Evidence for an important role of alcohol- and aldehyde-metabolizing genes in cancers of the upper aerodigestive tract

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 (350)Val allele (OR, 1.19; 95% Cl, 0.98-1.55) and ADHI C 272 Gin 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 (AF(c)) 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 AF, 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.