Abstract 2244: Differential DNA methylation analysis of TCGA cholangiocarcinoma data

Abstract

Abstract Cholangiocarcinoma (CCA), also known as bile duct cancer, is a rare malignancy that develops in bile duct, arising from the epithelial cells (cholangiocytes) lining the bile duct. CCA is the second most common type of primary liver cancer, and its incidence has been rising in the Unites States. Most of the patients with CCA are diagnosed at an advanced stage with a median survival of less than 1 year despite administering chemotherapy. In the current study, we analyze the global patterns of DNA methylation in CCA data from TCGA. Pathway and gene ontology (GO) enrichment analysis of differentially methylated genes (DMGs) enabled us to understand how changes in methylation and gene expression affect the biologic pathways involved in the progression of CCA. TCGA level-3 DNA methylation data were downloaded for 485,578 CpG sites with annotations. Further, we normalized β value by using Beta Mixed Integer-quantile normalization (BMIQ) to adjust type I and type II probes. For a CpG site to be considered differentially methylated, the difference in the median β value in primary tumor and normal samples should be at least 0.2 and the BH adjusted p-value should be less than 0.005 and AUC ≥ 0.7. A total of 12,259 differentially methylated (Δβ >) CpG were observed; out of these 9,534 are hypermethylated and 2,725 are hypomethylated. About 4,714 differentially methylated CpGs (dm-CpGs) were observed within 1.5Kb from the TSS of corresponding genes. Chromosome 1 has maximum number of dm-CpGs, while chromosome 18 has lowest number of dm-CpGs. Differential DNA methylation frequency per Mb was also calculated and it was observed that chromosome 17 has the highest differential methylation frequency (9.61 dm-CpGs/Mb) while chromosome 18 has the lowest (1.47 dm-CpG/Mb). KEGG pathway analysis of genes with differentially methylated CpGs (Δβ ≥ 0.2) observed the enrichment of cancer, cell division and differentiation, amino acid metabolism, xenobiotics degradation, and immune response pathways. Hippo signaling pathway also got affected by DNA methylation (FDR 3.70e-18), which also got affected by differential gene expression. Change in DNA methylation and gene expression level of hippo signaling pathway genes plays a vital role in CCA. Citation Format: Nitish K. Mishra, Niu Meng, Chittibabu Guda. Differential DNA methylation analysis of TCGA cholangiocarcinoma data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2244.