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Promoter methylation of DAP-kinase: association with advanced stage in non-small cell lung cancer

Oncogene volume 20, pages 1765–1770 (2001)Cite this article

Abstract

Death associated protein (DAP)-kinase is a 16 kDa calmodulin-dependent serine/threonine kinase that carries a death domain at its C-terminus. DAP-kinase functions as a positive mediator of apoptosis that is induced by interferon-γ. Recent studies suggest that DAP-kinase is involved in tumor metastasis and that it can be inactivated by methylation of CpG islands in the promoter region of the gene in some human tumors. However, little is known about the factors that are associated with the occurrence of DAP-kinase promoter methylation. We investigated both the possible associations of tobacco carcinogen and asbestos exposure with DAP-kinase promoter methylation, and the demographic and clinical factors associated with DAP-kinase promoter methylation in non-small cell lung cancer (NSCLC). One hundred and eighty-five patients diagnosed with NSCLC undergoing surgical resection from June, 1992 through December, 1996 at Massachusetts General Hospital participated in this study. Methylation-Specific PCR (MSP), performed using fresh-frozen tissue, was used to determine the methylation status of the promoter region of the DAP-kinase gene. Forty-seven (25%) of 185 tumors showed DAP-kinase promoter methylation. There was a significant association between methylation and an advanced pathologic stage (P=0.003, Fisher's exact test). Methylation of the DAP-kinase promoter was also associated with an increase in tumor size (P=0.009, Fisher's exact test) and lymph node involvement (P=0.04). No association was found between promoter methylation of DAP-kinase and k-ras or p53 mutation. In addition there was no association with a history of exposure to tobacco or asbestos. Controlling for age, sex, and histology, the odds ratios describing the association of DAP-kinase hypermethylation with stage were 2.70 (1.13–6.45), 3.11 (1.37–7.08) and 7.77 (1.21–50.03) in stages II, III and IV, respectively. Stage I cases with DAP-kinase promoter methylation had worse overall survival, but with the small sample size and limited follow-up this did not reach statistical significance. Our findings suggest that methylation of the promoter region of the DAP-kinase gene is not associated with exposure to tobacco or asbestos. However, they strongly suggest that DAP-kinase may be important in the progression of non-small cell lung cancer from early to late stage disease.

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Acknowledgements

The authors gratefully acknowledge Dr Joe Brain, Dr David Hunter and Dr Howard Liber for helpful discussion. We also thank Linda Lineback, Lucy-Ann Principe, Marlys Rogers and David Miller. We thank Dr Eric Duell for helping statistical analysis and Drs Ed Azzam and John B Little for kindly providing NCI H209 cell line. This work was supported by CA08357 CA74386; ES/CA 06409, CA06717 and ES00002.

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Authors and Affiliations

  1. Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, 02115, Massachusetts, MA, USA

    Duk-Hwan Kim, David C Christiani & Karl T Kelsey

  2. Department of Cancer Cell Biology, Harvard School of Public Health, 665 Huntington Avenue, Boston, 02115, Massachusetts, MA, USA

    Heather H Nelson & Karl T Kelsey

  3. Department of Epidemiology and Biostatistics, Laboratory for Molecular Epidemiology, School of Medicine, University of California, San Francisco, San Francisco, 94143, California, USA

    John K Wiencke

  4. Department of Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, MA, USA

    David C Christiani

  5. Department of Surgery, Thoracic Surgery Unit, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, MA, USA

    John C Wain

  6. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, MA, USA

    Eugene J Mark

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Kim, DH., Nelson, H., Wiencke, J. et al. Promoter methylation of DAP-kinase: association with advanced stage in non-small cell lung cancer. Oncogene 20, 1765–1770 (2001). https://doi.org/10.1038/sj.onc.1204302

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