Frequent death-associated protein-kinase promoter hypermethylation in brain metastases of solid tumors

Abstract

Death-associated protein (DAP) kinase is a gene that participates in apoptosis induced by interferon gamma. It appears to play a role in lung cancer metastasis in animal models, suggesting that DAP-kinase may function as a metastasis suppressor by inducing apoptosis. Expression silencing through CpG island methylation of DAP-kinase has been frequently found in connection with adverse survival, as cells lacking DAP-kinase appear to be more invasive and more metastatic in lung cancer. The purpose of this study was to analyze the promoter methylation status of DAP-kinase gene in brain metastases of solid tumors. Methylation-specific PCR was performed on ten brain metastasis samples derived from malignant melanoma (three cases), lung cancer (two), breast carcinoma (two), ovarian carcinoma (two) and colon carcinoma (one case), and in corresponding peripheral blood DNA samples. Two normal brain tissue samples were also analyzed, no promoter hypermethylation was observed in either case. DAP-kinase hypermethylated alleles were identified in nine metastases (90%), and in peripheral blood lymphocytes DNA from four cases. Our data suggest that silencing of DAP-kinase through promoter hypermethylation is a common event in the multistep process of tumor metastasis, including brain involvement.