Methylation of Dickkopf-3 as a prognostic factor in cirrhosis-related hepatocellular carcinoma.
OBJECTIVE
To investigate the prevalence and time of Dickkopf (DKK) family methylation and its clinical significance in hepatocarcinogenesis.


METHODS
Methylation of DKK family genes was quantitatively analyzed in 115 liver tissue samples, including 50 pairs of primary hepatocellular carcinoma (HCC) and matched noncancerous cirrhotic tissue samples, as well as 15 liver cirrhosis biopsy samples.


RESULTS
The methylation level of DKK3 was significantly higher in HCC tissue samples than in matched noncancerous cirrhotic tissue samples (P < 0.0001) or in liver cirrhosis biopsy samples (P = 0.0139). Receiver operator characteristic curve analysis confirmed that the percent of methylated reference (PMR) values of DKK3 could effectively discriminate HCC tissue samples from noncancerous tissue samples (AUC = 0.8146) or liver cirrhosis biopsy samples (AUC = 0.7093). Kaplan-Meier survival curves revealed that the progression-free survival time of patients with a higher DKK3 methylation level (PMR > 1%) was significantly shorter than that of those with a lower DKK3 methylation level (PMR < or = 1%) (P = 0.0255). Multivariate Cox analysis indicated that methylated DKK3 was significantly and independently related with a shorter survival time (relative risk = 2.527, 95% CI: 1.063-6.008, P = 0.036) of HCC patients.


CONCLUSIONS
Methylation of DKK3 is an important event in early malignant transformation and HCC progression, and therefore might be a prognostic indicator for risk assessment of HCC.
Key Laboratory of Artificial Cells, Third Central Hospital, Tianjin 300170, China.
Bin
B
Yang
Zhi
Z
Du
Ying-Tang
YT
Gao
Cheng
C
Lou
Shi-Guang
SG
Zhang
Tong
T
Bai
Yi-Jun
YJ
Wang
Wen-Qin
WQ
Song
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism*; D018925:Chemokines; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications*; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism*; D008297:Male; D008745:Methylation; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D012372:ROC Curve; D012189:Retrospective Studies; D018570:Risk Assessment
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins