Characterization of a multiple epigenetic marker panel for lung cancer detection and risk assessment in plasma.
BACKGROUND
Methylation patterns may be useful biomarkers of cancer detection and risk assessment.


METHODS
The methylation status of 6 genes, including a candidate tumor suppressor gene (BLU), the cadherin 13 gene (CDH13), the fragile histidine triad gene (FHIT), the cell cycle control gene p16, the retinoic acid receptor beta gene (RARbeta), and the Ras association domain family 1 gene (RASSF1A), was examined in plasma samples, corresponding tumor tissues, and normal lung tissues from a group of 63 patients with lung cancer and in plasma samples from 36 cancer-free individuals. The detection rate of the p16 gene was validated in a test group of 20 patients with lung cancer.


RESULTS
The concordance of methylation in tumor tissues and plasma samples was 86%, 87%, 80%, 75%, 76%, and 84% for the BLU, CDH13, FHIT, p16, RARbeta, and RASSF1A genes, respectively. The test group showed a similar concordance for p16 methylation detection. Multiple logistic regression analysis showed that the odds ratio for having lung cancer was 10.204 for individuals with p16 methylation (P = .013) and 9.952 for individuals with RASSFIA methylation (P = .019). After several trial tests, the authors established that methylation for >/=2 of the 6 markers met the criterion for an elevated risk of cancer. Comparisons yielded a sensitivity of 73%, a specificity of 82%, and a concordance of 75% between the methylation patterns in tumor tissues and in corresponding plasma samples. The detection rate was relatively high in cigarette smokers with advanced squamous cell lung cancer.


CONCLUSIONS
The current results indicated that multiple epigenetic markers in the plasma, especially the p16 and RASSF1A genes, can be used for lung cancer detection. This methylation marker panel should improve the detection of cancer or the risk assessment for lung cancer in combination with conventional diagnostic tools.
Hsu
Han-Shui
HS
Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
Chen
Tsz-Pei
TP
Hung
Chein-Hui
CH
Wen
Chiao-Kai
CK
Lin
Rou-Kai
RK
Lee
Hui-Chen
HC
Wang
Yi-Ching
YC
D017766:Acid Anhydride Hydrolases / Q000235:genetics; D014408:Biomarkers, Tumor / Q000032:analysis*; D015820:Cadherins / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D003598:Cytoskeletal Proteins; D019175:DNA Methylation; D017931:DNA Primers; D044127:Epigenesis, Genetic; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics; D015203:Reproducibility of Results; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012907:Smoking / Q000009:adverse effects; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D014408:Biomarkers, Tumor; D015820:Cadherins; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D009363:Neoplasm Proteins; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; D000099170:Bis(5'-adenosyl)triphosphatase; C099972:H-cadherin; C411762:RASSF1 protein, human; C472720:ZMYND10 protein, human; C082925:retinoic acid receptor beta