Clinical significance of DAPK promoter hypermethylation in lung cancer: a meta-analysis

Abstract

Death-associated protein kinase 1 (DAPK) is an important serine/threonine kinase involved in various cellular processes, including apoptosis, autophagy, and inflammation. DAPK expression and activity are deregulated in a variety of diseases including cancer. Methylation of the DAPK gene is common in many types of cancer and can lead to loss of DAPK expression. However, the association between DAPK promoter hypermethylation and the clinicopathological significance of lung cancer remains unclear. In this study, we searched the MEDLINE, PubMed, Web of Science, and Scopus databases, systematically investigated the studies of DAPK promoter hypermethylation in lung cancer and quantified the association between DAPK promoter hypermethylation and its clinicopathological significance by meta-analysis. We observed that the frequency of DAPK methylation was significantly higher in lung cancer than in non-malignant lung tissues (odds ratio 6.02, 95% confidence interval 3.17-11.42, P<0.00001). The pooled results also showed the presence of a prognostic impact of DAPK gene methylation in lung cancer patients (odds ratio 3.63, 95% confidence interval 1.09-12.06, P=0.04). In addition, we summarized these findings and discuss tumor suppressor function, clinicopathological significance, and potential drug targeting of DAPK in lung cancer.

Keywords: DAPK; adenocarcinoma; death-associated protein kinase gene; lung; meta-analysis; methylation; non-small cell lung cancer; squamous cell carcinoma.

Figure 1

Flow chart of study selection.

Figure 2

The included studies investigated DAPK methylation status between 733 lung cancer patients and 694 nonmalignant controls with the pooled odds ratio being 6.02 (95% CI 3.17–11.42, Z=5.50, P<0.00001). Abbreviations: CI, confidence interval; M–H, Mantel–Haenszel test.

Figure 3

The included studies investigated DAPK methylation status between 401 tumors of adenocarcinoma and 263 of squamous carcinomas. The combined odds ratio was 0.91 (95% CI 0.64–1.29, Z=0.54, P=0.59). Abbreviations: CI, confidence interval; M–H, Mantel–Haenszel test.

Figure 4

Pooled results of methylation analysis of DAPK gene in different disease stages (TNM I + II versus TNM III + IV) in lung cancer. The pooled odds ratio is 0.95, 95% CI 0.53–1.73, Z=0.16, P=0.88). Abbreviations: CI, confidence interval; M–H, Mantel–Haenszel test; TNM, tumor node metastasis staging system.

Figure 5

All three included studies estimated the relationship between overall survival and DAPK methylation. The pooled hazard ratio for overall survival showed that DAPK hypermethylation was associated with worse survival in lung cancer (hazard ratio 3.63, 95% CI 1.09–12.06, P=0.04). Abbreviations: CI, confidence interval; IV, inverse variance; SE, standard error.

Figure 6

Funnel plot of publication bias in the meta-analysis of DAPK hypermethylation and clinicopathological features. Notes: DAPK methylation in lung cancer (A), subtypes of histology (B), disease stages, TNM I + II versus III + IV (C), and overall survival (D). The x axis indicates the value of OR or HR and the y axis gives the SE multiplied by log scale of OR or HR. Abbreviations: HR, hazard ratio; OR, odds ratio; SE, standard error; TNM, tumor node metastasis staging system.