Aberrant promoter methylation of multiple genes in bronchial brush samples from former cigarette smokers.
Promoter hypermethylation plays an important role in the inactivation of tumor suppressor genes during tumorigenesis. Recent data suggest that such epigenetic abnormality may occur very early in lung carcinogenesis. To determine the extent of promoter hypermethylation in early lung tumorigenesis, we analyzed promoter methylation status of the p16, death-associated protein kinase (DAPK) and glutathione S-transferase P1 (GSTP1) genes using methylation-specific PCR in bronchial brush samples obtained from 100 former smokers enrolled in a chemoprevention clinical trial. We found that 17% of the samples showed methylation for p16 and 17% the same for DAPK, whereas only 6% of the samples displayed methylation for GSTP1. A total of 32% of the samples had methylation in at least one of the three genes tested, and 8% of the samples had methylation in two genes. The methylation status of p16 was correlated with that of DAPK (P = 0.04, Fisher's exact test). p16 methylation was higher in former smokers with a history of previous cancer than in former smokers without a history of cancer (P = 0.04, Fisher's exact test), and methylation of DAPK was detected more frequently in older patients than it was in younger patients (P = 0.01, Wilcoxon rank-sum test). Surprisingly, no correlation was found between methylation in any of these genes and the smoking characteristics of the individuals analyzed (packs per day, pack-years, smoking years, quitting years). The precise meaning of methylated genes in the bronchial brush samples of former smokers must be sought by means of careful follow-up of these individuals.
Soria
Jean-Charles
JC
Molecular Biology Laboratory, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Rodriguez
Marivonne
M
Liu
Diane D
DD
Lee
J Jack
JJ
Hong
Waun Ki
WK
Mao
Li
L
D000328:Adult; D000367:Age Factors; D000368:Aged; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000235:genetics; D001980:Bronchi / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D005260:Female; D019942:Genes, p16 / Q000502:physiology*; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics*; D008297:Male; D008871:Microvilli / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012907:Smoking / Q000009:adverse effects / Q000235:genetics*; D016540:Smoking Cessation
D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D007527:Isoenzymes; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases