Epigenetics and Cholangiocarcinoma

Cholangiocarcinoma is a malignant tumor occurring at left and right hepatic duct, primary hepatic duct, and common bile duct of pancreas. Progressive obstructive jaundice is the main clinical symptoms of the disease. The disease is characterized by slow growth of the tumor, late distant metastasis, mainly local lymph node metastasis.

Most of the patients do not die from tumor metastasis, but died of various complications caused by biliary obstruction. The incidence rate of bile duct cancer in autopsy is about 0.2%, accounting for 2% of all cancer patients, and accounting for 0.5% of the biliary tract operation. Cholangiocarcinoma mostly occurs between 50-70 years old. 90% of tissue type is adenocarcinoma, and 60% is well differentiated. The current clinical treatment includes operation treatment, radiotherapy, chemotherapy and other methods, but the prognosis is poor.

Since the limited success in the clinical management and a persistent increase in the incidence world-wide, Cholangiocarcinoma has been one of the most lethal and fastest growing malignancies. Researchers are working on the underlying biological traits of ICC and identified new therapeutic opportunities. Genome-wide studies of ICC including genetic profiling, transcriptomics, and epigenomics, are found to bring the new direction for this kind of disease treatment.

According to the epidemiological and experimental evidences, the carcinogenic liver fluke is a major risk factor of Cholangiocarcinoma. Besides, chronic inflammation induced by the infection also makes the biliary epithelium more susceptible to neoplastic transformation. Like other cancers, Cholangiocarcinoma is a result of a multistep and complex process in which genetic and epigenetic aberrations of regulatory genes are accumulated. Of which, genetic alterations of K-ras and p53 have been found in Cholangiocarcinoma.

For epigenetic studies, DNA methylation is a potential rich source of diagnostic, prognostic or predictive biomarkers of clinical outcome, and hypermethylation of tumor suppressor genes related to cell cycle, apoptosis and cell adhesion has been reported in the occurrence and development of Cholangiocarcinoma. For example, the highly frequent methylation of SFRP1, HIC1 and PTEN causes an increase in cell proliferation, inhibition of apoptosis and promotion of survival advantage in Cholangiocarcinoma by increasing Wnt/?-catenin signal transduction, impairing p53-responsive pathway and activating PI3K and its downstream effectors. The use of corresponding drugs targeting these signal pathway may provide more precise treatment.

Studies on the molecular pathogenesis of Cholangiocarcinoma help improving current clinical strategies and patient outcome, and also facilitates the delineation of patient subsets and individualization for precision therapies.