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Identification of Epigenetic Aberrant Promoter Methylation in Serum DNA Is Useful for Early Detection of Lung Cancer

¹ Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Medical School, ² Department of Respiratory Medicine, Okayama Institute of Health and Science, ³ Department of Cancer and Thoracic Surgery, Okayama University Graduate of Medicine and Dentistry, Okayama, Japan and ⁴ Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan

Requests for reprints: Masahiro Tabata, Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Phone: 81-86-235-7227; Fax: 81-86-232-8226; E-mail: tabata{at}md.okayama-u.ac.jp.

Purpose: The purpose of this study is to evaluate the usefulness of serum DNA methylation of five tumor suppressor genes for early detection of lung cancer.

Experimental Design: Methylation status in serum DNA from 200 patients undergoing bronchofiberscopic examination for abnormal findings on chest radiograph detected by lung cancer screening or surveillance was examined using methylation-specific PCR.

Results: Ninety-one patients were given a pathologic diagnosis of lung cancer, 9 other malignant diseases, and 100 nonmalignant pulmonary diseases. In patients with lung cancer, methylation was detected in 18.7% for MGMT, 15.4% for p16^INK4a, 12.1% for RASSF1A, 11.0% for DAPK, and 6.6% for RAR-ß, which was higher compared with that in patients with nonmalignant diseases. Age and smoking status seemed to associate with methylation status. Sensitivity, specificity, and predictive value of methylation in at least one gene for diagnosis of lung cancer were 49.5%, 85.0%, and 75.0%, respectively. Adjusted odds ratio (95% confidence interval) for having lung cancer was 5.28 (2.39-11.7) for patients with methylation in one gene and 5.89 (1.53-22.7) for those with methylation in two or more genes. It is of note that methylation was identified in 50.9% of stage I lung cancer patients, whereas serum protein tumor markers were positive in 11.3% of them.

Conclusions: These results suggest that identification of promoter methylation of tumor suppressor genes in serum DNA could be useful for early detection of lung cancer.

Key Words: Cancer surveillance and screening • chest radiograph • serum protein tumor markers • methylation-specific PCR

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