Comprehensive molecular characterization of clear cell renal cell carcinoma.
The Cancer Genome Atlas Research Network; Analysis working group: Baylor College of Medicine; Creighton, Chad J. 1,2; Morgan, Margaret 1; Gunaratne, Preethi H. 1,3; Wheeler, David A. 1; Gibbs, Richard A. 1; BC Cancer Agency; Robertson, Gordon A. 4; Chu, Andy 4; Broad Institute; Beroukhim, Rameen 5,6,54,56; Cibulskis, Kristian 6; Brigham & Women's Hospital; Signoretti, Sabina 7,54,59; Brown University; Hsin-Ta Wu, Fabio Vandin 8,8; Raphael, Benjamin J. 8; The University of Texas MD Anderson Cancer Center; Verhaak, Roel G. W. 9; Tamboli, Pheroze 10; Torres-Garcia, Wandaliz 9; Akbani, Rehan 9; Weinstein, John N. 9; Memorial Sloan-Kettering Cancer Center; Reuter, Victor 11; Hsieh, James J. 12; Brannon, Rose A. 11; Ari Hakimi, A. 12; Jacobsen, Anders 13; Ciriello, Giovanni 13; Reva, Boris 13; National Cancer Institute; Ricketts, Christopher J. 14; Linehan, Marston W. 14; University of California Santa Cruz; Stuart, Joshua M. 15; University of North Carolina, Chapel Hill; Rathmell, Kimryn W. 16; University of Southern California; Shen, Hui 17; Laird, Peter W. 17; Genome sequencing centres: Baylor College of Medicine; Muzny, Donna 1; Davis, Caleb 1; Xi, Liu 1; Chang, Kyle 1; Kakkar, Nipun 1; Trevino, Lisa R. 1; Benton, Susan 1; Reid, Jeffrey G. 1; Morton, Donna 1; Doddapaneni, Harsha 1; Han, Yi 1; Lewis, Lora 1; Dinh, Huyen 1; Kovar, Christie 1; Zhu, Yiming 1; Santibanez, Jireh 1; Wang, Min 1; Hale, Walker 1; Kalra, Divya 1; Getz, Gad 6,57; Lawrence, Michael S. 6; Sougnez, Carrie 6; Carter, Scott L. 6; Sivachenko, Andrey 6; Lichtenstein, Lee 6; Stewart, Chip 6; Voet, Doug 6; Fisher, Sheila 6; Gabriel, Stacey B. 6; Lander, Eric 6; Genome characterization centres: Broad Institute; Schumacher, Steve E. 6,56; Tabak, Barbara 6,56; Saksena, Gordon 6; Onofrio, Robert C. 6; Cherniack, Andrew D. 6; Gentry, Jeff 6; Ardlie, Kristin 6; Meyerson, Matthew 6,7,54; Chun, Hye-Jung E. 4; Mungall, Andrew J. 4; Sipahimalani, Payal 4; Stoll, Dominik 4; Ally, Adrian 4; Balasundaram, Miruna 4; Butterfield, Yaron S. N. 4; Carlsen, Rebecca 4; Carter, Candace 4; Chuah, Eric 4; Coope, Robin J. N. 4; Dhalla, Noreen 4; Gorski, Sharon 4; Guin, Ranabir 4; Hirst, Carrie 4; Hirst, Martin 4; Holt, Robert A. 4; Lebovitz, Chandra 4; Lee, Darlene 4; Li, Haiyan I. 4; Mayo, Michael 4; Moore, Richard A. 4; Pleasance, Erin 4; Plettner, Patrick 4; Schein, Jacqueline E. 4; Shafiei, Arash 4; Slobodan, Jared R. 4; Tam, Angela 4; Thiessen, Nina 4; Varhol, Richard J. 4; Wye, Natasja 4; Zhao, Yongjun 4; Birol, Inanc 4; Jones, Steven J. M. 4; Marra, Marco A. 4; Auman, Todd J. 18; Tan, Donghui 19; Jones, Corbin D. 20; Hoadley, Katherine A. 16,21,22; Mieczkowski, Piotr A. 22; Mose, Lisle E. 21; Jefferys, Stuart R. 22; Topal, Michael D. 21,22; Liquori, Christina 16; Turman, Yidi J. 16; Shi, Yan 16; Waring, Scot 16; Buda, Elizabeth 16; Walsh, Jesse 16; Wu, Junyuan 16; Bodenheimer, Tom 16; Hoyle, Alan P. 16; Simons, Janae V. 16; Soloway, Mathew G. 16; Balu, Saianand 16; Parker, Joel S. 16; Hayes, Neil D. 16,23; Perou, Charles M. 16,21,22; Harvard Medical School; Kucherlapati, Raju 24,25; Park, Peter 25,26,27; University of Southern California & Johns Hopkins University; Triche, Timothy Jr 17; Weisenberger, Daniel J. 17; Lai, Phillip H. 17; Bootwalla, Moiz S. 17; Maglinte, Dennis T. 17; Mahurkar, Swapna 17; Berman, Benjamin P. 17; Van Den Berg, David J. 17; Cope, Leslie 28; Baylin, Stephen B. 28; Genome data analysis: Baylor College of Medicine; Noble, Michael S. 6; DiCara, Daniel 6; Zhang, Hailei 6; Cho, Juok 6; Heiman, David I. 6; Gehlenborg, Nils 6,26; Mallard, William 6; Lin, Pei 6; Frazer, Scott 6; Stojanov, Petar 6,54; Liu, Yingchun 6; Zhou, Lihua 6; Kim, Jaegil 6; Chin, Lynda 6,31; Vandin, Fabio 8; Wu, Hsin-Ta 8; Buck Institute for Research on Aging; Benz, Christopher 55; Yau, Christina 55; Institute for Systems Biology; Reynolds, Sheila M. 29; Shmulevich, Ilya 29; Verhaak, Roel G.W. 9; Vegesna, Rahul 9; Kim, Hoon 9; Zhang, Wei 10; Cogdell, David 10; Jonasch, Eric 9; Ding, Zhiyong 9; Lu, Yiling 30; Zhang, Nianxiang 9; Unruh, Anna K. 9; Casasent, Tod D. 9; Wakefield, Chris 9; Tsavachidou, Dimitra 30; Mills, Gordon B. 30; Schultz, Nikolaus 13; Antipin, Yevgeniy 13; Gao, Jianjiong 13; Cerami, Ethan 13; Gross, Benjamin 13; Aksoy, Arman B. 13; Sinha, Rileen 13; Weinhold, Nils 13; Sumer, Onur S. 13; Taylor, Barry S. 13; Shen, Ronglai 13; Ostrovnaya, Irina 32; Berger, Michael F. 11; Ladanyi, Marc 12; Sander, Chris 13; Oregon Health & Science University; Fei, Suzanne S. 33; Stout, Andrew 33; Spellman, Paul T. 33; Stanford University; Rubin, Daniel L. 34; Liu, Tiffany T. 34; Ng, Sam 15; Paull, Evan O. 15; Carlin, Daniel 15; Goldstein, Theodore 15; Waltman, Peter 15; Ellrott, Kyle 15; Zhu, Jing 15; Haussler, David 15,35; University of Houston; Xiao, Weimin 3; Biospecimen core resource: International Genomics Consortium; Shelton, Candace 36; Gardner, Johanna 36; Penny, Robert 36; Sherman, Mark 36; Mallery, David 36; Morris, Scott 36; Paulauskis, Joseph 36; Burnett, Ken 36; Shelton, Troy 36; Tissue source sites: Brigham & Women's Hospital; Dana-Farber Cancer Institute; Kaelin, William G. 54,60; Choueiri, Toni 54; Georgetown University; Atkins, Michael B. 37; International Genomics Consortium; Curley, Erin 36; Tickoo, Satish 11; University of North Carolina at Chapel Hill; Thorne, Leigh 16; Boice, Lori 16; Huang, Mei 16; Fisher, Jennifer C. 16; Vocke, Cathy D. 14; Peterson, James 14; Worrell, Robert 14; Merino, Maria J. 14; Schmidt, Laura S. 14,38; Czerniak, Bogdan A. 10; Aldape, Kenneth D. 10; Wood, Christopher G. 39; Fox Chase Cancer Center; Boyd, Jeff 40; Weaver, JoEllen 40; Helen F Graham Cancer Center at Christiana Care; Iacocca, Mary V. 41; Petrelli, Nicholas 41; Witkin, Gary 41; Brown, Jennifer 41; Czerwinski, Christine 41; Huelsenbeck-Dill, Lori 41; Rabeno, Brenda 41; Penrose-St. Francis Health Services; Myers, Jerome 42; Morrison, Carl 42,43; Bergsten, Julie 42; Eckman, John 42; Harr, Jodi 42; Smith, Christine 42; Tucker, Kelinda 42; Zach, Leigh Anne 42; Roswell Park Cancer Institute; Bshara, Wiam 43; Gaudioso, Carmelo 43; University of Pittsburgh; Dhir, Rajiv 44; Maranchie, Jodi 44; Nelson, Joel 44; Parwani, Anil 44; Cureline; Potapova, Olga 45; St. Petersburg City Clinical Oncology Dispensary; Fedosenko, Konstantin 46; Mayo Clinic; Cheville, John C. 58; Thompson, Houston R. 58; Disease working group: Brigham & Women's Hospital; Weill Cornell Medical College; Mosquera, Juan M. 47; Rubin, Mark A. 47; Massachusetts General Hospital; Blute, Michael L. 48; Data coordination centre; Pihl, Todd 49; Jensen, Mark 49; Sfeir, Robert 49; Kahn, Ari 49; Chu, Anna 49; Kothiyal, Prachi 49; Snyder, Eric 49; Pontius, Joan 49; Ayala, Brenda 49; Backus, Mark 49; Walton, Jessica 49; Baboud, Julien 49; Berton, Dominique 49; Nicholls, Matthew 49; Srinivasan, Deepak 49; Raman, Rohini 49; Girshik, Stanley 49; Kigonya, Peter 49; Alonso, Shelley 49; Sanbhadti, Rashmi 49; Barletta, Sean 49; Pot, David 49; Project team: National Cancer Institute; Sheth, Margi 50; Demchok, John A. 50; Davidsen, Tanja 50; Wang, Zhining 50; Yang, Liming 50; Tarnuzzer, Roy W. 50; Zhang, Jiashan 50; Eley, Greg 51; Ferguson, Martin L. 52; Mills Shaw, Kenna R. 50; National Human Genome Research Institute; Guyer, Mark S. 53; Ozenberger, Bradley A. 53; Sofia, Heidi J. 53
[Article]
Nature.
499(7456):43-49, July 4, 2013.
(Format: HTML, PDF)
: Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen 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, decreased AMPK 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.
(C) 2013 Nature Publishing Group