Hypermethylation of the Death-Associated Protein (DAP) Kinase Promoter and Aggressiveness in Stage I Non-Small-Cell Lung Cancer

Abstract

BACKGROUND: Death-associated protein (DAP) kinase is a serine/threonine kinase that is important in ligand-induced programmed cell death and plays an important role in lung cancer metastasis in animal models. Hypermethylation of the promoter represses the expression of the DAP kinase gene. Our purpose was to determine whether the hypermethylation status of the DAP kinase promoter influences the prognosis of non-small-cell lung cancer (NSCLC). METHODS: We retrospectively studied 135 patients with pathologic stage I NSCLC who had undergone curative surgery. Methylation-specific polymerase chain reaction was used to determine the methylation status of the DAP kinase promoter in resected specimens from patients with primary NSCLC. Statistical analyses, all two-sided, were performed to determine the prognostic effect of methylation status on various clinical parameters. RESULTS: Hypermethylation of the DAP kinase promoter was found in 59 (44%) of the 135 tumors. Patients whose tumors exhibited such hypermethylation had a statistically significantly poorer probability of overall survival at 5 years after surgery than those without such hypermethylation (.46 versus.68; P: =.007). Moreover, the groups with and without hypermethylation of the DAP kinase promoter showed a striking difference in the probability of disease-specific survival; i.e., among people who died of lung cancer-related causes specifically, the probability of 5-year survival was.56 for those with such hypermethylation and.92 for those without it (P:<.001). Multivariate analysis indicated that hypermethylation of the DAP kinase promoter is the only independent predictor for disease-specific survival among clinical and histologic parameters tested. CONCLUSIONS: Hypermethylation of the DAP kinase promoter is a common abnormality in early-stage NSCLC. This abnormality is strongly associated with survival, suggesting that DAP kinase plays an important role in determining the biologic aggressiveness of early-stage NSCLC.