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. 2011 Apr 12;104(8):1313-8.
doi: 10.1038/bjc.2011.102. Epub 2011 Mar 29.

CpG-island methylation study of liver fluke-related cholangiocarcinoma

R Sriraksa  1 , C Zeller, M A El-Bahrawy, W Dai, J Daduang, P Jearanaikoon, S Chau-In, R Brown, T Limpaiboon
Affiliations

CpG-island methylation study of liver fluke-related cholangiocarcinoma

R Sriraksa et al. Br J Cancer. .

Abstract

Background: Genetic changes have been widely reported in association with cholangiocarcinoma (CCA), while epigenetic changes are poorly characterised. We aimed to further evaluate CpG-island hypermethylation in CCA at candidate loci, which may have potential as diagnostic or prognostic biomarkers.

Methods: We analysed methylation of 26 CpG-islands in 102 liver fluke related-CCA and 29 adjacent normal samples using methylation-specific PCR (MSP). Methylation of interest loci was confirmed using pyrosequencing and/or combined bisulfite restriction analysis, and protein expression by immunohistochemistry.

Results: A number of CpG-islands (OPCML, SFRP1, HIC1, PTEN and DcR1) showed frequency of hypermethylation in >28% of CCA, but not adjacent normal tissues. The results showed that 91% of CCA were methylated in at least one CpG-island. The OPCML was the most frequently methylated locus (72.5%) and was more frequently methylated in less differentiated CCA. Patients with methylated DcR1 had significantly longer overall survival (Median; 41.7 vs 21.7 weeks, P=0.027). Low-protein expression was found in >70% of CCA with methylation of OPCML or DcR1.

Conclusion: Aberrant hypermethylation of certain loci is a common event in liver fluke-related CCA and may potentially contribute to cholangiocarcinogenesis. The OPCML and DcR1 might serve as methylation biomarkers in CCA that can be readily examined by MSP.

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Figures

Figure 1
Figure 1
Methylation profile of 26 CpG-islands in cholangiocarcinoma and adjacent normal samples. Black and grey boxes represent positive and negative methylation by MSP, respectively.
Figure 2
Figure 2
Histogram represented frequency of methylation of 26 CpG-islands in adjacent normal samples (n=29) and cholangiocarcinoma (n=102).
Figure 3
Figure 3
Methylation index (MI) between adjacent normal samples and CCA in which CCA samples showed significantly higher MI than adjacent normal tissues.
Figure 4
Figure 4
The association between methylation of DcR1 and overall survival time of cholangiocarcinoma patients. Patients with methylated DcR1 had longer overall survival time than those without (Kaplan–Meier analysis using log-rank test, P=0.027).
See this image and copyright information in PMC

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