Transcriptome and DNA methylation analysis reveals molecular mechanisms underlying intrahepatic cholangiocarcinoma progression.

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive malignancy with increasing incidence. It has been suggested that DNA methylation drives cancer development. However, the molecular mechanisms underlying iCCA progression and the roles of DNA methylation still remain elusive. In this study, weighted correlation networks were constructed to identify gene modules and hub genes associated with the tumour stage. We identified 12 gene modules, two of which were significantly positively or negatively related to the tumour stage， respectively. Key hub genes SLC2A1, CDH3 and EFHD2 showed increased expression across the tumour stage and were correlated with poor survival, whereas decrease of FAM171A1, ONECUT1 and PHYHIPL was correlated with better survival. Pathway analysis revealed hedgehog pathway was activated in CDH3 up-regulated tumours, and chromosome separation was elevated in tumours expressing high EFHD2. JAK-STAT pathway was overrepresented in ONECUT1 down-regulated tumours, whereas Rho GTPases-formins signalling was activated in PHYHIPL down-regulated tumours. Finally, significant negative associations between expression of EFHD2, PHYHIPL and promoter DNA methylation were detected, and alterations of DNA methylation were correlated with tumour survival. In summary, we identified key genes and pathways that may participate in progression of iCCA and proposed putative roles of DNA methylation in iCCA.