Glutathione S -Transferase Polymorphisms and the Synergy of Alcohol and Tobacco in Oral, Pharyngeal, and Laryngeal Carcinoma Edward S. Peters, 1 Michael D. McClean, 2 Carmen J. Marsit, 3 Brian Luckett, 1 and Karl T. Kelsey 3 1 Division of Epidemiology, Louisiana State University Health Sciences School of Public Health, New Orleans, Louisiana; and 2 Department of Environmental Health, Boston University School of Public Health and 3 Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts Abstract Investigations of the ability of polymorphisms in the GSTM1, GSTT1 , and GSTP1 genes to alter susceptibility to head and neck squamous cell carcinoma (HNSCC) have examined gene-environment interaction in their detoxifica- tion of tobacco-associated carcinogens. Little work has been done to ask if these variant genes also modify the interaction of tobacco and alcohol in the development of HNSCC. To test this hypothesis, we conducted a case-control study, enrolling 692 incident cases of HNSCC and 753 population controls. Information about lifetime tobacco and alcohol use was ascertained through questionnaires, and genotypes for GSTM1, GSTT1 , and GSTP1 were determined from constitu- tional DNA. Genotype frequencies were compared among cases and controls, and the association between genotypes and tobacco use was evaluated on cancer risk through logistic regression. Deletion of GSTM1 was associated with an increased risk for HNSCC [odds ratio (OR), 1.3; 95% confidence interval (95% CI), 1.0-1.6]. GSTT1 deletion was associated with a slight decreased HNSCC risk (OR, 0.8; 95% CI, 0.6-1.0). Among those with GSTM1 present, the OR of cancer for heavy smoking was 2.6 (95% CI, 1.6-4.3) compared with 4.2 for those with the GSTM1 deleted (95% CI, 2.6-6.7). The combination of consuming 10 to 20 alcohol drinks weekly and smoking >45 pack-years was associated with a 13-fold elevated risk (OR, 12.6; 95% CI, 4.0-40.2) among the GSTM1 deleted subjects compared with an OR of 3.6 (95% CI, 1.5-8.7) among the GSTM1 present individuals. These data (showing that the GSTM1 deletion affects on the tobacco and alcohol synergy) suggest that the interaction of these carcinogens is, at least in part, driven by alcohol, enhancing thecarcinogenicactionoftobaccosmoke. (CancerEpidemiol BiomarkersPrev2006;15(11):2196–202) Introduction Head and neck squamous cell carcinoma (HNSCC) is the 8th most common cancer worldwide for both sexes, the 6th most common cancer in developing nations, and is the 10th most common cancer in the United States (1, 2). The use of tobacco and alcohol accounts for f75% of all HNSCCs in the United States (3, 4). Rothman (5) and Blot et al. (3) have shown that alcohol and tobacco have both independent and synergistic roles in the genesis of HNSCC, as strong dose-response relationships for alcohol and for tobacco consumption as well asamultiplicativeinteractionofbothareobservedinvirtually all of the HNSCC studies published to date. Tobacco smoke is well recognized as a complete carcinogen, but the mechanism by which alcohol exerts its carcinogenicity remains unclear. Alcohol may act as a solvent for other carcinogens or perhaps generate and exacerbate coincident inflammation, producing significant reactive oxygen species (6, 7). Although the combined exposures of tobacco and alcohol are primarily responsible for the genesis of this disease, interindividual geneticvariabilitymayplayanimportantroleinmodifyingthe potency of these carcinogens and mediating potential suscep- tibility to the action of both tobacco and alcohol either individually or as they interact to induce cancer (8, 9). Indeed, genetic polymorphisms affecting the expression or activity of metabolic enzymes responsible for the detoxification of tobacco and alcohol are thought to influence an individual’s susceptibility to oral cancer (10, 11). Glutathione S -transferases (GST) are phase II xenobiotic metabolizing enzymes directly involved in catalyzing the conjugation of reactive intermediates of electrophilic xeno- biotics with glutathione (8, 11, 12). The GSTs are composed of four major groups: GSTA (a), GSTT1 (u), GSTM1 (A), and GSTP1 (k). The u class of glutathione transferases is also well known to activate haloalkanes (13), such as those found in the chlorination by-products in treated drinking water (14, 15), and methyl chloride, which is found in tobacco smoke (16). GSTexpressionvariesamongindividuals,andthisvariationis tissueandgenderspecific(17). GSTM1, GSTT1 ,and GSTP1 are well known to be polymorphic, and deleted variants of the GSTM1 and GSTT1 loci result in loss of functional activity (18-20). Deletion of the GSTM1 and GSTT1 genes has been reported in approximately 50% and 20% of the Caucasian population, respectively (21-23). Two polymorphisms in the GSTP1 gene, one at codon 105 with an A to G transition resulting in an isoleucine to valine amino acid change and anotheratcodon114(alaninetovalinesubstitution),havebeen reported to cause differences in catalytic activity (9). Various studies have shown positive associations between the GSTM1 and GSTT1 null genotypes and increased risk for skin, lung, bladder, and oral cancer (9, 24-29). Despite several independentstudiesandsubsequentmeta-analysis,thereports about the association of HNSCC and the GST variants remain inconclusive (11, 30). The GSTs play an important role in the metabolism of chemical carcinogens, especially with regard to thosepresentintobaccosmoke.Further,althoughtobaccoand alcohol are major independent risk factors for HNSCC, it is in their interaction that the most profound risk of HNSCC is incurred.Themechanismofthisinteractionisnotknown,and 2196 Cancer Epidemiol Biomarkers Prev 2006;15(11). November 2006 Received 6/20/06; revised 8/4/06; accepted 8/22/06. Grant Support: NIH grants CA78609, CA100679 and The Flight Attendants Medical Research Institute. 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. Requests for reprints: KarlT.Kelsey,DepartmentofGeneticsandComplexDiseases,Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115. Phone: 617-432-3313; Fax: 617-432-0107; E-mail: Kelsey@hsph.harvard.edu Copyright D 2006 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-06-0503 on June 7, 2020. © 2006 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from