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.


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).


CONCLUSIONS
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.
Department of Hepatobiliary Surgery, Affiliated Yantai Yuhuangding Hospital, Qingdao University Medical College, Yantai 264000, China. Liu634@263.net
Liu
L
Xiaofang
Tang
T
Kun
Yu
Y
Shaoping
Wang
W
Zaiqiu
Su
S
Hailong
D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000401:mortality; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics*; D053468:CARD Signaling Adaptor Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000401:mortality; D003598:Cytoskeletal Proteins / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D064550:Death-Associated Protein Kinases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015996:Survival Rate; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; C402202:PYCARD protein, human; C495901:TP53 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases