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

Cholangiocarcinoma (CCA) is an aggressive malignancy\nof the bile ducts, with poor prognosis and\nlimited treatment options. Here, we describe the\nintegrated analysis of somatic mutations, RNA\nexpression, copy number, and DNA methylation\nby The Cancer Genome Atlas of a set of predominantly\nintrahepatic CCA cases and propose a molecular\nclassification scheme. We identified an IDH\nmutant-enriched subtype with distinct molecular\nfeatures including low expression of chromatin\nmodifiers, elevated expression of mitochondrial\ngenes, and increased mitochondrial DNA copy\nnumber. Leveraging the multi-platform data, we\nobserved that ARID1A exhibited DNA hypermethylation\nand decreased expression in the IDH mutant\nsubtype. More broadly, we found that IDH mutations\nare associated with an expanded histological\nspectrum of liver tumors with molecular features\nthat stratify with CCA. Our studies reveal insights\ninto the molecular pathogenesis and heterogeneity\nof cholangiocarcinoma and provide classification\ninformation of potential therapeutic significance.