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1.
Cancer Res ; 62(8): 2248-52, 2002 Apr 15.
Article in English | MEDLINE | ID: mdl-11956078

ABSTRACT

Inactivation of the p16(INK4a) tumor suppressor gene and O(6)-methylguanine-DNA methyltransferase (MGMT) DNA repair gene by aberrant promoter methylation 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.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p16/genetics , DNA Methylation , Glutathione Transferase/genetics , Isoenzymes/genetics , Lung Neoplasms/genetics , NAD(P)H Dehydrogenase (Quinone)/genetics , O(6)-Methylguanine-DNA Methyltransferase/genetics , Occupational Diseases/genetics , Sputum/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , DNA-Binding Proteins/genetics , Genes, p16 , Glutathione S-Transferase pi , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/etiology , Mining , NAD(P)H Dehydrogenase (Quinone)/metabolism , O(6)-Methylguanine-DNA Methyltransferase/metabolism , Occupational Diseases/enzymology , Occupational Diseases/etiology , Polymorphism, Genetic , Promoter Regions, Genetic , Sputum/enzymology , X-ray Repair Cross Complementing Protein 1
2.
Cancer Res ; 62(8): 2370-7, 2002 Apr 15.
Article in English | MEDLINE | ID: mdl-11956099

ABSTRACT

Recent studies from our laboratory suggest that gene-specific methylation changes in sputum could be good intermediate markers for the early detection of lung cancer and defining the efficacy of chemopreventive interventions. The purpose of our study was to determine the prevalence for aberrant promoter methylation of the p16, O(6)-methylguanine-DNA methyltransferase (MGMT), death-associated protein (DAP) kinase, and Ras effector homologue (RASSFIA) genes in nonmalignant bronchial epithelial cells from current and former smokers in a hospital-based, case control study of lung cancer. The relationship between loss of heterozygosity, at 9p and p16 methylation in bronchial epithelium and the prevalence for methylation of these four genes in sputum from cancer-free, current and former smokers were also determined. Aberrant promoter methylation of p16 was seen in at least one bronchial epithelial site from 44% of cases and controls. Methylation of the DAP kinase gene was seen in only 1 site from 5 cases and 4 controls, whereas methylation of the RASSFIA was not detected in the bronchial epithelium. Promoter methylation for p16 and DAP kinase was seen as frequently in bronchial epithelium from current smokers as from former smokers. No promoter methylation of these genes was detected in bronchial epithelium from never-smokers. Methylation of the p16 gene was detected in sputum from 23 of 66 controls. DAP kinase gene promoter methylation was also seen in sputum from 16 controls, and 8 of these subjects were positive for p16 methylation. Methylation of the MGMT gene was seen in sputum from 9 controls, whereas RASSFIA promoter methylation was only seen in 2 controls. The correlation between p16 status in the bronchial epithelium obtained from lung lobes that did not contain the primary tumor and the tumor itself was examined. Seventeen of 18 tumors (94%) showed an absolute concordance, being either methylated in the tumor and at least 1 bronchial epithelial site, or unmethylated in both tumor and bronchial epithelium. These results indicate that aberrant promoter hypermethylation of the p16 gene, and to a lesser extent, DAP kinase, occurs frequently in the bronchial epithelium of lung cancer cases and cancer-free controls and persists after smoking cessation. The strong association seen between p16 methylation in the bronchial epithelium and corresponding primary tumor substantiates that inactivation of this gene, although not transforming by itself, is likely permissive for the acquisition of additional genetic and epigenetic changes leading to lung cancer.


Subject(s)
Bronchi/physiology , DNA Methylation , Genes, Tumor Suppressor , Lung Neoplasms/genetics , Promoter Regions, Genetic , Smoking/genetics , Sputum/metabolism , Tumor Suppressor Proteins , Adult , Aged , Aged, 80 and over , Apoptosis Regulatory Proteins , Bronchi/metabolism , Bronchi/ultrastructure , Calcium-Calmodulin-Dependent Protein Kinases/genetics , Case-Control Studies , Cells, Cultured , Chromosomes, Human, Pair 9 , Death-Associated Protein Kinases , Epithelial Cells/metabolism , Epithelial Cells/physiology , Epithelial Cells/ultrastructure , Female , Genes, p16/physiology , Humans , Loss of Heterozygosity , Lung Neoplasms/etiology , Lung Neoplasms/metabolism , Male , Middle Aged , Neoplasm Proteins/genetics , O(6)-Methylguanine-DNA Methyltransferase/genetics , Smoking/adverse effects , Smoking/metabolism , Sputum/cytology
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