Evidence for an Important Role of Alcohol- and Aldehyde-Metabolizing Genes in Cancers of the Upper Aerodigestive Tract
- Mia Hashibe1,
- Paolo Boffetta1,
- David Zaridze2,
- Oxana Shangina2,
- Neonila Szeszenia-Dabrowska3,
- Dana Mates4,
- Vladimir Janout5,
- Eleonóra Fabiánová6,
- Vladimir Bencko7,
- Norman Moullan1,
- Amelie Chabrier1,
- Rayjean Hung1,8,
- Janet Hall1,
- Federico Canzian1 and
- Paul Brennan1
- 1IARC, Lyons, France; 2Cancer Research Centre, Moscow, Russia; 3Institute of Occupational Medicine, Lodz, Poland; 4Institute of Hygiene, Public Health, Health Services and Management, Bucharest, Romania; 5Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic; 6Specialized State Health Institute, Banská Bystrica, Slovakia; 7Institute of Hygiene and Epidemiology, Prague, Czech Republic; and 8University of California Berkeley School of Public Health, Berkeley, California
- Requests for reprints:
Paul Brennan, Genetic Epidemiology Group, IARC, 150 cours Albert Thomas, 69372 Lyons, France. Phone: 33-4-72-73-83-91; Fax: 33-4-72-73-83-20. E-mail: brennan{at}iarc.fr
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)
Footnotes
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Grant support: European Commission's INCO-COPERNICUS Program contract no. IC15-CT98-0332, NIH/National Cancer Institute grant CA92039, and World Cancer Research Foundation grant WCRF 99A28.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted February 9, 2006.
- Received September 12, 2005.
- Revision received January 26, 2006.
