Abstract

BackgroundCholangiocarcinoma (CCA) is a rare disease, but it is amongst the most lethal cancers with a median survival under 1 year. Variations in DNA methylation and gene expression have been extensively studied in other cancers for their role in pathogenesis and disease prognosis, but these studies are very limited in CCA. This study focusses on the identification of DNA methylation and gene expression prognostic biomarkers using multi-omics data of CCA tumors from The Cancer Genome Atlas (TCGA).MethodWe have conducted a genome-wide analysis of differential DNA methylation and gene/miRNA expression using data from 36 CCA tumor and 9 normal samples from TCGA. The impact of DNA methylation in promoters and long-range distal enhancers on the regulation and expression of CCA-associated genes was examined using linear regression. Next, we conducted network analyses on genes which are regulated by DNA methylation as well as by miRNA. Finally, we performed Kaplan–Meier and Cox proportional hazards regression analyses in order to identify the role of selected methylation sites and specific genes and miRNAs in patient survival. We also performed real-time quantitative PCR (qPCR) to confirm the change in gene expression in CCA patients’ tumor and adjacent normal samples.ResultsAltered DNA methylation was observed on 12,259 CpGs across all chromosomes, of which 78% were hypermethylated. We observed a strong negative relationship between promoter hypermethylation and corresponding gene expression in 92% of the CpGs. Differential expression analyses revealed altered expression patterns in 3,305 genes and 101 miRNAs. Finally, we identified 17 differentially methylated promoter CpGs, 72 differentially expressed genes, and two miRNAs that are likely associated with patient survival. Pathway analysis suggested that cell division, bile secretion, amino acid metabolism, PPAR signaling, hippo signaling were highly affected by gene expression and DNA methylation alterations. The qPCR analysis further confirmed that MDK, HNF1B, PACS1, and GLUD1 are differentially expressed in CCA.ConclusionBased on the survival analysis, we conclude that DEPDC1, FUT4, MDK, PACS1, PIWIL4 genes, miR-22, miR-551b microRNAs, and cg27362525 and cg26597242 CpGs can strongly support their use as prognostic markers of CCA.

Highlights

  • Cholangiocarcinoma (CCA), commonly known as the bile duct cancer, induces tumors in epithelial cells that line the bile ducts (Lazaridis and Gores, 2005)

  • We found that Engrailed Homeobox 1 (EN1) gene had the highest number of differentially methylated CpGs (dm-CpGs) (Kramer et al, 2014), where most of them were hypermethylated in the gene body and none in the promoter region

  • DNA methylation analysis of cholangiocarcinoma data shows significant changes in tumor methylomes compared to normal pancreatic tissues

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Summary

Introduction

Cholangiocarcinoma (CCA), commonly known as the bile duct cancer, induces tumors in epithelial cells (cholangiocytes) that line the bile ducts (Lazaridis and Gores, 2005). CCA tumors may originate in the ducts that are inside (intrahepatic) or outside (extrahepatic) the liver. CCA is predominantly extrahepatic with only 10% of the cases having an intrahepatic origin. Cholangiocarcinoma (CCA) is a rare disease, but it is amongst the most lethal cancers with a median survival under 1 year. Variations in DNA methylation and gene expression have been extensively studied in other cancers for their role in pathogenesis and disease prognosis, but these studies are very limited in CCA. This study focusses on the identification of DNA methylation and gene expression prognostic biomarkers using multi-omics data of CCA tumors from The Cancer Genome Atlas (TCGA)

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