Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles

TLDR

Cholangiocarcinoma is an aggressive bile‑duct malignancy with poor prognosis and limited treatment options. The study aims to integrate TCGA somatic mutation, RNA, copy‑number, and methylation data to propose a molecular classification of intrahepatic cholangiocarcinoma. The authors performed integrated multi‑omic analysis of predominantly intrahepatic CCA cases. They identified an IDH‑mutant‑enriched subtype characterized by low chromatin‑modifier expression, high mitochondrial gene expression and copy number, ARID1A hypermethylation with reduced expression, and broader histological diversity, providing insights into pathogenesis and potential therapeutic targets.

Abstract

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.