Evidence for an Important Role of Alcohol- and Aldehyde-Metabolizing Genes in Cancers of the Upper Aerodigestive Tract
- 1 April 2006
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Epidemiology, Biomarkers & Prevention
- Vol. 15 (4), 696-703
- https://doi.org/10.1158/1055-9965.epi-05-0710
Abstract
Background: Incidence and mortality rates of upper aerodigestive tract cancers in Central Europe are among the highest in the world and have increased substantially in recent years. This increase is likely to be due to patterns of alcohol and tobacco consumption. Genetic susceptibility to upper aerodigestive tract cancer in relation to such exposures is an important aspect that should be investigated among populations in this region. Methods: A multicenter case-control study comprising 811 upper aerodigestive tract cancer cases and 1,083 controls was conducted in: Bucharest (Romania), Lodz (Poland), Moscow (Russia), Banska Bystrika (Slovakia), and Olomouc and Prague (Czech Republic). We analyzed six SNPs in three genes related to ethanol metabolism: alcohol dehydrogenase 1B and 1C (ADH1B, ADH1C) and aldehyde dehydrogenase 2 (ALDH2). Results: The ADH1B histidine allele at codon 48 was associated with a decreased risk of upper aerodigestive tract cancer; odds ratios (OR) were 0.36 [95% confidence interval (95% CI), 0.17-0.77] for medium/heavy drinkers and 0.57 (95% CI, 0.36-0.91) for never/light drinkers. Moderately increased risks were observed for the ADH1C 350Val allele (OR, 1.19; 95% CI, 0.98-1.55) and ADH1C 272Gln allele (OR, 1.24; 95% CI, 0.98-1.55). Medium/heavy drinkers who were heterozygous or homozygous at ALDH2 nucleotide position 248 were at a significantly increased risk of upper aerodigestive tract cancer (OR, 1.76; 95% CI, 1.13-2.75; OR, 5.79; 95% CI, 1.49-22.5, respectively), with a significant dose response for carrying variant alleles (P = 0.0007). Similar results were observed for the ALDH2 +82A>G and ALDH2 −261C>T polymorphisms. When results were analyzed by subsite, strong main effects were observed for squamous cell carcinoma of the esophagus for all six variants. Among the 30% of the population who were carriers of at least one ALDH2 variant, the attributable fraction among carriers (AFc) was 24.2% (5.7-38.3%) for all upper aerodigestive tract cancers, increasing to 58.7% (41.2-71.0%) for esophageal cancer. Among carriers who drank alcohol at least thrice to four times a week, the AFc for having at least one ALDH2 variant was 49% (21.3-66.8%) for all upper aerodigestive tract cancers, increasing to 68.9% (42.9-83.1%) for esophageal cancer. Conclusions: Polymorphisms in the ADH1B and ALDH2 genes are associated with upper aerodigestive tract cancer in Central European populations and interact substantially with alcohol consumption. (Cancer Epidemiol Biomarkers Prev 2006;15(4):696–703)Keywords
This publication has 29 references indexed in Scilit:
- Large-Scale Investigation of Base Excision Repair Genetic Polymorphisms and Lung Cancer Risk in a Multicenter StudyJNCI Journal of the National Cancer Institute, 2005
- The ADH1C polymorphism modifies the risk of squamous cell carcinoma of the head and neck associated with alcohol and tobacco useCancer Epidemiology, Biomarkers & Prevention, 2005
- Assessing Exposure Misclassification by Expert Assessment in Multicenter Occupational StudiesEpidemiology, 2003
- Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common diseaseNature Genetics, 2003
- Alcohol and Aldehyde Dehydrogenase Gene Polymorphisms Influence Susceptibility to Esophageal Cancer in Japanese AlcoholicsAlcohol: Clinical and Experimental Research, 1999
- Rising trends of oral cancer mortality among males worldwide: the return of an old public health problemCancer Causes & Control, 1994
- Purification and steady-state kinetic characterization of human liver .beta.3.beta.3 alcohol dehydrogenaseBiochemistry, 1989
- Nucleotide Sequence of the ADH23 Gene Encoding the Human Alcohol Dehydrogenase β3 SubunitAlcohol: Clinical and Experimental Research, 1989
- The gamma1 and gamma2 subunits of human liver alcohol dehydrogenase. cDNA structures, two amino acid replacements, and compatibility with changes in the enzymatic propertiesEuropean Journal of Biochemistry, 1986
- Relationship between kinetics of liver alcohol dehydrogenase and alcohol metabolismPharmacology Biochemistry and Behavior, 1983