the predominant retinol-oxidizing enzymes could impair atRA production. The most abundant of these genes, ADH1B and ADH1C, display decreased expression during progression from adenoma to early and more advanced stage of colorectal carcinomas. The diminished atRA biosynthesis may lead to alteration of cell growth and differentiation in the colon and rectum, thus contributing to the progression of colorectal cancer.

Chen C, Wang L, Liao Q, et al.
Association between six genetic polymorphisms and colorectal cancer: a meta-analysis.
Genet Test Mol Biomarkers. 2014; 18(3):187-95 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The aim of this study was to determine whether six genetic polymorphisms confer susceptibility to colorectal cancer (CRC).
METHODS: A systematic search for candidate genes of CRC was performed among several online databases, including PubMed, Embase, Web of Science, the Cochrane Library, CNKI, and Wanfang online libraries. After a comprehensive filtering procedure, we harvested five genes, including MGMT (rs12917 and rs2308321), ADH1B (rs1229984), SOD2 (rs4880), XPC (rs2228001), and PPARG (rs1801282). Using the REVMAN and Stata software, six meta-analyses were conducted for associations between CRC and the just-mentioned genetic variants.
RESULTS: A total of 34 comparative studies among 17,289 cases and 54,927 controls were involved in our meta-analyses. Significant association was found between ADH1B rs1229984 polymorphism and CRC (p=0.03, odds ratio [OR]=1.18, 95% confidence interval [CI]=1.01-1.36). We also found significant association between PPARG rs1801282 polymorphism and CRC (p=0.004, OR=1.498, 95% CI=1.139-1.970), and this significant association is specific in Caucasians (p=0.004, OR=1.603, 95% CI=1.165-2.205).
CONCLUSIONS: The current meta-analysis has established that ADH1B (rs1229984) and PPARG (rs1801282) are two risk variants of CRC.

Anantharaman D, Chabrier A, Gaborieau V, et al.
Genetic variants in nicotine addiction and alcohol metabolism genes, oral cancer risk and the propensity to smoke and drink alcohol: a replication study in India.
PLoS One. 2014; 9(2):e88240 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Genetic variants in nicotinic acetylcholine receptor and alcohol metabolism genes have been associated with propensity to smoke tobacco and drink alcohol, respectively, and also implicated in genetic susceptibility to head and neck cancer. In addition to smoking and alcohol, tobacco chewing is an important oral cancer risk factor in India. It is not known if these genetic variants influence propensity or oral cancer susceptibility in the context of this distinct etiology.
METHODS: We examined 639 oral and pharyngeal cancer cases and 791 controls from two case-control studies conducted in India. We investigated six variants known to influence nicotine addiction or alcohol metabolism, including rs16969968 (CHRNA5), rs578776 (CHRNA3), rs1229984 (ADH1B), rs698 (ADH1C), rs1573496 (ADH7), and rs4767364 (ALDH2).
RESULTS: The CHRN variants were associated with the number of chewing events per day, including in those who chewed tobacco but never smoked (P =  0.003, P =  0.01 for rs16969968 and rs578776 respectively). Presence of the variant allele contributed to approximately 13% difference in chewing frequency compared to non-carriers. While no association was observed between rs16969968 and oral cancer risk (OR =  1.01, 95% CI =  0.83- 1.22), rs578776 was modestly associated with a 16% decreased risk of oral cancer (OR =  0.84, 95% CI =  0.72- 0.98). There was little evidence for association between polymorphisms in genes encoding alcohol metabolism and oral cancer in this population.
CONCLUSION: The association between rs16969968 and number of chewing events implies that the effect on smoking propensity conferred by this gene variant extends to the use of smokeless tobacco.

Zhang L, Jiang Y, Wu Q, et al.
Gene-environment interactions on the risk of esophageal cancer among Asian populations with the G48A polymorphism in the alcohol dehydrogenase-2 gene: a meta-analysis.
Tumour Biol. 2014; 35(5):4705-17 [PubMed] Related Publications
The aim of this study is to investigate the gene-environment interactions between the G48A polymorphism in the alcohol dehydrogenase-2 (ADH2) gene and environmental factors in determining the risk of esophageal cancer (EC). A literature search was conducted in the PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar databases to indentify eligible studies published before November 1, 2013. We performed a meta-analysis of 18 case-control studies with a total of 8,906 EC patients and 13,712 controls. The overall analysis suggested that individuals with the GG genotype were associated with a 2.77-fold increased risk of EC, compared with carriers of the GA and AA genotypes. In a stratified analysis by ethnic group, Japanese, Mainland Chinese, and Taiwan Chinese with the GG genotype had a significantly higher risk of EC, compared with Thai and Iranian populations, indicating ethnic variance in EC susceptibility. An analysis of combined effect indicated that GG genotype of ADH2 G48A was associated with the highest risk of EC in heavy drinkers and smokers. A striking difference was found to exist between males and females, showing gender variance for the association between ADH2 G48A and EC risk. This meta-analysis shows that the GG genotype of ADH2 G48A may be associated with an increased risk of EC in Asian populations. In addition, significant gene-environment interactions were found. Heavy drinkers, smokers, and males with the GG genotype may have a higher EC risk. Thus, our results shed new light on the complex gene-environment interactions that exist between environmental factors and ADH2 G48A polymorphism in EC risk.

Guo XF, Wang J, Yu SJ, et al.
Meta-analysis of the ADH1B and ALDH2 polymorphisms and the risk of colorectal cancer in East Asians.
Intern Med. 2013; 52(24):2693-9 [PubMed] Related Publications
OBJECTIVE: The aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) genes have been implicated in the development of colorectal cancer (CRC). However, the results are inconsistent. In this study, a meta-analysis was performed to assess the associations between the ALDH2 and ADH1B polymorphisms and the risk of CRC.
METHODS: Relevant studies were identified using PubMed, Web of Science and CNKI up to February, 2013. The pooled odds ratio (OR) with a 95% confidence interval (CI) was calculated using the fixed- or random-effects model.
RESULTS: A total of 11 case-controlled studies were selected. Of these, 11 studies included 2,893 cases and 3,817 controls concerning the ALDH2 Glu487Lys polymorphism and six studies included 1,864 cases and 3,502 controls concerning the ADH1B polymorphism. The results indicated that there was a statistically significant link between the ALDH2 polymorphism and the risk of CRC (Glu/Lys+Lys/Lys vs. Glu/Glu: OR=0.87, 95%CI: 0.78-0.96, p=0.10; Glu/Lys vs. Glu/Glu: OR=0.87, 95%CI: 0.77-0.97, p=0.38); however, no significant associations were observed between the ADH1B polymorphism and the risk of CRC win any of the genetic models.
CONCLUSION: This meta-analysis demonstrated that the ALDH2 polymorphism, but not the ADH1B polymorphism, significantly increases the risk of CRC in East Asians.

Crous-Bou M, Rennert G, Cuadras D, et al.
Polymorphisms in alcohol metabolism genes ADH1B and ALDH2, alcohol consumption and colorectal cancer.
PLoS One. 2013; 8(11):e80158 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included alcohol intake, which is mainly metabolized to acetaldehyde by alcohol dehydrogenase and further oxidized to acetate by aldehyde dehydrogenase; consequently, the role of genes in the alcohol metabolism pathways is of particular interest. The aim of this study is to analyze the association between SNPs in ADH1B and ALDH2 genes and CRC risk, and also the main effect of alcohol consumption on CRC risk in the study population.
METHODOLOGY/PRINCIPAL FINDINGS: SNPs from ADH1B and ALDH2 genes, included in alcohol metabolism pathway, were genotyped in 1694 CRC cases and 1851 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. A positive association between alcohol consumption and CRC risk was observed in male participants from the Molecular Epidemiology of Colorectal Cancer study (MECC) study (OR = 1.47; 95%CI = 1.18-1.81). Moreover, the SNPs rs1229984 in ADH1B gene was found to be associated with CRC risk: under the recessive model, the OR was 1.75 for A/A genotype (95%CI = 1.21-2.52; p-value = 0.0025). A path analysis based on structural equation modeling showed a direct effect of ADH1B gene polymorphisms on colorectal carcinogenesis and also an indirect effect mediated through alcohol consumption.
CONCLUSIONS/SIGNIFICANCE: Genetic polymorphisms in the alcohol metabolism pathways have a potential role in colorectal carcinogenesis, probably due to the differences in the ethanol metabolism and acetaldehyde oxidation of these enzyme variants.

Hakenewerth AM, Millikan RC, Rusyn I, et al.
Effects of polymorphisms in alcohol metabolism and oxidative stress genes on survival from head and neck cancer.
Cancer Epidemiol. 2013; 37(4):479-91 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Heavy alcohol consumption increases risk of developing squamous cell carcinoma of the head and neck (SCCHN). Alcohol metabolism to cytotoxic and mutagenic intermediates acetaldehyde and reactive oxygen species is critical for alcohol-drinking-associated carcinogenesis. We hypothesized that polymorphisms in alcohol metabolism-related and antioxidant genes influence SCCHN survival.
METHODS: Interview and genotyping data (64 polymorphisms in 12 genes) were obtained from 1227 white and African-American cases from the Carolina Head and Neck Cancer Epidemiology study, a population-based case-control study of SCCHN conducted in North Carolina from 2002 to 2006. Vital status, date and cause of death through 2009 were obtained from the National Death Index. Kaplan-Meier log-rank tests and adjusted hazard ratios were calculated to identify alleles associated with survival.
RESULTS: Most tested SNPs were not associated with survival, with the exception of the minor alleles of rs3813865 and rs8192772 in CYP2E1. These were associated with poorer cancer-specific survival (HRrs3813865, 95% CI=2.00, 1.33-3.01; HRrs8192772, 95% CI=1.62, 1.17-2.23). Hazard ratios for 8 additional SNPs in CYP2E1, GPx2, SOD1, and SOD2, though not statistically significant, were suggestive of differences in allele hazards for all-cause and/or cancer death. No consistent associations with survival were found for SNPs in ADH1B, ADH1C, ADH4, ADH7, ALDH2, GPx2, GPx4, and CAT.
CONCLUSIONS: We identified some polymorphisms in alcohol and oxidative stress metabolism genes that influence survival in subjects with SCCHN. Previously unreported associations of SNPs in CYP2E1 warrant further investigation.

Marttila E, Bowyer P, Sanglard D, et al.
Fermentative 2-carbon metabolism produces carcinogenic levels of acetaldehyde in Candida albicans.
Mol Oral Microbiol. 2013; 28(4):281-91 [PubMed] Related Publications
UNLABELLED: Acetaldehyde is a carcinogenic product of alcohol fermentation and metabolism in microbes associated with cancers of the upper digestive tract. In yeast acetaldehyde is a by-product of the pyruvate bypass that converts pyruvate into acetyl-Coenzyme A (CoA) during fermentation.
THE AIMS OF OUR STUDY WERE: (i) to determine the levels of acetaldehyde produced by Candida albicans in the presence of glucose in low oxygen tension in vitro; (ii) to analyse the expression levels of genes involved in the pyruvate-bypass and acetaldehyde production; and (iii) to analyse whether any correlations exist between acetaldehyde levels, alcohol dehydrogenase enzyme activity or expression of the genes involved in the pyruvate-bypass. Candida albicans strains were isolated from patients with oral squamous cell carcinoma (n = 5), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients with chronic oral candidosis (n = 5), and control patients (n = 5). The acetaldehyde and ethanol production by these isolates grown under low oxygen tension in the presence of glucose was determined, and the expression of alcohol dehydrogenase (ADH1 and ADH2), pyruvate decarboxylase (PDC11), aldehyde dehydrogenase (ALD6) and acetyl-CoA synthetase (ACS1 and ACS2) and Adh enzyme activity were analysed. The C. albicans isolates produced high levels of acetaldehyde from glucose under low oxygen tension. The acetaldehyde levels did not correlate with the expression of ADH1, ADH2 or PDC11 but correlated with the expression of down-stream genes ALD6 and ACS1. Significant differences in the gene expressions were measured between strains isolated from different patient groups. Under low oxygen tension ALD6 and ACS1, instead of ADH1 or ADH2, appear the most reliable indicators of candidal acetaldehyde production from glucose.

Mutka SC, Green LH, Verderber EL, et al.
ADH IB expression, but not ADH III, is decreased in human lung cancer.
PLoS One. 2012; 7(12):e52995 [PubMed] Free Access to Full Article Related Publications
Endogenous S-nitrosothiols, including S-nitrosoglutathione (GSNO), mediate nitric oxide (NO)-based signaling, inflammatory responses, and smooth muscle function. Reduced GSNO levels have been implicated in several respiratory diseases, and inhibition of GSNO reductase, (GSNOR) the primary enzyme that metabolizes GSNO, represents a novel approach to treating inflammatory lung diseases. Recently, an association between decreased GSNOR expression and human lung cancer risk was proposed in part based on immunohistochemical staining using a polyclonal GSNOR antibody. GSNOR is an isozyme of the alcohol dehydrogenase (ADH) family, and we demonstrate that the antibody used in those studies cross reacts substantially with other ADH proteins and may not be an appropriate reagent. We evaluated human lung cancer tissue arrays using monoclonal antibodies highly specific for human GSNOR with minimal cross reactivity to other ADH proteins. We verified the presence of GSNOR in ≥85% of specimens examined, and extensive analysis of these samples demonstrated no difference in GSNOR protein expression between cancerous and normal lung tissues. Additionally, GSNOR and other ADH mRNA levels were evaluated quantitatively in lung cancer cDNA arrays by qPCR. Consistent with our immunohistochemical findings, GSNOR mRNA levels were not changed in lung cancer tissues, however the expression levels of other ADH genes were decreased. ADH IB mRNA levels were reduced (>10-fold) in 65% of the lung cancer cDNA specimens. We conclude that the previously reported results showed an incorrect association of GSNOR and human lung cancer risk, and a decrease in ADH IB, rather than GSNOR, correlates with human lung cancer.

Ferrari P, McKay JD, Jenab M, et al.
Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphisms, alcohol intake and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study.
Eur J Clin Nutr. 2012; 66(12):1303-8 [PubMed] Related Publications
BACKGROUND/OBJECTIVES: Heavy alcohol drinking is a risk factor of colorectal cancer (CRC), but little is known on the effect of polymorphisms in the alcohol-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) on the alcohol-related risk of CRC in Caucasian populations.
SUBJECTS/METHODS: A nested case-control study (1269 cases matched to 2107 controls by sex, age, study centre and date of blood collection) was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the impact of rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms on CRC risk. Using the wild-type variant of each polymorphism as reference category, CRC risk estimates were calculated using conditional logistic regression, with adjustment for matching factors.
RESULTS: Individuals carrying one copy of the rs1229984(A) (ADH1B) allele (fast metabolizers) showed an average daily alcohol intake of 4.3 g per day lower than subjects with two copies of the rs1229984(G) allele (slow metabolizers) (P(diff)<0.01). None of the polymorphisms was associated with risk of CRC or cancers of the colon or rectum. Heavy alcohol intake was more strongly associated with CRC risk among carriers of the rs1573496(C) allele, with odds ratio equal to 2.13 (95% confidence interval: 1.26-3.59) compared with wild-type subjects with low alcohol consumption (P(interaction)=0.07).
CONCLUSIONS: The rs1229984(A) (ADH1B) allele was associated with a reduction in alcohol consumption. The rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms were not associated with CRC risk overall in Western-European populations. However, the relationship between alcohol and CRC risk might be modulated by the rs1573496 (ADH7) polymorphism.

Chung CS, Lee YC, Liou JM, et al.
Tag single nucleotide polymorphisms of alcohol-metabolizing enzymes modify the risk of upper aerodigestive tract cancers: HapMap database analysis.
Dis Esophagus. 2014; 27(5):493-503 [PubMed] Related Publications
Although alcohol is associated with higher upper aerodigestive tract (UADT) cancer risk, only a small fraction of alcoholics develop cancers. There is a lack of evidence proving the association of tag single nucleotide polymorphisms of alcohol-metabolizing enzymes with cancer risk. The aim of this study was to determine the association of these genetic polymorphisms with UADT cancer risk in a Chinese population. It was a hospital-based case-control candidate gene study. The databases of the International HapMap Project were searched for haplotype tag single nucleotide polymorphisms of the genes alcohol dehydrogenase (ADH)1B, ADH1C, and aldehyde dehydrogenase (ALDH)2. The genotyping was performed by the Sequenom MassARRAY system. Totally, 120 head and neck squamous cell carcinoma, 138 esophageal squamous cell carcinoma patients, and 276 age- and gender-matched subjects were enrolled between June 2008 and June 2010.Minor alleles of ADH1B (rs1229984) and ALDH2(rs671) were not only associated with the risk of UADT cancers (odds ratio [OR] [95% confidence interval, CI]: 3.53 [2.14-5.80] and 2.59 [1.79-3.75], respectively) but also potentiated the carcinogenic effects of alcohol (OR [95% CI]: 53.44 [25.21-113.29] and 70.08 [33.65-145.95], respectively). Similar effects were observed for head/neck and esophageal cancer subgroups. Multivariate logistic regression analysis identified four significant risk factors, including habitual use of cigarettes, alcohol, betel quid, and lower body mass index (P < 0.001). The haplotypes GAGC (OR 1.61, 95% CI 1.08-2.40, P = 0.018) and CCAATG (OR 1.69, 95% CI 1.24-2.30, P < 0.001) on chromosomes 4 and 12, respectively, were associated with higher cancer risk. These findings suggested that risk allele or haplotype carriers who consume alcohol and other carcinogens should be advised to undergo endoscopy screening. The information can be used to determine the degree of susceptibility of each subject and can be combined with other environmental factors, like carcinogen consumption, in the screening analysis.

Wu C, Kraft P, Zhai K, et al.
Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions.
Nat Genet. 2012; 44(10):1090-7 [PubMed] Free Access to Full Article Related Publications
We conducted a genome-wide association study (GWAS) and a genome-wide gene-environment interaction analysis of esophageal squamous-cell carcinoma (ESCC) in 2,031 affected individuals (cases) and 2,044 controls with independent validation in 8,092 cases and 8,620 controls. We identified nine new ESCC susceptibility loci, of which seven, at chromosomes 4q23, 16q12.1, 17q21, 22q12, 3q27, 17p13 and 18p11, had a significant marginal effect (P=1.78×10(-39) to P=2.49×10(-11)) and two of which, at 2q22 and 13q33, had a significant association only in the gene-alcohol drinking interaction (gene-environment interaction P (PG×E)=4.39×10(-11) and PG×E=4.80×10(-8), respectively). Variants at the 4q23 locus, which includes the ADH cluster, each had a significant interaction with alcohol drinking in their association with ESCC risk (PG×E=2.54×10(-7) to PG×E=3.23×10(-2)). We confirmed the known association of the ALDH2 locus on 12q24 to ESCC, and a joint analysis showed that drinkers with both of the ADH1B and ALDH2 risk alleles had a fourfold increased risk for ESCC compared to drinkers without these risk alleles. Our results underscore the direct genetic contribution to ESCC risk, as well as the genetic contribution to ESCC through interaction with alcohol consumption.

Wu M, Chang SC, Kampman E, et al.
Single nucleotide polymorphisms of ADH1B, ADH1C and ALDH2 genes and esophageal cancer: a population-based case-control study in China.
Int J Cancer. 2013; 132(8):1868-77 [PubMed] Free Access to Full Article Related Publications
Alcohol drinking is a major risk factor for esophageal cancer (EC) and the metabolism of ethanol has been suggested to play an important role in esophageal carcinogenesis. Epidemiologic studies, including genomewide association studies (GWAS), have identified single nucleotide polymorphisms (SNPs) in alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) to be associated with EC. Using a population-based case-control study with 858 EC cases and 1,081 controls conducted in Jiangsu Province, China, we aimed to provide further information on the association of ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms with EC in a Chinese population. Results showed that ADH1B (rs1229984) was associated with EC with odds ratios (ORs) of 1.34 [95% confidence interval (CI): 1.08-1.66] for G-allele carriers compared to A/A homozygotes. No heterogeneity was detected on this association across different strata of alcohol drinking and tobacco smoking. Statistical interaction between ALDH2 (rs671) and alcohol drinking on EC susceptibility in both additive and multiplicative scales was observed. Compared to G/G homozygotes, A-allele carriers were positively associated with EC among moderate/heavy drinkers (OR = 1.64, 95% CI: 1.12-2.40) and inversely associated with EC among never/light drinks (OR = 0.75, 95% CI: 0.54-1.03). In addition, statistical interaction between ALDH2 and ADH1B polymorphisms on EC susceptibility among never/light drinkers was indicated. We did not observe association of ADH1C polymorphism with EC. In conclusion, our findings indicated that ADH1B (rs1229984) was associated with EC independent of alcohol drinking and tobacco smoking status and alcohol drinking interacted with ALDH2 (rs671) on EC susceptibility in this high-risk Chinese population.

Cadoni G, Boccia S, Petrelli L, et al.
A review of genetic epidemiology of head and neck cancer related to polymorphisms in metabolic genes, cell cycle control and alcohol metabolism.
Acta Otorhinolaryngol Ital. 2012; 32(1):1-11 [PubMed] Free Access to Full Article Related Publications
The purpose of this report is to review the relationship between genetic polymorphisms involved in carcinogen metabolism, alcohol metabolism and cell-cycle control with the risk of head and neck cancer. The review was performed on available studies on genetic polymorphisms and head and neck cancer (HNC) published in PubMed up to September 2011. 246 primary articles and 7 meta-analyses were published. Among these, a statistically significant association was reported for glutathione S-transferases (GSTM1), glutathione S-transferases (GSTT1) and human microsomal epoxide hydrolase (EPHX1) genes. An increased risk for HNC was also associated reported for P53 codon 72 Pro/Pro, ALDH2 and three variants of the ADH gene: ADH1B (rs1229984), ADH7 (rs1573496) and ADH1C (rs698).

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