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Molecular Biology and Genetics |
Departments of Environmental Health [D-H.K., D.C.C.] and Cancer Cell Biology [H.H.N., K.T.K.], Harvard School of Public Health, Boston, Massachusetts 02115; Laboratory for Molecular Epidemiology, Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, San Francisco, California 94143 [J.K.W., S.Z.]; and Pulmonary and Critical Care Unit, Departments of Medicine [D.C.C.], Surgery, Thoracic Surgery Unit [J.C.W.], and Pathology [E.J.M.], Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114
The p16INK4a protein inhibits cyclin-dependent kinase 4, a key regulator of progression through the G1 phase of the cell cycle. Methylation of CpG islands in the promoter region is an important avenue for inactivation of p16. The mechanism of methylation of the p16 promoter region, however, has not been elucidated. Recent reports investigating p16 methylation in non-small cell lung cancer (NSCLC) suggest that carcinogens in tobacco smoke induce the DNA methylation process. We investigated the association between methylation of the p16 promoter region and exposure to tobacco smoke in 185 primary NSCLCs. We also studied the relationship of p16 methylation with mutation of the K-ras and p53 genes, as well as with methylation at the DAP-kinase and p14ARF loci. Finally, we evaluated the prognostic significance of p16 methylation in NSCLC. The prevalence of p16 methylation was greater in squamous cell carcinoma (41%) compared with adenocarcinoma (22%; P = 0.03; Fisher’s exact test). Methylation of p16 was significantly associated with pack-years smoked (P = 0.007; Wilcoxon rank sum test), duration of smoking (P = 0.0009; Wilcoxon rank sum test), and negatively with the time since quitting smoking (P = 0.03; Wilcoxon rank sum test). No methylation of the nearby p14ARF locus was detected, and methylation of the DAP-kinase locus was not associated with either p16 methylation or with exposure to tobacco smoke. In patients with stage 1 adenocarcinoma, p16 methylation was an independent risk factor predicting significantly shorter postsurgery survival (P = 0.03), controlling for the significant effects of other factors, including K-ras mutation. These findings suggest that methylation of CpG islands in tobacco-associated cancers occurs in a gene- and tissue-specific manner and is induced directly or indirectly by exposure to tobacco smoke in NSCLC.
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J.-C. Soria, M. Rodriguez, D. D. Liu, J. J. Lee, W. Ki Hong, and L. Mao Aberrant Promoter Methylation of Multiple Genes in Bronchial Brush Samples from Former Cigarette Smokers Cancer Res., January 1, 2002; 62(2): 351 - 355. [Abstract] [Full Text] [PDF]
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