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Glutathione S-Transferase P1 and NADPH Quinone Oxidoreductase Polymorphisms Are Associated with Aberrant Promoter Methylation of P16^INK4a and O⁶-Methylguanine-DNA Methyltransferase in Sputum¹

Keck School of Medicine, Department of Preventive Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90089-9021 [F. D. G., Y-F. L.]; University of New Mexico School of Medicine [H. J. H.], and Division of Pulmonary, Critical Care and Allergy [R. E. C.], University of New Mexico, Albuquerque, New Mexico 87106; Pulmonary and Critical Care, New Mexico Veterans Healthcare System, Albuquerque, New Mexico 87108-5153 [R. E. C.]; and Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 [R. W., S. A. B.]

Inactivation of the p16^INK4a tumor suppressor gene and O⁶-methylguanine-DNAmethyltransferase (MGMT) DNA repair gene by aberrant promotermethylation appears to be an important step in respiratory carcinogenesis after exposure to tobacco smoke and radon progeny. The determinants of aberrant promoter methylation are not well characterized. Polymorphic variants of genes of which the products are involved in pathways that modulate and repair DNA damage after carcinogen exposure may affect the occurrence of de novo promoter methylation. On the basis of their associations with risk of lung cancer, we hypothesized that functional polymorphic variants of the NADPH quinone oxidoreductase, glutathione S-transferases P1 and M1, myeloperoxidase, and XRCC1 genes are associated with p16 and/or MGMT promoter methylation in sputum from cancer-free subjects at high risk for developing lung cancer. This hypothesis was tested by conducting a cross-sectional study of 70 former uranium miners from the Uranium Epidemiological Study cohort who were at high risk for lung cancer. The polymorphic variant genotypes were characterized through PCR-RFLP on DNA isolated from peripheral lymphocytes, and the methylation status of the p16 and MGMT promoters was determined by methylation-specific PCR on DNA isolated from sputum. Subjects who had at least one GSTP1 polymorphic allele (A-to-G at bp 104) had an increased risk for MGMT methylation [odds ratio (OR), 4.8; 95% confidence interval (CI), 1.2–18.6] or for either p16 or MGMT methylation (OR, 4.4; 95% CI, 1.3–14.2). Lack of a wild-type NADPH quinone oxidoreductase allele (C at bp 609) was also associated with methylation of either p16 or MGMT (OR, 3.1; 95% CI, 1.0–9.2). These results provide the first link between germ-line functional deficits in pathways that protect the cell from tobacco- and radon-induced DNA damage, and the development of aberrant promoter methylation of the p16 and MGMT genes in the respiratory epithelium of individuals at high risk for lung cancer.

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