Carcinogenesis Advance Access published online on July 16, 2008
Carcinogenesis, doi:10.1093/carcin/bgn169
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Aberrant promoter hypermethylation in serum DNA from patients with silicosis
1 Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
2 Department of Respiratory, Okayama Rosai Hospital, Okayama, Japan
3 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
4 Department of Respiratory Medicine, Okayama Medical Center, Okayama, Japan
5 Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan
6 Department of Medical Oncology, NHO Sanyo Hospital, Ube, Japan
7 Department of Internal Medicine, Okayama Rosai Hospital, Okayama, Japan
* Address correspondence to: Nobukazu Fujimoto, M.D., Ph.D., Department of Respiratory Medicine, Okayama Rosai Hospital, 1-10-25 Chikkomidorimachi, Okayama 702-8055, Japan., Tel: +81-86-2620131; Fax: +81-86-2623391; E-mail: nfuji{at}okayamaH.rofuku.go.jp
It is well established that patients with silicosis are at high risk for lung cancer, however, it is difficult to detect lung cancer by chest radiography during follow-up treatment of patients with silicosis because of pre-existing diffuse pulmonary shadows. The purpose of this study is to evaluate the usefulness of detection of serum DNA methylation for early detection of lung cancer in silicosis. Serum samples from healthy controls (n = 20), and silicosis patients with (n = 11) and without (n = 67) lung cancer were tested for aberrant hypermethylation at the promoters of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT), p16INK4a, ras association domain family 1A (RASSF1A), the apoptosis-related gene death-associated protein kinase (DAPK), and retinoic acid receptor β (RARβ) by methylation-specific PCR. Aberrant promoter methylation in at least one of five tumor suppressor genes was detected more frequently in the serum DNA of silicosis patients with lung cancer than in that of patients without it (P = 0.006). Furthermore, the odds ratio of having lung cancer was 9.77 (P = 0.009) for those silicosis patients with methylation of at least one gene. Extended exposure to silica (>30 years) was correlated with an increased methylation frequency (P = 0.017); however, methylation status did not correlate with age, smoking history, or radiographic findings of silicosis. These results suggest that testing for aberrant promoter methylation of tumor suppressor genes using serum DNA may facilitate early detection of lung cancer in patients with silicosis.
Key Words: serum DNA • early detection • p16 • DAPK • ras
Received February 6, 2008; revised July 9, 2008; accepted July 10, 2008.