Maria Consiglia Bragazzi

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.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

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.