Tumor-specific methylation in bronchial lavage for the early detection of non-small-cell lung cancer.
OBJECTIVE
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.


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 beta (RARbeta) 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 RARbeta, 3% for H-cadherin, 4% for RASSF1A, and 28% for FHIT. Hypermethylation of the p16, RARbeta, 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, RARbeta, H-cadherin, and RASSF1A genes.


CONCLUSIONS
Our study suggests that tumor-specific methylation of the p16, RASSF1A, H-cadherin, and RARbeta 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.
Kim
Hojoong
H
Department of Thoracic Surgery, Sungkyunkwan University, School of Medicine, Seoul, Korea.
Kwon
Young Mi
YM
Kim
Jin Seuk
JS
Lee
Haengbyoung
H
Park
Jung-Ho
JH
Shim
Young Mog
YM
Han
Joungho
J
Park
Joobae
J
Kim
Duk-Hwan
DH
D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000367:Age Factors; D000368:Aged; D014408:Biomarkers, Tumor; D018893:Bronchoalveolar Lavage; D015820:Cadherins / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012907:Smoking; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D014408:Biomarkers, Tumor; D015820:Cadherins; D009363:Neoplasm Proteins; D018168:Receptors, Retinoic Acid; D000099170:Bis(5'-adenosyl)triphosphatase; C099972:H-cadherin; C082925:retinoic acid receptor beta