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

2017; Cell Press; Volume: 18; Issue: 11 Linguagem: Inglês

10.1016/j.celrep.2017.02.033

2639-1856

Farshad Farshidfar, Siyuan Zheng, Marie‐Claude Gingras, Yulia Newton, Juliann Shih, A. Gordon Robertson, Toshinori Hinoue, Katherine A. Hoadley, Ewan A. Gibb, Jason Roszik, Kyle R. Covington, Chia-Chin Wu, Eve Shinbrot, Nicolas Stransky, Apurva M. Hegde, Ju Dong Yang, Ed Reznik, Sara Sadeghi, Chandra Sekhar Pedamallu, Akinyemi I. Ojesina, Julian M. Hess, J. Todd Auman, Suhn K. Rhie, Reanne Bowlby, Mitesh J. Borad, Andrew X. Zhu, Joshua M. Stuart, Chris Sander, Rehan Akbani, Andrew D. Cherniack, Vikram Deshpande, Taofic Mounajjed, Wai Chin Foo, Michael Torbenson, David E. Kleiner, Peter W. Laird, David A. Wheeler, Autumn J. McRee, Oliver F. Bathe, Jesper B. Andersen, Nabeel Bardeesy, Lewis R. Roberts, Lawrence N. Kwong, Rehan Akbani, Loretta K. Allotey, Adrian Ally, Domenico Alvaro, Jesper B. Andersen, Elizabeth L. Appelbaum, Arshi Arora, J. Todd Auman, Miruna Balasundaram, Saianand Balu, Nabeel Bardeesy, Oliver F. Bathe, Stephen B. Baylin, Rameen Beroukhim, Mario Berríos, Tom Bodenheimer, Lori Boice, Arnoud Boot, Mitesh J. Borad, Jay Bowen, Reanne Bowlby, Maria Consiglia Bragazzi, Denise Brooks, Vincenzo Cardinale, Rebecca Carlsen, Guido Carpino, André Lopes Carvalho, Roongruedee Chaiteerakij, Vishal C. Chandan, Andrew D. Cherniack, Lynda Chin, Juok Cho, Gina Choe, Eric Chuah, Sudha Chudamani, Carrie Cibulskis, Matthew G. Cordes, Kyle R. Covington, Daniel Crain, Erin Curley, Agostino Maria De Rose, Timothy Defreitas, John A. Demchok, Vikram Deshpande, Noreen Dhalla, Li Ding, Kimberley Evason, Farshad Farshidfar, Ina Felau, Martin L. Ferguson, Wai Chin Foo, Antonio Franchitto, Scott Frazer, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Stacey Gabriel, Johanna Gardner, Julie M. Gastier‐Foster, Eugenio Gaudio, Nils Gehlenborg, Giannicola Genovese, Mark Gerken, Gad Getz, Nasra H. Giama, Richard A. Gibbs, Marie‐Claude Gingras, Felice Giuliante, Gian Luca Grazi, D. Neil Hayes, Apurva M. Hegde, David I. Heiman, Julian M. Hess, Toshinori Hinoue, Katherine A. Hoadley, Andrea Holbrook, Robert A. Holt, Alan P. Hoyle, Mei Huang, Carolyn M. Hutter, Joshua M. Stuart, Steven J.M. Jones, Corbin D. Jones, L. Sylvia, Robin Kate Kelley, Jaegil Kim, David E. Kleiner, Jean‐Pierre Kocher, Lawrence N. Kwong, Phillip H. Lai, Peter W. Laird, Michael S. Lawrence, Kristen Leraas, Tara M. Lichtenberg, Pei Lin, Wenbin Liu, Jia Liu, Laxmi Lolla, Yiling Lu, Yussanne Ma, David Mallery, Elaine R. Mardis, Marco A. Marra, Marcus Matsushita, Michael Mayo, Michael D. McLellan, Autumn J. McRee, Thomas J. Giordano, Shaowu Meng, Matthew Meyerson, Piotr A. Mieczkowski, Christopher A. Miller, Gordon B. Mills, Richard A. Moore, Scott Morris, Lisle E. Mose, Catherine D. Moser, Taofic Mounajjed, Andrew J. Mungall, Karen Mungall, Bradley A. Murray, Rashi Naresh, Yulia Newton, Michael S. Noble, Daniel R. O’Brien, Akinyemi I. Ojesina, Joel S. Parker, Tushar Patel, Joseph Paulauskis, Chandra Sekhar Pedamallu, Robert Penny, Charles M. Perou, Amy H. Perou, Todd Pihl, Amie Radenbaugh, Nilsa C. Ramirez, W. Kimryn Rathmell, Ed Reznik, Suhn K. Rhie, Jeffrey Roach, Lewis R. Roberts, A. Gordon Robertson, Sara Sadeghi, Gordon Saksena, Chris Sander, Jacqueline E. Schein, Heather K. Schmidt, Steven E. Schumacher, Candace Shelton, Troy Shelton, Ronglai Shen, Margi Sheth, Yan Shi, Juliann Shih, Eve Shinbrot, Rachna T. Shroff, Janae V. Simons, Payal Sipahimalani, Tara Skelly, Heidi J. Sofia, Matthew G. Soloway, Hubert Stöppler, Nicolas Stransky, Joshua M. Stuart, Qiang Sun, Angela Tam, Donghui Tan, Roy Tarnuzzer, Nina Thiessen, Leigh B. Thorne, Michael Torbenson, David Van Den Berg, Umadevi Veluvolu, Roel G.W. Verhaak, Doug Voet, Yunhu Wan, Linghua Wang, John N. Weinstein, Daniel J. Weisenberger, David A. Wheeler, Richard K. Wilson, Lisa Wise, Tina Wong, Chia-Chin Wu, Ye Wu, Xi Liu, Ju Dong Yang, Liming Yang, Jean C. Zenklusen, Hailei Zhang, Jiashan Zhang, Siyuan Zheng, Erik Zmuda,

Cancer Genomics and Diagnostics

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.