Epigenetic DNA hypermethylation in cholangiocarcinoma: potential roles in pathogenesis, diagnosis and identification of treatment targets

Abstract

Cholangiocarcinomas (CCs) are highly lethal malignant tumours arising from the biliary tract epithelium. The disease is notoriously difficult to diagnose and is usually fatal because of its typically late clinical presentation and the lack of effective non-surgical therapeutic modalities. The overall survival rate, including resected patients is poor, with less than 5% of patients surviving 5 years, a rate which has not changed significantly over the past 30 years. Although CC is a relatively uncommon tumor, interest in this disease is rising as incidence and mortality rates for intrahepatic cholangiocarcinoma are increasing markedly worldwide. A variety of risk factors, including primary sclerosing cholangitis, liver fluke infestation, and hepatolithiasis have been described. However, for most CCs the cause is unknown, and affected individuals have no history of exposure to, or association with, known risk factors. Recent advances in molecular pathogenesis have highlighted the importance of epigenetic alterations in the form of promoter region hypermethylation and histone deacetylation in addition to genetic changes in the process of cholangiocarcinogenesis. This review provides a comprehensive overview of the genes reported to be methylated in CC to date and their putative roles in cholangiocarcinogenesis. Future directions in the study of methylated genes and their potential roles as diagnostic and prognostic markers are also discussed.

Fig. 1

Anatomic classification of cholangiocarcinoma (CC). CCs are classified as intrahepatic, hilar or extrahepatic based on their anatomical location.

Fig. 2

Proposed aetiopathogenetic mechanism of cholangiocarcinogenesis showing interactions between aetiological agents and cholangiocyte response to injury.

Fig. 3

Promoter region hypermethylation inhibits transcription factor–DNA interactions. In a normal cell, transcription factors interact with the promoter region of a gene and initiate, enhance or repress gene transcription. Hypermethylation of CpG islands in the promoter region inhibits the interaction between transcription factors and promoter DNA, typically leading to inhibition of gene transcription.

Fig. 4

Genes reported to be methylated in cholangiocarcinoma with their respective potential functions in tumour initiation and progression.