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Tumor-Specific Methylation in Bronchial Lavage for the Early Detection of Non-Small-Cell Lung Cancer

From the Division of Pulmonary and Critical Care Medicine, Department of Thoracic Surgery, and Department of Pathology, Samsung Medical Center, Sungkyunkwan University, School of Medicine; Center for Genome Research, Samsung Biomedical Research Institute, Seoul; and Department of Molecular Cell Biology, Sungkyunkwan University, School of Medicine, Suwon, Korea

Address reprint requests to Duk-Hwan Kim, MD, Center for Genome Research, Samsung Biomedical Research Institute, Rm B155, #50 Ilwon-dong, Kangnam-Ku, Seoul, Korea, 135-710; e-mail: dukhwan{at}samsung.co.kr

PURPOSE: The aim of this study was to identify tumor-specific methylation in bronchial lavage for the early detection of non-small-cell lung cancer (NSCLC) by differentiating the age-related methylation from the tumor-specific methylation in NSCLC.

PATIENTS AND METHODS: Eighty-five NSCLC patients and 127 cancer-free subjects participated in this study. Aberrant methylation at the promoters of the p16, Ras association domain family 1A (RASSF1A), fragile histidine triad (FHIT), H-cadherin, and retinoic acid receptor ß (RARß) genes were evaluated in the resected tumor tissues and bronchial lavage samples of NSCLC patients and in the bronchial lavage samples of cancer-free subjects by methylation-specific polymerase chain reaction.

RESULTS: Of the 127 cancer-free samples, methylation was detected in 6% for p16, 13% for RARß, 3% for H-cadherin, 4% for RASSF1A, and 28% for FHIT. Hypermethylation of the p16, RARß, H-cadherin, and RASSF1A genes was not associated with patient age and smoking, whereas hypermethylation of the FHIT promoter occurred more frequently in older patients (P = .02) and was associated with exposure to tobacco smoke (P = .001). A strong correlation between age and smoking was found in patients with hypermethylation of the FHIT gene (r = 0.36; P = .03). A total of 68% of the bronchial lavage samples from the 85 NSCLC patients showed methylation of at least one of p16, RARß, H-cadherin, and RASSF1A genes.

CONCLUSION: Our study suggests that tumor-specific methylation of the p16, RASSF1A, H-cadherin, and RARß genes may be a valuable biomarker for the early detection of NSCLC in bronchial lavage, and that the age-related methylation of FHIT gene in the normal bronchial epithelium is related to the exposure to tobacco smoke.

Supported by the Samsung Biomedical Research Institute, Seoul; and Samsung Advanced Institute of Technology, Suwon, Korea.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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