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

Cui, Ri; Kamatani, Yoichiro; Takahashi, Atsushi; Usami, Masayuki; Hosono, Naoya; Kawaguchi, Takahisa; Tsunoda, Tatsuhiko; Kamatani, Naoyuki; Kubo, Michiaki; Nakamura, Yusuke; Matsuda, Koichi

doi:10.1053/j.gastro.2009.07.070

Cited by 283 publications

(264 citation statements)

References 38 publications

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“…Our results suggest a potential role of ADH1B and ALDH2 SNPs on the etiology of esophageal cancer. Two recent genome-wide association studies identified the variation of ADH1B rs1229984 and ALDH2 rs671 polymorphism as risk factors for esophageal cancer in a Japanese population (11,12). However, in another three genome-wide association studies in larger Chinese populations, the results presented negative or protective efforts of these polymorphisms for esophageal cancer risk (2,3,14).…”

Section: Discussionmentioning

confidence: 79%

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A variant allele of ADH1B and ALDH2, is associated with the risk of esophageal cancer

Gong

Ding

et al. 2012

Experimental and Therapeutic Medicine

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Abstract. Alcoholic beverages are causally related to esophageal cancer. The genetic polymorphisms of the alcohol-metabolizing enzymes ADH1B rs1229984 and ALDH2 rs671 may modulate individual differences in alcohol-oxidizing capability. A case-control study was conducted to evaluate the genetic effects of these two functional single nucleotide polymorphisms (SNPs) on the development of esophageal cancer. A total of 380 esophageal squamous cell carcinoma cases and 380 controls were recruited. Genotypes were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Variant alleles of the functional polymorphism ADH1B rs1229984 SNP were associated with an increased risk of esophageal cancer [adjusted odds ratio (OR)=2.39, 95% confidence interval (CI)=1.42-4.03 for ADH1B rs1229984 GG vs. AA]. There was a borderline-significantly decreased risk between the ALDH2 rs671 genotype and esophageal cancer (adjusted OR=0.47, 95% CI=0.22-1.00 for ALDH2 rs671 AA vs. GG). Stratified analyses indicated that both of these effects were more evident among male, younger subjects and smokers. In conclusion, the functional polymorphisms ADH1B rs1229984 and ALDH2 rs671 may contribute to susceptibility to esophageal cancer, particularly among male, younger subjects and smokers. IntroductionEsophageal cancer is an extremely aggressive cancer, of which China has high-incidence regions (1). Esophageal squamous cell carcinoma (ESCC) is a subtype of esophageal cancer which accounts for >90% of cases (2). Esophageal cancer is known to be associated with environmental carcinogens. Epidemiological studies indicate that use of tobacco and consumption of alcohol are major risk factors for esophageal cancer. However, only a subset of individuals exposed to tobacco and alcohol develop esophageal cancer, suggesting a role of host susceptibility factors in cancer development. The genetic basis of esophageal cancer is complex and appears to involve multiple genes. Some studies have suggested that genetic polymorphisms might explain individual differences in susceptibility to esophageal cancer (3).Alcohol intake may be causally related to cancer of the oral cavity, pharynx, larynx and esophagus. Ethanol is oxidized to acetaldehyde and then to acetate by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH); both of which have genetic polymorphisms. The genetic polymorphisms of alcohol-metabolizing enzymes modulate individual differences in alcohol-oxidizing capability and drinking behavior (4).In humans, the major enzymes involved in the alcohol-metabolizing pathways are alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2). Alcohol is first oxidized by ADH to acetaldehyde, which is oxidized to acetate by ALDH. These enzymes are mainly expressed in the liver, but are also present in the gastrointestinal tract (5). A variant allele of

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Section: Discussionmentioning

confidence: 79%

“…Another genome-wide association study reported that variations of ADH1B rs1229984 and ALDH2 rs671 coupled with alcohol drinking and smoking synergistically enhanced the risk of esophageal cancer (12).…”

Section: Introductionmentioning

confidence: 99%

A variant allele of ADH1B and ALDH2, is associated with the risk of esophageal cancer

Gong

Ding

et al. 2012

Experimental and Therapeutic Medicine

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

Section: Introductionmentioning

confidence: 99%

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

Lee

Wang

et al. 2011

Cancer Prevention Research

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We quantified field cancerization of squamous cell carcinoma in the upper aerodigestive tract with epigenetic markers and evaluated their performance for risk assessment. Methylation levels were analyzed by quantitative methylation-specific PCR of biopsied specimens from a training set of 255 patients and a validation set of 224 patients. We also measured traditional risk factors based on demographics, lifestyle, serology, genetic polymorphisms, and endoscopy. The methylation levels of four markers increased stepwise, with the lowest levels in normal esophageal mucosae from healthy subjects without carcinogen exposure, then normal mucosae from healthy subjects with carcinogen exposure, then normal mucosae from cancer patients, and the highest levels were in cancerous mucosae (P < 0.05). Cumulative exposure to alcohol increased methylation of homeobox A9 in normal mucosae (P < 0.01). Drinkers had higher methylation of ubiquitin carboxyl-terminal esterase L1 and metallothionein 1M (P < 0.05), and users of betel quid had higher methylation of homeobox A9 (P ¼ 0.01). Smokers had increased methylation of all four markers (P < 0.05). Traditional risk factors allowed us to discriminate between patients with and without cancers with 74% sensitivity (95% CI: 67%-81%), 74% specificity (66%-82%), and 80% area under the curve (67%-91%); epigenetic markers in normal esophageal mucosa had values of 74% (69%-79%), 75% (67%-83%), and 83% (79%-87%); and both together had values of 82% (76%-88%), 81% (74%-88%), and 91% (88%-94%). Epigenetic markers done well in the validation set with 80% area under the curve (73%-85%). We concluded that epigenetics could improve the accuracies of risk assessment.

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“…Accumulating evidence suggests that a drinking habit for an individual with the ALDH2*2 allele increases the risk of cancerous diseases, including upper aerodigestive, gastric, colorectal, hepatic, and lung cancer [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47]. For example, it was reported that individuals with the ALDH2*1/*2 genotype who were heavy drinkers (C46 g ethanol/day and C5 days/week) had a 38-fold greater risk of developing oesophageal cancer compared to non-drinking individuals with the ALDH2*1/*1 genotype, while drinkers with the ALDH2*1/*1 allele had only a 2-fold greater risk [47].…”

Section: Effect Of Aldh2*2 On Cancerous Diseasesmentioning

confidence: 99%

Roles of defective ALDH2 polymorphism on liver protection and cancer development

Matsumoto

Thompson

Chen³

et al. 2016

Environ Health Prev Med

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

Cited by 283 publications

References 38 publications

A variant allele of ADH1B and ALDH2, is associated with the risk of esophageal cancer

A variant allele of ADH1B and ALDH2, is associated with the risk of esophageal cancer

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

Roles of defective ALDH2 polymorphism on liver protection and cancer development

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