Comprehensivemolecular characterization of clear cell renal cell carcinoma

Chad J. Creighton, Margaret Morgan, Preethi H. Gunaratne, David A. Wheeler, Richard A. Gibbs, Gordon Robertson, Andy Chu, Rameen Beroukhim, Kristian Cibulskis, Sabina Signoretti, Fabio Vandin, Hsin Ta Wu, Benjamin J. Raphael, Roel G.W. Verhaak, Pheroze Tamboli, Wandaliz Torres-Garcia, Rehan Akbani, John N. Weinstein, Victor Reuter, James J. HsiehA. Rose Brannon, A. Ari Hakimi, Anders Jacobsen, Giovanni Ciriello, Boris Reva, Christopher J. Ricketts, W. Marston Linehan, Joshua M. Stuart, W. Kimryn Rathmell, Shen Hui, Peter W. Laird, Donna Muzny, Caleb Davis, Xi Liu, Kyle Chang, Nipun Kakkar, Lisa R. Treviño, Susan Benton, Jeffrey G. Reid, Donna Morton, Harsha Doddapaneni, Han Yi, Lora Lewis, Dinh Huyen, Christie Kovar, Yiming Zhu, Jireh Santibanez, Wang Min, Walker Hale, Divya Kalra, Gad Getz, Michael S. Lawrence, Carrie Sougnez, Scott L. Carter, Andrey Sivachenko, Lichtenstein Lee, Chip Stewart, Doug Voet, Sheila Fisher, Stacey B. Gabriel, Eric Lander, Steve E. Schumacher, Barbara Tabak, Gordon Saksena, Robert C. Onofrio, Andrew D. Cherniack, Jeff Gentry, Kristin Ardlie, Matthew Meyerson, Hye Jung E. Chun, Andrew J. Mungall, Payal Sipahimalani, Dominik Stoll, Adrian Ally, Miruna Balasundaram, Yaron S.N. Butterfield, Rebecca Carlsen, Candace Carter, Eric Chuah, Robin J.N. Coope, Noreen Dhalla, Sharon Gorski, Ranabir Guin, Carrie Hirst, Martin Hirst, Robert A. Holt, Chandra Lebovitz, Darlene Lee, Haiyan I. Li, Michael Mayo, Richard A. Moore, Erin Pleasance, Patrick Plettner, Jacqueline E. Schein, Arash Shafiei, Jared R. Slobodan, Angela Tam, Nina Thiessen, Richard J. Varhol, Natasja Wye, Yongjun Zhao, Inanc Birol, Steven J.M. Jones, Marco A. Marra, J. Todd Auman, Donghui Tan, Corbin D. Jones, Katherine A. Hoadley, Piotr A. Mieczkowski, Lisle E. Mose, Stuart R. Jefferys, Michael D. Topal, Christina Liquori, Yidi J. Turman, Shi Yan, Scot Waring, Elizabeth Buda, Jesse Walsh, Junyuan Wu, Tom Bodenheimer, Alan P. Hoyle, Janae V. Simons, Mathew G. Soloway, Saianand Balu, Joel S. Parker, D. Neil Hayes, Charles M. Perou, Raju Kucherlapati, Peter Park, Timothy Triche, Daniel J. Weisenberger, Phillip H. Lai, Moiz S. Bootwalla, Dennis T. Maglinte, Swapna Mahurkar, Benjamin P. Berman, David J. Van Den Berg, Leslie Cope, Stephen B. Baylin, Michael S. Noble, Daniel DiCara, Hailei Zhang, Juok Cho, David I. Heiman, Nils Gehlenborg, William Mallard, Lin Pei, Scott Frazer, Petar Stojanov, Yingchun Liu, Lihua Zhou, Jaegil Kim, Lynda Chin, Christopher Benz, Christina Yau, Sheila M. Reynolds, Ilya Shmulevich, Rahul Vegesna, Hoon Kim, Zhang Wei, David Cogdell, Eric Jonasch, Zhiyong Ding, Yiling Lu, Nianxiang Zhang, Anna K. Unruh, Tod D. Casasent, Chris Wakefield, Dimitra Tsavachidou, Gordon B. Mills, Jianjiong Gao, Ethan Cerami, Benjamin Gross, B. Arman Aksoy, Rileen Sinha, Nils Weinhold, S. Onur Sumer, Barry S. Taylor, Ronglai Shen, Irina Ostrovnaya, Michael F. Berger, Marc Ladanyi, Chris Sander, Suzanne S. Fei, Andrew Stout, Paul T. Spellman, Daniel L. Rubin, Tiffany T. Liu, Ng Sam, Evan O. Paull, Daniel Carlin, Theodore Goldstein, Peter Waltman, Kyle Ellrott, Zhu Jing, David Haussler, Weimin Xiao, Candace Shelton, Johanna Gardner, Robert Penny, Mark Sherman, David Mallery, Scott Morris, Joseph Paulauskis, Ken Burnett, Troy Shelton, William G. Kaelin, Toni Choueiri, Michael B. Atkins, Erin Curley, Satish Tickoo, Leigh Thorne, Lori Boice, Huang Mei, Jennifer C. Fisher, Cathy D. Vocke, James Peterson, Robert Worrell, Maria J. Merino, Laura S. Schmidt, Bogdan A. Czerniak, Kenneth D. Aldape, Christopher G. Wood, Jeff Boyd, Jo Ellen Weaver, Mary V. Iacocca, Nicholas Petrelli, Gary Witkin, Jennifer Brown, Christine Czerwinski, Lori Huelsenbeck-Dill, Brenda Rabeno, Jerome Myers, Carl Morrison, Julie Bergsten, John Eckman, Jodi Harr, Christine Smith, Kelinda Tucker, Leigh Anne Zach, Wiam Bshara, Carmelo Gaudioso, Rajiv Dhir, Jodi Maranchie, Joel Nelson, Anil Parwani, Cureline Olga Potapova, Konstantin Fedosenko, John C. Cheville, R. Houston Thompson, Juan M. Mosquera, Mark A. Rubin, Michael L. Blute, Todd Pihl, Mark Jensen, Robert Sfeir, Ari Kahn, Anna Chu, Prachi Kothiyal, Eric Snyder, Joan Pontius, Brenda Ayala, Mark Backus, Jessica Walton, Julien Baboud, Dominique Berton, Matthew Nicholls, Deepak Srinivasan, Rohini Raman, Stanley Girshik, Peter Kigonya, Shelley Alonso, Rashmi Sanbhadti, Sean Barletta, David Pot, Margi Sheth, John A. Demchok, Tanja Davidsen, Zhining Wang, Liming Yang, Roy W. Tarnuzzer, Jiashan Zhang, Greg Eley, Martin L. Ferguson, Kenna R. Mills Shaw, Mark S. Guyer, Bradley A. Ozenberger, Heidi J. Sofia

Research output: Contribution to journalArticlepeer-review

1666 Scopus citations

Abstract

Genetic changes underlying clear cell renal cell carcinoma(ccRCC) include alterations in genes controlling cellularoxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreasedAMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.

Original languageEnglish
Pages (from-to)43-49
Number of pages7
JournalNature
Volume499
Issue number7456
DOIs
StatePublished - 2013

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