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Hypermethylation of the TSLC1/IGSF4 promoter is associated with tobacco smoking and a poor prognosis in primary nonsmall cell lung carcinoma
Article first published online: 13 MAR 2006
Copyright © 2006 American Cancer Society
Volume 106, Issue 8, pages 1751–1758, 15 April 2006
How to Cite
Kikuchi, S., Yamada, D., Fukami, T., Maruyama, T., Ito, A., Asamura, H., Matsuno, Y., Onizuka, M. and Murakami, Y. (2006), Hypermethylation of the TSLC1/IGSF4 promoter is associated with tobacco smoking and a poor prognosis in primary nonsmall cell lung carcinoma. Cancer, 106: 1751–1758. doi: 10.1002/cncr.21800
- Issue published online: 4 APR 2006
- Article first published online: 13 MAR 2006
- Manuscript Accepted: 7 NOV 2005
- Manuscript Revised: 11 OCT 2005
- Manuscript Received: 1 JUL 2005
- Third-Term Comprehensive Control Research for Cancer from the Ministry of Health, Labor, and Welfare of Japan
- Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Program for the Promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan
- Research Resident Fellowships from the Foundation for the Promotion of Cancer Research of Japan
- promoter methylation;
- TSLC1/IGSF4 gene;
- nonsmall cell lung carcinoma;
- tobacco smoking;
- DAL-1/4.1B gene;
- bisulfite single-strand conformational polymorphism
The tumor suppressor gene TSLC1/IGSF4 on chromosomal region 11q23 is frequently inactivated by promoter methylation in various cancers, including nonsmall cell lung carcinoma (NSCLC). Several studies have demonstrated that the hypermethylation of the CpG islands of genes, including tumor suppressors, is associated with exposure to tobacco smoke. The purpose of this study was to investigate the possible association of TSLC1/IGSF4 methylation with tobacco smoking as well as with the clinical characteristics of tumors using a large number of primary NSCLC.
The promoter methylation of TSLC1/IGSF4 was analyzed in 103 primary NSCLC. TSLC1/IGSF4 expression was examined by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry, whereas its methylation status was determined by bisulfite single-strand conformation polymorphism (SSCP) coupled with bisulfite sequencing.
The TSLC1/IGSF4 promoter was methylated in 45 (44%) of 103 primary NSCLC. Methylation was observed in all histologic subtypes of NSCLC, including adenocarcinoma (29 of 68, 43%), squamous cell carcinoma (14 of 26, 54%), adenosquamous carcinoma (1 of 2, 50%), and large cell carcinoma (1 of 7, 14%). The incidence of methylation in tumors was significantly higher in male patients than in female patients (P = .027). The TSLC1/IGSF4 methylation was preferentially observed in heavy smokers (smoking index ≥ 800) (P = .0054). Furthermore, in smokers the methylation was significantly associated with pack-years smoked (P = .034) and cigarettes per day (P = .021). The TSLC1/IGSF4 methylation was also significantly associated with a shorter disease-free survival (P = .049), providing an independent prognostic factor (P = .038) in adenocarcinoma patients.
TSLC1/IGSF4 methylation is associated with tobacco smoking and could be an indicator of poor prognosis. Cancer 2006. © 2006 American Cancer Society.