Correlation between promoter methylation of p14(ARF), TMS1/ASC, and DAPK, and p53 mutation with prognosis in cholangiocarcinoma

BACKGROUND: To study the methylation status of genes that play a role in the p53-Bax mitochondrial apoptosis pathway and its clinical significance in cholangiocarcinoma. PATIENTS AND METHODS: Out of 36 cases cholangiocarcinoma patients from April 2000 to May 2005 were collected.Promoter hypermethylation of DAPK, p14(ARF), and ASC were detected by methylation-specific PCR on cholangiocarcinoma and normal adjacent tissues samples. Mutation of the p53 gene was examined by automated sequencing. Correlation between methylation of these genes and/or p53 mutation status with clinical characteristics of patients was investigated by statistical analysis. RESULTS: We found 66.7% of 36 cholangiocarcinoma patients had methylation of at least one of the tumor suppressor genes analyzed. p53 gene mutation was found in 22 of 36 patients (61.1%). Combined p53 mutation and DAPK, p14(ARF), and/or ASC methylation was detected in 14 cases (38.9%). There were statistically significant differences in the extent of pathologic biology, differentiation, and invasion between patients with combined p53 mutation and DAPK, p14(ARF), and/or ASC methylation compared to those without (P < 0.05). The survival rate of patients with combined DAPK, p14(ARF), and ASC methylation and p53 mutation was poorer than other patients (P < 0.05). CONCLUSION: Our study indicates that methylation of DAPK, p14(ARF), and ASC in cholangiocarcinoma is a common event. Furthermore, p53 mutation combined with DAPK, p14(ARF), and/or ASC methylation correlates with malignancy and poor prognosis.