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Differential DNA Hypermethylation of Critical Genes Mediates the Stage-Specific Tobacco Smoke-Induced Neoplastic Progression of Lung Cancer

Authors' Affiliations: Departments of ¹ Medicine (Genetics Program and Cancer Research Center), ² Genetics and Genomics, and ³ Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts and ⁴ Department of Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Research Division, Johns Hopkins Medical Institutions, Baltimore, Maryland

Requests for reprints: Sam Thiagalingam, Genetics Program, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118. Phone: 617-638-6013; Fax: 617-638-4275; E-mail: samthia{at}bu.edu.

Promoter DNA methylation status of six genes in samples derived from 27 bronchial epithelial cells and matching blood samples from 22 former/current smokers and five nonsmokers as well as 49 primary non–small cell lung cancer samples with corresponding blood controls was determined using methylation-specific PCR (MSP). Lung tumor tissues showed a significantly higher frequency of promoter DNA methylation in p16, MGMT, and DAPK (P < 0.05; Fisher's exact test). p16 promoter DNA methylation in tumors was observed at consistently higher levels when compared with all the other samples analyzed (P = 0.001; Fisher's exact test). ECAD and DAPK exhibited statistically insignificant differences in their levels of DNA methylation among the tumors and bronchial epithelial cells from the smokers. Interestingly, similar levels of methylation were observed in bronchial epithelial cells and corresponding blood from smokers for all four genes (ECAD, p16, MGMT, and DAPK) that showed smoking/lung cancer–associated methylation changes. In summary, our data suggest that targeted DNA methylation silencing of ECAD and DAPK occurs in the early stages and that of p16 and MGMT in the later stages of lung cancer progression. We also provide preliminary evidence that peripheral lymphocytes could potentially be used as a surrogate for bronchial epithelial cells to detect altered DNA methylation in smokers.

Key Words: DNA Methylation • MSP • tobacco smoke • lung cancer • blood lymphocytes • diagnostic markers

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