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Selected Genetic Polymorphisms in MGMT, XRCC1, XPD, and XRCC3 and Risk of Head and Neck Cancer: A Pooled Analysis

¹ Division of Cancer Epidemiology and Genetics and ² Pediatric Oncology Branch, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland; ³ Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; ⁴ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; ⁵ Department of Epidemiology, University of Washington, Seattle, Washington, and ⁶ Core Genotyping Facility, Advanced Technology Center, National Cancer Institute-Frederick, Gaithersburg, Maryland

Requests for reprints: Wen-Yi Huang, Division of Cancer Epidemiology and Genetics, National Cancer Institute, EPS 8113, MSC 7240, Bethesda, MD 20892. Phone: 301-435-4710; Fax: 301-402-1819. E-mail: huangw{at}mail.nih.gov

Tobacco and alcohol consumption are the major risk factors for head and neck cancer, likely due to DNA-damaging processes. Genetic variations in DNA repair genes may affect an individual's susceptibility to head and neck cancer. Pooling data and DNA specimens from three case-control studies in western Washington State, North Carolina, and Puerto Rico, totaling 555 cases (430 whites) and 792 controls (695 whites), we studied the risk of head and neck cancer in relation to common nonsynonymous single-nucleotide polymorphisms in four DNA repair genes: MGMT (Leu₈₄Phe and Ile₁₄₃Val), XRCC1 (Arg₃₉₉Gln), XPD (Lys₇₅₁Gln), and XRCC3 (Thr₂₄₁Met). All single-nucleotide polymorphisms were assayed in a single laboratory. Among whites, carriage of the MGMT Phe₈₄ [odds ratio (OR), 0.71; 95% confidence interval (95% CI), 0.51-0.98] or Val₁₄₃ (OR, 0.66; 95% CI, 0.47-0.92) allele was associated with a decreased risk of head and neck cancer; the haplotype distribution for MGMT differed significantly between cases and controls (covariate-adjusted global permutation test, P = 0.012). The XRCC1 GlnGln₃₉₉ genotype was also associated with decreased risk among whites (OR, 0.56; 95% CI, 0.32-0.94), whereas XPD₇₅₁ and XRCC3₂₄₁ were not associated with risk. Alcohol-related risks tended to vary with DNA repair genotypes, especially for MGMT variants, whereas no effect modification was noted with tobacco use. Consistent findings from three case-control studies suggest that selected DNA repair enzymes may play a role in head and neck carcinogenesis.

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