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

Our plain-English summary of Promoter methylation of DAP-kinase: association with advanced stage in non-small cell lung cancer, by D.H. Kim, H.H. Nelson, J.K. Wiencke, et al (Oncogene, 2001).

The study

• Authors: D.H. Kim, H.H. Nelson, J.K. Wiencke, D.C. Christiani, J.C. Wain, E.J. Mark, K.T. Kelsey
• Journal: Oncogene
• Published: 2001;20(14):1765-70
• Cited by: 120 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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-gamma. 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.

In plain English

This study examined tumors from 185 non-small cell lung cancer patients who had surgery at Massachusetts General Hospital between June 1992 and December 1996. The authors tested the tumors for promoter methylation of the DAP-kinase gene, which helps trigger cell death; this chemical change may switch a gene off. They also tested whether methylation was linked to smoking, to occupational asbestos exposure reported on a questionnaire (no fiber type stated), or to features of the cancer. Methylation was found in 47 of 185 tumors (25%). It was not associated with smoking measures or with asbestos exposure. Among asbestos-exposed patients, 3 tumors were methylated and 19 were not (P=0.20). Methylation was more common in more advanced cancers. Compared with stage I, adjusted odds ratios were 2.70 (95% CI 1.13 to 6.45) for stage II, 3.11 (1.37 to 7.08) for stage III and 7.77 (1.21 to 50.03) for stage IV. Among stage I patients, survival did not differ significantly by methylation status. The authors concluded that this methylation is not associated with tobacco or asbestos exposure but may be important in lung cancer progression. They noted that the survival analysis was limited by few patients and short follow-up.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Molecular epidemiology study of surgically removed tumor tissue, with questionnaire data on exposures and statistical comparison of tumors with and without DAP-kinase promoter methylation
• Who was studied: 185 patients with non-small cell lung cancer who had surgical resection at Massachusetts General Hospital, June 1992 through December 1996; more than 90% lived in Eastern Massachusetts
• Exposure: Smoking (duration, years since last smoked, pack-years) and occupational asbestos exposure assessed by a validated questionnaire. Patients reporting only environmental exposures, such as changing brake shoes or home maintenance of pipes, furnaces or shingles, were not counted as exposed. No fiber type was specified. The study also examined k-ras codon 12 and p53 mutations.
• Main results:
  • DAP-kinase promoter methylation was detected in 47 of 185 tumors (25%)
  • Occupational asbestos exposure was not associated with methylation. Among exposed patients, 19 tumors were unmethylated and 3 were methylated. Among unexposed patients, 116 were unmethylated and 43 were methylated (P=0.20). Asbestos data were missing for four patients.
  • The smoking variables (duration of smoking, years since last smoked, pack-years) were not associated with methylation
  • Methylation was more frequent in advanced-stage disease (P=0.003). It was also associated with tumor size (P=0.009) and lymph node involvement (P=0.04). For distant metastasis the P-value was 0.10.
  • Adjusted for age, sex and histology, the odds ratios for methylation compared with stage I were 2.70 (95% CI 1.13 to 6.45) for stage II, 3.11 (1.37 to 7.08) for stage III and 7.77 (1.21 to 50.03) for stage IV
  • Methylation was not associated with k-ras codon 12 mutation or with p53 mutation (exons 5 to 9)
  • In stage I patients, methylation was not significantly associated with overall survival. Median survival was approximately 61 months with methylated tumors and 91 months with unmethylated tumors.
• The authors' conclusion: The authors concluded that DAP-kinase methylation increased with stage but was not associated with tobacco carcinogen exposure, asbestos exposure, histology or gender. They concluded that DAP-kinase may be important in the progression of non-small cell lung cancer from early to late stage disease.
• Limitations the authors state:
  • The survival analysis was limited by the number of patients and the relatively short follow-up
  • The lack of significance in the histology-stratified p53 comparison may reflect small sample size
  • Other ways the gene could be inactivated (deletion, point mutation, rearrangement) were not studied

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Non-Small Cell Lung Cancer, Apoptosis, Metastasis, Asbestos Exposure, Surgical Resection, Histology, Odds Ratio, Overall Survival.

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