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

• Published in: Cell reports (Cambridge) Vol. 18; no. 11; pp. 2780 - 2794
• Main Authors: Gingras, Marie-Claude, Shih, Juliann, Hinoue, Toshinori, Hoadley, Katherine A., Gibb, Ewan A., Covington, Kyle R., Sadeghi, Sara, Pedamallu, Chandra Sekhar, Auman, J. Todd, Andersen, Jesper B., Bardeesy, Nabeel, Berrios, Mario, Bodenheimer, Tom, Boice, Lori, Bootwalla, Moiz S., Bowlby, Reanne, Bragazzi, Maria Consiglia, Cardinale, Vincenzo, Carlsen, Rebecca, Carpino, Guido, Chaiteerakij, Roongruedee, Chandan, Vishal C., Cherniack, Andrew D., Cho, Juok, Chuah, Eric, Chudamani, Sudha, Cordes, Matthew G., Crain, Daniel, Curley, Erin, De Rose, Agostino Maria, Defreitas, Timothy, Demchok, John A., Ferguson, Martin L., Foo, Wai Chin, Franchitto, Antonio, Frazer, Scott, Fulton, Lucinda A., Gardner, Johanna, Gastier-Foster, Julie M., Gehlenborg, Nils, Genovese, Giannicola, Giama, Nasra H., Hegde, Apurva M., Heiman, David I., Holbrook, Andrea, Holt, Robert A., Hoyle, Alan P., Jefferys, Stuart R., Jones, Steven J.M., Kasaian, Katayoon, Kwong, Lawrence N., Lai, Phillip H., Liu, Wenbin, Lolla, Laxmi, Lu, Yiling, Mardis, Elaine R., Matsushita, Marcus M., Mayo, Michael, McLellan, Michael D., Meier, Sam, Mounajjed, Taofic, Naresh, Rashi, Newton, Yulia, Noble, Michael S., Ojesina, Akinyemi I., Parker, Joel S., Patel, Tushar C., Pihl, Todd, Radenbaugh, Amie J., Ramirez, Nilsa C., Reznik, Ed, Robertson, A. Gordon, Saksena, Gordon, Schein, Jacqueline E., Schmidt, Heather K., Shelton, Troy, Shroff, Rachna, Simons, Janae V., Skelly, Tara, Stransky, Nicolas, Tan, Donghui, Thiessen, Nina, Veluvolu, Umadevi, Verhaak, Roel G.W., Wang, Zhining, Weinstein, John N., Wilson, Richard K., Wu, Chia-Chin, Yang, Liming, Zmuda, Erik, Stuart, Josh M., Sander, Chris, Laird, Peter W., Wheeler, David A., Roberts, Lewis R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.03.2017; Elsevier
• Subjects: Adult; Aged; Aged, 80 and over; ARID1A; Bile Duct Neoplasms - enzymology; Bile Duct Neoplasms - genetics; cholangiocarcinoma; Cholangiocarcinoma - enzymology; Cholangiocarcinoma - genetics; Chromatin - metabolism; DNA methylation; DNA Methylation - genetics; Female; Gene Expression Regulation, Neoplastic; Genomics - methods; Humans; IDH; integrative genomics; Isocitrate Dehydrogenase - genetics; Liver - pathology; Liver Neoplasms - genetics; Liver Neoplasms - pathology; lncRNAs; Male; Middle Aged; Mitochondria - metabolism; multi-omics; Mutation - genetics; Nuclear Proteins - genetics; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Promoter Regions, Genetic - genetics; RNA sequencing; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; TCGA; Transcription Factors - genetics; whole exome; RNA sequencing; lncRNAs; integrative genomics; whole exome; multi-omics; DNA methylation; IDH; ARID1A; cholangiocarcinoma; TCGA
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.02.033

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. [Display omitted] •IDH mutant CCAs have distinct mRNA, copy number, and DNA methylation features•IDH mutant CCAs display high mitochondrial and low chromatin modifier gene expression•IDH mutant CCAs methylate the ARID1A promoter and show low ARID1A expression•Other IDH mutant liver cancers show multiplatform similarities to CCA Farshidfar et al. present The Cancer Genome Atlas (TCGA) marker analysis of cholangiocarcinoma. Through multi-platform analyses, they identify a distinct subtype enriched for IDH mutants. This subtype shows increased mitochondrial and decreased chromatin modifier gene expression, including potential epigenetic silencing of ARID1A. Other IDH-mutant liver cancers molecularly resemble cholangiocarcinoma.