Introduction: One of the most important risk factors for hepatocellular carcinoma (HCC) is alcohol consumption: Studies in different populations suggest that the risk of liver disease could be associated with genetic variants of the enzymes involved in alcohol metabolism, such as alcohol dehydrogenase (ADH) and cytochrome P450 CYP2E1. Objective: To identify and characterize the allelic variants of ADH1B, ADH1C and CYP2E1 genes in Colombian patients with cirrhosis and/or HCC. Materials and methods: We included samples from patients attending the hepatology unit between 2005-2007 and 2014-2016 of a hospital in Medellin. Samples were genotyped using PCR-RFLP. We compared the results with two control groups and the 1000 Genomes Project database. Results: We collected 97 samples from patients with a diagnosis of cirrhosis and/or HCC. The two main risk factors were chronic alcohol consumption (18.6%) and cholangiopathies (17.5%). The most frequent genotypes in the study population were ADH1B*1/1 (82%), ADH1C*1/1 (59%), and CYP2E1*C/C (84%). Conclusions: This first study of polymorphisms in Colombian patients diagnosed with cirrhosis and/or HCC showed genotypes ADH1B*1/1, ADH1C*1/1 and CYP2E1*C/C as the most frequent. We found no significant differences in the genotype frequency between cases and controls. Further studies are necessary to explore the association between polymorphisms and the risk of end-stage liver disease from alcohol consumption.

BACKGROUND Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. The relationships of alcohol dehydrogenase (ADH) enzymes, encoded by the genes ADH1 (1A), ADH1B (ADH2), ADH1C (ADH3), ADH4, ADH5, ADH6, and ADH7, with NSCLC have not been studied. The aim of this study was to explore the associations between NSCLC prognosis and the expression patterns of ADH family members. MATERIAL AND METHODS The online resource Metabolic gEne RApid Visualizer was used to assess the expression patterns of ADH family members in normal and primary lung tumor tissues. The GeneMANIA plugin of Cytoscape software and STRING website were used to evaluate the relationships of the 7 ADH family members at the gene and protein levels. Gene ontology enrichment analysis and KEGG pathway analysis were performed using DAVID. The online website Kaplan-Meier Plotter was used to construct survival curves between NSCLC and ADH isoforms. RESULTS The prognosis of patients with high expression levels of the ADH1B, ADH1C, ADH4, and ADH5 genes was better than those with low expression in adenocarcinoma and all (containing adenocarcinoma and squamous cell cancer) histological types (all P<0.05). Low expression of ADH7 was associated with a better prognosis in patients with both the adenocarcinoma and squamous cell cancer histological types (P=9e-05). Moreover, expression of ADH family members was associated with smoking status, clinical stage, and chemotherapy status. CONCLUSIONS ADH1B, ADH1C, ADH4, ADH5, and ADH7 appear to be useful biomarkers for the prognosis of NSCLC patients.

Previous work suggested a genetic component affecting the risk of hepatocellular carcinoma (HCC) and mediation analyses have elucidated potential indirect pathways of these genetic effects. Specifically, the effects of alcohol dehydrogenase (ADH1B) and aldehyde dehydrogenase (ALDH2) genes on HCC risk vary based on alcohol consumption habits. However, alcohol consumption may not be the only mediator in the identified pathway: factors related to alcohol consumption may contribute to the same indirect pathway. Thus, we developed a multimediator model to quantify the genetic effects on HCC risk through sequential dichotomous mediators under the counterfactual framework. Our method provided a closed form formula for the mediation effects through different indirect paths, which requires no assumption for the rarity of outcome. In simulation studies of a finite sample, we presented the utility of the method with the variance of the effects estimated using the delta method and bootstrapping. We applied our method to data from participants in Taiwan (580 cases and 3,207 controls) and quantified the mediation effects of single nucleotide polymorphisms (SNPs) in the ADH1B and ALDH2 genes on HCC through alcohol consumption (yes/no) and high alanine transaminase (ALT) levels (greater than or equal to 45 U/L or below 45 U/L). Assuming a dominant risk model, we identified that the SNPs' effects through alcohol consumption is more significant than through ALT levels on HCC risk. This new method provides insight to the magnitude of various casual mechanisms as a closed form solution and can be readily applied in other genomic studies.

Background: Epidemiological research has highlighted the global burden of primary liver cancer cases due to alcohol consumption, even in a low consumption country like India. Alcohol detoxification is governed by ADH1B, ALDH2, GSTM1 and GSTT1 genes that encode functional enzymes which are coordinated with each other to remove highly toxic metabolites i.e. acetaldehyde as well as reactive oxygen species generated through detoxification processes. Some communities in the population appears to be at greater risk for development of the liver cancer due to genetic predispositions. Methods: The aim of this study was to screen the arcadian population of central India in order to investigate and compare the genotype distribution and allele frequencies of alcohol metabolizing genes (ADH1B, ALDH2, GSTM1 and GSTT1) in both alcoholic (N=121) and control (N=145) healthy subjects. The gene polymorphism analysis was conducted using PCR and RFLP methods. Results: The allele frequency of ALDH2 *1 was 0.79 and of ALDH2*2 was 0.21 (OR:1.12; CI (95%): 0.74-1.71). The null allele frequency for GSTM1 was 0.28 (OR:0.85; CI (95%): 0.50-1.46) and for GSTT1 was 0.20 (OR:1.93; CI (95%): 1.05-3.55). No gene polymorphism for ADH1B was not observed. The total prevalence of polymorphisms was 3.38% for ALDH2, GSTM1 and GSTT1. Conclusion: The results of this study suggested that individuals of the Central India population under study are at risk for liver disorders due to ALDH2, GSTM1 and GSTT1 gene polymorphisms. This results may have significance for prevention of alcohol dependence, alcoholic liver disorders and the likelihood of liver cancer.

The alcohol-colorectal cancer (CRC) association may differ by sex and ADH1B and ADH1C genotypes. ADH enzymes oxidize ethanol to acetaldehyde, both of which are human carcinogens. The Netherlands Cohort Study includes 120 852 participants, aged 55-69 years at baseline (1986), and has 20.3 years follow-up (case-cohort: nsubcohort = 4774; ncases = 4597). The baseline questionnaire included questions on alcohol intake at baseline and 5 years before. Using toenail DNA, available for ~75% of the cohort, we successfully genotyped six ADH1B and six ADH1C SNPs (nsubcohort = 3897; ncases = 3558). Sex- and subsite-specific Cox hazard ratios and 95% confidence intervals for CRC were estimated comparing alcohol categories, genotypes within drinkers and alcohol categories within genotype strata. We used a dominant genetic model and adjusted for multiple testing. Alcohol intake increased CRC risk in both sexes, though in women only in the (proximal) colon when in excess of 30 g/day. In male drinkers, ADH1B rs4147536 increased (distal) colon cancer risk. In female drinkers, ADH1C rs283415 increased proximal colon cancer risk. ADH1B rs3811802 and ADH1C rs4147542 decreased CRC risk in heavy (>30 g/day) and stable drinkers (compared to 5 years before baseline), respectively. Rs3811802 and rs4147542 significantly modified the alcohol-colon cancer association in women (Pfor interaction = 0.004 and 0.02, respectively). A difference in associations between genotype strata was generally clearer in men than women. In conclusion, men showed increased CRC risks across subsites and alcohol intake levels, while only colon cancer risk was increased in women at heavy intake levels. ADH1B rs3811802 and ADH1C rs4147542 significantly modified the alcohol-colon cancer association in women.

BACKGROUND: The purpose of this research was to investigate the association between alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) polymorphisms and hypopharyngeal squamous cell carcinoma (SCC) survival.
METHODS: We genotyped ADH1B (rs1229984) and ALDH2 (rs671) single nucleotide polymorphisms (SNPs) in 85 Japanese male patients with hypopharyngeal SCC. The independent prognostic values of ADH1B-ALDH2 genotypes were analyzed by univariate and multivariate proportional hazard Cox regression, taking well-known clinical risk factors into account.
RESULTS: Heavy drinkers with ALDH2*2 allele resulted in significantly worse overall survival (OS; P = .028) and disease-free survival (DFS; P = .029) compared with other patients. Heavy drinkers with ALDH2*2 allele remained statistically significant in multivariate analysis for OS and DFS, indicating independent poor prognostic factor (hazard ratio [HR] 2.251; 95% confidence interval [CI] 1.018-4.975 and HR 2.261; 95% CI 1.021-5.006, respectively).
CONCLUSION: We conclude that heavy drinkers with the ALDH2*2 allele are associated with poor outcome in hypopharyngeal SCC.

BACKGROUND: Colorectal cancer (CRC) is a common cancer with high morbidity and mortality. However, its molecular mechanism is not clear, nor the genes related to CRC stages.
METHODS: Gene expression data in CRC and healthy colorectal tissues were obtained from gene expression omnibus. Limma package was used to identify the differentially expressed genes (DEGs) between control and CRC (stage I, II, III, and IV), obtaining 4 DEG sets. VennPlex was utilized to find all DEGs and intersection DEGs. Functional interactions between all DEGs and protein-protein interactions (PPIs) between intersection DEGs were analyzed using ReactomeFIViz and STRING, respectively, and networks were visualized. Known CRC-related genes were down-loaded from Comparative Toxicogenomics Database and mapped to PPI network.
RESULTS: Totally, 851, 760, 729, and 878 DEGs were found between control and CRC stage I, II, III, and IV, respectively. Taken together, 1235 DEGs were found, as well as 128 up-regulated intersection DEGs, 365 down-regulated intersection DEGs, and 0 contra-regulated DEG. A functional interaction network of all DEGs and a PPI network of intersection DEGs were constructed, in which CDC20, PTTG1, and MAD2L1 interacted with BUB1B; UGT2B17 interacted with ADH1B; MCM7 interacted with MCM2. BUB1B, ADH1B, and MCM2 were known CRC-related genes. Gradually upregulated expressions of CDC20, PTTG1, MAD2L1, UGT2B17, and MCM7 in stage I, II, III, and IV CRC were confirmed by using quantitative PCR. Besides, up-regulated intersection DEGs enriched in pathways about Cell cycle, DNA replication, and p53 signaling.
CONCLUSION: CDC20, PTTG1, MAD2L1, UGT2B17, and MCM7 might be CRC stage-related genes.

BACKGROUND: Gastric cancer (GC) is one of the most frequently diagnosed digestive tract cancers and carries a high risk of mortality. Acetaldehyde (AA), a carcinogenic intermediate of ethanol metabolism contributes to the risk of GC. The accumulation of AA largely depends on the activity of the major metabolic enzymes, alcohol dehydrogenase and aldehyde dehydrogenase encoded by the ADH (ADH1 gene cluster: ADH1A, ADH1B and ADH1C) and ALDH2 genes, respectively. This study aimed to evaluate the association between genetic variants in these genes and GC risk in West Bengal, India.
METHODS: We enrolled 105 GC patients (cases), and their corresponding sex, age and ethnicity was matched to 108 normal individuals (controls). Genotyping for ADH1A (rs1230025), ADH1B (rs3811802, rs1229982, rs1229984, rs6413413, rs4147536, rs2066702 and rs17033), ADH1C (rs698) and ALDH2 (rs886205, rs968529, rs16941667 and rs671) was performed using DNA sequencing and RFLP.
RESULTS: Genotype and allele frequency analysis of these SNPs revealed that G allele of rs17033 is a risk allele (A vs G: OR = 3.67, 95% CI = 1.54-8.75, p = 0.002) for GC. Significant association was also observed between rs671 and incidence of GC (p = 0.003). Moreover, smokers having the Lys allele of rs671 had a 7-fold increased risk of acquiring the disease (OR = 7.58, 95% CI = 1.34-42.78, p = 0.009).
CONCLUSION: In conclusion, rs17033 of ADH1B and rs671 of ALDH2 SNPs were associated with GC risk and smoking habit may further modify the effect of rs671. Conversely, rs4147536 of ADH1B might have a protective role in our study population. Additional studies with a larger patient population are needed to confirm our results.

BACKGROUND: Colon cancer occurrence is increasing worldwide, making it the third most frequent cancer. Although many therapeutic options are available and quite efficient at the early stages, survival is strongly decreased when the disease has spread to other organs. The identification of molecular markers of colon cancer is likely to help understanding its course and, eventually, to uncover novel genes to be targeted by drugs. In this study, we compared gene expression in a set of 95 human colon cancer samples to that in 19 normal colon mucosae, focusing on 401 genes from 5 selected pathways (Apoptosis, Cancer, Cholesterol metabolism and lipoprotein signaling, Drug metabolism, Wnt/beta-catenin). Deregulation of mRNA levels largely matched that of proteins, leading us to build in silico protein networks, starting from mRNA levels, to identify key proteins central to network activity.
RESULTS: Among the analyzed genes, 10.5% (42) had no reported link with colon cancer, including the SFRP1, IGF1 and ADH1B (down), and MYC and IL8 (up), whose encoded proteins were most interacting with other proteins from the same or even distinct networks. Analyzing all pathways globally led us to uncover novel functional links between a priori unrelated or rather remotely connected pathways, such as the Drug metabolism and the Cancer pathways or, even more strikingly, between the Cholesterol metabolism and lipoprotein signaling and the Cancer pathways. In addition, we analyzed the responsiveness of some of the deregulated genes essential to network activities, to chemotherapeutic agents used alone or in presence of Lovastatin, a lipid-lowering drug. Some of these treatments could oppose the deregulations occurring in cancer samples, including those of the CHECK2, CYP51A1, HMGCS1, ITGA2, NME1 or VEGFA genes.
CONCLUSIONS: Our network-based approach allowed discovering genes not previously known to play regulatory roles in colon cancer. Our results also showed that selected drug treatments might revert the cancer-specific deregulation of genes playing prominent roles within the networks operating to maintain colon homeostasis. Among those genes, some could constitute novel testable targets to eliminate colon cancer cells, either directly or, potentially, through the use of lipid-lowering drugs such as statins, in association with selected anticancer drugs.

Although alcohol is an established risk factor of head and neck cancer (HNC), insufficiencies exist in the literature in several aspects. We analyzed detailed alcohol consumption data (amount and type of alcoholic beverage) of 811 HNC patients and 940 controls to evaluate the association between alcohol and HNC by HNC sites and by genotypes of ADH1B and ALDH2. Alcohol was associated with an increased HNC risk in a dose-response relationship, with the highest risk observed for hypopharyngeal cancer, followed by oropharyngeal and laryngeal cancers. Liquor showed a stronger positive association with HNC than beer and wine. The highest HNC risk occurred in individuals with the slow ADH1B and slow/non-functional ALDH2 genotype combination. In our study population, 21.8% of HNCs, 55.7% of oropharyngeal cancers, and 89.1% of hypopharyngeal cancers could be attributed to alcohol. Alcohol accounted for 47.3% of HNCs among individuals with the slow ADH1B and slow/non-functional ALDH2 genotype combination. The HNC risk associated with alcohol became comparable to that of never/occasional drinkers after ten or more years of cessation from regular alcohol drinking. In conclusion, alcohol use is associated with an increased HNC risk, particularly for individuals with slow ethanol metabolism. HNC incidence may be reduced by alcohol cessation.

Heterogeneity in transcriptional data hampers the identification of differentially expressed genes (DEGs) and understanding of cancer, essentially because current methods rely on cross-sample normalization and/or distribution assumption-both sensitive to heterogeneous values. Here, we developed a new method, Cross-Value Association Analysis (CVAA), which overcomes the limitation and is more robust to heterogeneous data than the other methods. Applying CVAA to a more complex pan-cancer dataset containing 5,540 transcriptomes discovered numerous new DEGs and many previously rarely explored pathways/processes; some of them were validated, both

Alcohol is a major risk factor for oesophageal squamous cell carcinoma (OSCC), the most prevalent histological subtype of oesophageal cancer (OC) worldwide. The metabolism of alcohol is regulated by specific enzymes whose activity and expression is influenced by genetic polymorphisms. We conducted a systematic review of current epidemiological evidence of the relationship between alcohol intake and OC risk, including the role of tobacco smoking and functional polymorphisms of alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs). Potential biological mechanisms underlying oesophageal carcinogenesis are also discussed. Frequency and intensity of alcohol intake have been consistently associated with an increased risk of OSCC in regions with low and high incidence of the disease. The highest risk was reported among tobacco smokers, whereas the association between alcohol and OSCC risk was weak in the absence of tobacco use. The ADH1B, ADH1C and ALDH2 gene polymorphisms influence the risk of OSCC through modulation of acetaldehyde metabolism and propensity to alcohol intake. These functional variants may be suitable proxies of alcohol exposure for use in Mendelian randomization studies if complemented by reported alcohol intake data. Recent epidemiological and experimental studies investigating the role of alcohol consumption in OC development have implicated the microbiome as a new promising avenue for research, which entail novel potential mechanisms of alcohol-related oesophageal carcinogenesis. Microbial communities associated with alcohol consumption might be used as biomarkers to raise the potential of intervening among susceptible individuals.

The aim of the present study was to investigate the prognostic value of genes that participate in the development of gastric adenocarcinoma, via exploring gene cross talk in disease‑related pathways. Differentially expressed genes (DEGs) in the gastric samples were identified by analyzing the expression data downloaded from the GEO database. The DEGs were subjected to the human protein‑protein interaction (PPI) network to construct the PPI network of DEGs, which was then used for the identification of key genes in cancer samples via the expression deviation score and degree in the network. A total of 635 DEGs, including 432 downregulated and 203 upregulated ones were screened in the gastric adenocarcinomas samples. The PPI network of DEGs comprised 590 DEGs and 4,299 interaction pairs. A total of 200 key genes were obtained, which were significantly enriched in six downregulated and six upregulated pathways. Cross talk genes in the connected pathways were analyzed, and the Kyoto Encyclopedia of Genes and Genomes pathways hsa00980 (Metabolism of xenobiotics by cytochrome P450) and hsa00982 (Drug metabolism) were reported to share 8 cross talk genes: ADH7, ALDH3A1, GSTA1, GSTA2, UGT2B17, UGT2B10, ADH1B and CYP2C18. Among all cross talk genes, ADH7, ALDH3A1 and CLDN3 were the most specific genes. The high‑ and low‑risk samples identified by the prognosis model presented a remarkable difference in total survival time, indicating its robustness and sensitivity as the prognosis genes for gastric adenocarcinoma. ADH7, ALDH3A1, GSTA1, GSTA2, UGT2B17, UGT2B10, ADH1B, CYP2C18ADH7, ALDH3A1 and CLDN3 may be used as the prognosis markers and target biomarkers for chemotherapies in gastric adenocarcinoma.

The ADH1B (Alcohol Dehydrogenase 1B (class I), Beta Polypeptide) gene and its best-known functional alleles, Arg48His (rs1229984, ADH1B*2) and Arg370Cys (rs2066702, ADH1B*3), have been investigated in relation to many phenotypic traits; most frequently including alcohol metabolism and alcohol drinking behaviors, but also human evolution, liver function, cancer, and, recently, the comprehensive human phenome. To understand ADH1B functions and consequences, we provide here a bioinformatic analysis of its gene regulation and molecular functions, literature review of studies focused on this gene, and a discussion regarding future research perspectives. Certain ADH1B alleles have large effects on alcohol metabolism, and this relationship particularly encourages further investigations in relation to alcoholism and alcohol-associated cancer to understand better the mechanisms by which alcohol metabolism contributes to alcohol abuse and carcinogenesis. We also observed that ADH1B has complex mechanisms that regulate its expression across multiple human tissues, and these may be involved in cardiac and metabolic traits. Evolutionary data strongly suggest that the selection signatures at the ADH1B locus are primarily related to effects other than those on alcohol metabolism. This is also supported by the involvement of ADH1B in multiple molecular pathways and by the findings of our recent phenome-wide association study. Accordingly, future studies should also investigate other functions of ADH1B potentially relevant for the human phenome. © 2017 Wiley Periodicals, Inc.

BACKGROUND AND OBJECTIVE: Alcohol and its metabolites play an important role in carcinogenesis. This effect could be modulated by polymorphisms in genes encoding enzymes involved in the metabolism of alcohol and folate. Therefore, we analyzed the effect of alcohol consumption and ADH1B Arg48His, ADH1B Arg370Cys, ADH1C Ile349Val, ALDH2 Glu540Lys, CYP2E1 RsaI, CYP2E1 DraI, CYP2E1 TaqI and MTHFR C677T polymorphisms on the risk of developing lung cancer.
PATIENTS AND METHODS: We included 876 lung cancer cases and 840 controls of the CAPUA hospital-based case-control study. Genotyping was performed using the Sequenom MassArray (iPLEX GOLD) technology.
RESULTS: An alcohol consumption of 0.1-9.9g/day decreased lung cancer risk (OR
CONCLUSIONS: Alcohol and polymorphisms in genes involved in the metabolism of alcohol and folate are related to the onset of lung cancer.

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.

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.

In this study, we assessed the association between single nucleotide polymorphisms (SNPs) in candidate genes and the prognosis of laryngeal cancer (LC) patients. Thirty-seven SNPs in 26 genes were genotyped in 170 male Han Chinese patients with LC. The effects of the candidate genes on the prognosis of LC patients were evaluated using Kaplan-Meier curves and Cox proportional hazards regression models. The GA genotype of rs1229984 (hazard ratio [HR], 0.537; 95% confidence interval [CI], 0.340-0.848; p = 0.008) in alcohol dehydrogenase 1B (ADH1B), and the AA genotype of rs9929218 (HR, 6.074; 95% CI, 1.426-25.870; p = 0.015) in CDH1 were associated with overall survival. Our data suggest that polymorphisms in ADH1B and CDH1 may be prognostic indicators in LC.

BACKGROUND: It has been shown that gene polymorphisms may play an important role in the carcinogenesis of esophageal cancer. This study is to investigate the role of alcohol dehydrogenase 1B (ADH1B) gene Arg47His polymorphism in esophageal cancer susceptibility.
METHODS: Case-control studies published between January 2000 and June 2015 were searched to retrieve relevant articles. The pooled odds ratio (OR) and 95 % confidence interval (CI) were employed to calculate the strength of association.
RESULTS: A total of 23 relevant articles were finally selected for the analysis, including 9338 esophageal cancer patients and 14,896 matched controls. Overall, we found that the 47His allele was significant associated with the decreased risk of esophageal cancer when compared with the 47Arg allele in total populations (A vs. G: OR = 0.67, 95 % CI = 0.59-0.76, P < 0.00001). This protective relationship was observed under other genetic models as well (P < 0.00001). Subgroup analysis by ethnicity showed that ADH1B Arg47His variant was associated with the decreased esophageal cancer risk under all the genetic models (P < 0.00001) among Asians, especially in Chinese and Japanese; while in non-Asians, no significant correlation was detected in any genetic models (P > 0.05). Furthermore, Arg/Arg genotype of ADH1B Arg47His variant combined with drinking, smoking and males appeared to show a high risk in patients with esophageal cancer.
CONCLUSIONS: Our results suggested that ADH1B gene Arg47His variant was associated with the decreased esophageal cancer risk. Genetic-environmental interaction should be further considered in the future researches.

UNLABELLED: Lysine acetylated modification was indicated to impact colorectal cancer (CRC)'s distant metastasis. However, the global acetylated proteins in CRC and the differential expressed acetylated proteins and acetylated sites between CRC primary and distant metastatic tumor remains unclear. Our aim was to construct a complete atlas of acetylome in CRC and paired liver metastases. Combining high affinity enrichment of acetylated peptides with high sensitive mass spectrometry, we identified 603 acetylation sites from 316 proteins, among which 462 acetylation sites corresponding to 243 proteins were quantified. We further classified them into groups according to cell component, molecular function and biological process and analyzed the metabolic pathways, domain structures and protein interaction networks. Finally, we evaluated the differentially expressed lysine acetylation sites and revealed that 31 acetylated sites of 22 proteins were downregulated in CRC liver metastases compared to that in primary CRC while 40 acetylated sites of 32 proteins were upregulated, of which HIST2H3AK19Ac and H2BLK121Ac were the acetylated histones most changed, while TPM2 K152Ac and ADH1B K331Ac were the acetylated non-histones most altered. These results provide an expanded understanding of acetylome in CRC and its distant metastasis, and might prove applicable in the molecular targeted therapy of metastatic CRC.
BIOLOGICAL SIGNIFICANCE: This study described provides, for the first time, that full-scale profiling of lysine acetylated proteins were identified and quantified in colorectal cancer (CRC) and paired liver metastases. The novelty of the study is that we constructed a complete atlas of acetylome in CRC and paired liver metastases. Moreover, we analyzed these differentially expressed acetylated proteins in cell component, molecular function and biological process. In addition, metabolic pathways, domain structures and protein interaction networks of acetylated proteins were also investigated. Our approaches shows that of the differentially expressed proteins, HIST2H3AK19Ac and H2BLK121Ac were the acetylated histones most changed, while TPM2 K152Ac and ADH1B K331Ac were the acetylated non-histones most altered. Our findings provide an expanded understanding of acetylome in CRC and its distant metastasis, and might prove applicable in the molecular targeted therapy of metastatic CRC.

A previous genome-wide association study identified two novel esophageal squamous cell carcinoma (ESCC) susceptibility genes, ADH1B and ALDH2. We investigated the characteristics of ESCC, and the relationship between metachronous esophageal and/or pharyngeal squamous cell carcinoma (SCC) and the ADH1B & ALDH2 risk alleles. One hundred and seventeen superficial ESCC patients who underwent treatment with endoscopic submucosal dissection (ESD) were followed up using endoscopy for ≥12 months. First, we performed a replication analysis to confirm the relationship between ESCC and the ADH1B & ALDH2 risk alleles using 117 superficial ESCC cases and 1125 healthy controls. Next, we investigated the incidence and genetic/environmental factors associated with metachronous SCC development after ESD. We also analyzed the potential risk factors for metachronous SCC development using Cox's proportional hazards model. rs1229984 GG located on ADH1B and rs671 GA located on ALDH2 were significantly associated with ESCC progression (P = 7.93 × 10(-4) and P = 1.04 × 10(-5) ). Patients with rs1229984 GG, those with rs671 GA, smokers, heavy alcohol drinkers (44 g/day ethanol), and presence of multiple Lugol-voiding lesions (LVLs) developed metachronous SCC more frequently (P = 3.20 × 10(-3) , 7.00 × 10(-4) , 4.00 × 10(-4) , 2.15 × 10(-2) , and 4.41 × 10(-3) , respectively), with hazard ratios were 2.84 (95% confidence interval [CI] = 1.43-5.63), 4.57 (95% CI = 1.80-15.42), 4.84 (95% CI = 1.89-16.41), and 2.34 (95% CI = 1.12-5.31), respectively. Multiple logistic regression analysis revealed that rs1229984 GG, rs671 GA, and smoking status were independently associated with the risk of developing metachronous SCCs after ESD. Moreover, we found cumulative effects of these two genetic factors (rs1229984 GG and rs671 GA) and one environmental factor (tobacco smoking) which appear to increase metachrous SCCs after ESD of ESCC risk approximately nearly 12-fold. Our findings elucidated the crucial role of multiple genetic variations in ADH1B and ALDH2 as biomarkers of metachronous ESCC.

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].

BACKGROUND & AIMS: Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer in Japan. Smoking and drinking alcohol are environmental risk factors for ESCC, whereas single nucleotide polymorphisms in ADH1B and ALDH2, which increase harmful intermediates produced by drinking alcohol, are genetic risk factors. We conducted a large-scale genomic analysis of ESCCs from patients in Japan to determine the mutational landscape of this cancer.
METHODS: We performed whole-exome sequence analysis of tumor and nontumor esophageal tissues collected from 144 patients with ESCC who underwent surgery at 5 hospitals in Japan. We also performed single-nucleotide polymorphism array-based copy number profile and germline genotype analyses of polymorphisms in ADH1B and ALDH2. Polymorphisms in CYP2A6, which increase harmful effects of smoking, were analyzed. Functions of TET2 mutants were evaluated in KYSE410 and HEK293FT cells.
RESULTS: A high proportion of mutations in the 144 tumor samples were C to T substitution in CpG dinucleotides (called the CpG signature) and C to G/T substitutions with a flanking 5' thymine (called the APOBEC signature). Based on mutational signatures, patients were assigned to 3 groups, which associated with environmental (drinking and smoking) and genetic (polymorphisms in ALDH2 and CYP2A6) factors. Many tumors contained mutations in genes that regulate the cell cycle (TP53, CCND1, CDKN2A, FBXW7); epigenetic processes (MLL2, EP300, CREBBP, TET2); and the NOTCH (NOTCH1, NOTCH3), WNT (FAT1, YAP1, AJUBA) and receptor-tyrosine kinase-phosphoinositide 3-kinase signaling pathways (PIK3CA, EGFR, ERBB2). Mutations in EP300 and TET2 correlated with shorter survival times, and mutations in ZNF750 associated with an increased number of mutations of the APOBEC signature. Expression of mutant forms of TET2 did not increase cellular levels of 5-hydroxymethylcytosine in HEK293FT cells, whereas knockdown of TET2 increased the invasive activity of KYSE410 ESCC cells. Computational analyses associated the mutations in NFE2L2 we identified with transcriptional activation of its target genes.
CONCLUSIONS: We associated environmental and genetic factors with base substitution patterns of somatic mutations and provide a registry of genes and pathways that are disrupted in ESCCs. These findings might be used to design specific treatments for patients with esophageal squamous cancers.

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.

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.

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.

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.

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.

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.

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.