Matthew G. Cordes

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.

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.

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.