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. Hsieh; A. 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

doi:10.1038/nature12222

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

^*Corresponding author for this work

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Research output: Contribution to journal › Article › peer-review

2884 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 language	English
Pages (from-to)	43-49
Number of pages	7
Journal	Nature
Volume	499
Issue number	7456
DOIs	https://doi.org/10.1038/nature12222
State	Published - 2013

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10.1038/nature12222

Cite this

Creighton, C. J., Morgan, M., Gunaratne, P. H., Wheeler, D. A., Gibbs, R. A., Robertson, G., Chu, A., Beroukhim, R., Cibulskis, K., Signoretti, S., Vandin, F., Wu, H. T., Raphael, B. J., Verhaak, R. G. W., Tamboli, P., Torres-Garcia, W., Akbani, R., Weinstein, J. N., Reuter, V., ... Sofia, H. J. (2013). Comprehensivemolecular characterization of clear cell renal cell carcinoma. Nature, 499(7456), 43-49. https://doi.org/10.1038/nature12222

@article{74ce97c8eba640c5ba2052edba4e323c,

title = "Comprehensivemolecular characterization of clear cell renal cell carcinoma",

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.",

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

year = "2013",

doi = "10.1038/nature12222",

language = "English",

volume = "499",

pages = "43--49",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7456",

}

Creighton, CJ, Morgan, M, Gunaratne, PH, Wheeler, DA, Gibbs, RA, Robertson, G, Chu, A, Beroukhim, R, Cibulskis, K, Signoretti, S, Vandin, F, Wu, HT, Raphael, BJ, Verhaak, RGW, Tamboli, P, Torres-Garcia, W, Akbani, R, Weinstein, JN, Reuter, V, Hsieh, JJ, Brannon, AR, Hakimi, AA, Jacobsen, A, Ciriello, G, Reva, B, Ricketts, CJ, Linehan, WM, Stuart, JM, Rathmell, WK, Hui, S, Laird, PW, Muzny, D, Davis, C, Liu, X, Chang, K, Kakkar, N, Treviño, LR, Benton, S, Reid, JG, Morton, D, Doddapaneni, H, Yi, H, Lewis, L, Huyen, D, Kovar, C, Zhu, Y, Santibanez, J, Min, W, Hale, W, Kalra, D, Getz, G, Lawrence, MS, Sougnez, C, Carter, SL, Sivachenko, A, Lee, L, Stewart, C, Voet, D, Fisher, S, Gabriel, SB, Lander, E, Schumacher, SE, Tabak, B, Saksena, G, Onofrio, RC, Cherniack, AD, Gentry, J, Ardlie, K, Meyerson, M, Chun, HJE, Mungall, AJ, Sipahimalani, P, Stoll, D, Ally, A, Balasundaram, M, Butterfield, YSN, Carlsen, R, Carter, C, Chuah, E, Coope, RJN, Dhalla, N, Gorski, S, Guin, R, Hirst, C, Hirst, M, Holt, RA, Lebovitz, C, Lee, D, Li, HI, Mayo, M, Moore, RA, Pleasance, E, Plettner, P, Schein, JE, Shafiei, A, Slobodan, JR, Tam, A, Thiessen, N, Varhol, RJ, Wye, N, Zhao, Y, Birol, I, Jones, SJM, Marra, MA, Auman, JT, Tan, D, Jones, CD, Hoadley, KA, Mieczkowski, PA, Mose, LE, Jefferys, SR, Topal, MD, Liquori, C, Turman, YJ, Yan, S, Waring, S, Buda, E, Walsh, J, Wu, J, Bodenheimer, T, Hoyle, AP, Simons, JV, Soloway, MG, Balu, S, Parker, JS, Hayes, DN, Perou, CM, Kucherlapati, R, Park, P, Triche, T, Weisenberger, DJ, Lai, PH, Bootwalla, MS, Maglinte, DT, Mahurkar, S, Berman, BP, Van Den Berg, DJ, Cope, L, Baylin, SB, Noble, MS, DiCara, D, Zhang, H, Cho, J, Heiman, DI, Gehlenborg, N, Mallard, W, Pei, L, Frazer, S, Stojanov, P, Liu, Y, Zhou, L, Kim, J, Chin, L, Benz, C, Yau, C, Reynolds, SM, Shmulevich, I, Vegesna, R, Kim, H, Wei, Z, Cogdell, D, Jonasch, E, Ding, Z, Lu, Y, Zhang, N, Unruh, AK, Casasent, TD, Wakefield, C, Tsavachidou, D, Mills, GB, Gao, J, Cerami, E, Gross, B, Aksoy, BA, Sinha, R, Weinhold, N, Sumer, SO, Taylor, BS, Shen, R, Ostrovnaya, I, Berger, MF, Ladanyi, M, Sander, C, Fei, SS, Stout, A, Spellman, PT, Rubin, DL, Liu, TT, Sam, N, Paull, EO, Carlin, D, Goldstein, T, Waltman, P, Ellrott, K, Jing, Z, Haussler, D, Xiao, W, Shelton, C, Gardner, J, Penny, R, Sherman, M, Mallery, D, Morris, S, Paulauskis, J, Burnett, K, Shelton, T, Kaelin, WG, Choueiri, T, Atkins, MB, Curley, E, Tickoo, S, Thorne, L, Boice, L, Mei, H, Fisher, JC, Vocke, CD, Peterson, J, Worrell, R, Merino, MJ, Schmidt, LS, Czerniak, BA, Aldape, KD, Wood, CG, Boyd, J, Weaver, JE, Iacocca, MV, Petrelli, N, Witkin, G, Brown, J, Czerwinski, C, Huelsenbeck-Dill, L, Rabeno, B, Myers, J, Morrison, C, Bergsten, J, Eckman, J, Harr, J, Smith, C, Tucker, K, Zach, LA, Bshara, W, Gaudioso, C, Dhir, R, Maranchie, J, Nelson, J, Parwani, A, Potapova, CO, Fedosenko, K, Cheville, JC, Thompson, RH, Mosquera, JM, Rubin, MA, Blute, ML, Pihl, T, Jensen, M, Sfeir, R, Kahn, A, Chu, A, Kothiyal, P, Snyder, E, Pontius, J, Ayala, B, Backus, M, Walton, J, Baboud, J, Berton, D, Nicholls, M, Srinivasan, D, Raman, R, Girshik, S, Kigonya, P, Alonso, S, Sanbhadti, R, Barletta, S, Pot, D, Sheth, M, Demchok, JA, Davidsen, T, Wang, Z, Yang, L, Tarnuzzer, RW, Zhang, J, Eley, G, Ferguson, ML, Mills Shaw, KR, Guyer, MS, Ozenberger, BA & Sofia, HJ 2013, 'Comprehensivemolecular characterization of clear cell renal cell carcinoma', Nature, vol. 499, no. 7456, pp. 43-49. https://doi.org/10.1038/nature12222

TY - JOUR

T1 - Comprehensivemolecular characterization of clear cell renal cell carcinoma

AU - Creighton, Chad J.

AU - Morgan, Margaret

AU - Gunaratne, Preethi H.

AU - Wheeler, David A.

AU - Gibbs, Richard A.

AU - Robertson, Gordon

AU - Chu, Andy

AU - Beroukhim, Rameen

AU - Cibulskis, Kristian

AU - Signoretti, Sabina

AU - Vandin, Fabio

AU - Wu, Hsin Ta

AU - Raphael, Benjamin J.

AU - Verhaak, Roel G.W.

AU - Tamboli, Pheroze

AU - Torres-Garcia, Wandaliz

AU - Akbani, Rehan

AU - Weinstein, John N.

AU - Reuter, Victor

AU - Hsieh, James J.

AU - Brannon, A. Rose

AU - Hakimi, A. Ari

AU - Jacobsen, Anders

AU - Ciriello, Giovanni

AU - Reva, Boris

AU - Ricketts, Christopher J.

AU - Linehan, W. Marston

AU - Stuart, Joshua M.

AU - Rathmell, W. Kimryn

AU - Hui, Shen

AU - Laird, Peter W.

AU - Muzny, Donna

AU - Davis, Caleb

AU - Liu, Xi

AU - Chang, Kyle

AU - Kakkar, Nipun

AU - Treviño, Lisa R.

AU - Benton, Susan

AU - Reid, Jeffrey G.

AU - Morton, Donna

AU - Doddapaneni, Harsha

AU - Yi, Han

AU - Lewis, Lora

AU - Huyen, Dinh

AU - Kovar, Christie

AU - Zhu, Yiming

AU - Santibanez, Jireh

AU - Min, Wang

AU - Hale, Walker

AU - Kalra, Divya

AU - Getz, Gad

AU - Lawrence, Michael S.

AU - Sougnez, Carrie

AU - Carter, Scott L.

AU - Sivachenko, Andrey

AU - Lee, Lichtenstein

AU - Stewart, Chip

AU - Voet, Doug

AU - Fisher, Sheila

AU - Gabriel, Stacey B.

AU - Lander, Eric

AU - Schumacher, Steve E.

AU - Tabak, Barbara

AU - Saksena, Gordon

AU - Onofrio, Robert C.

AU - Cherniack, Andrew D.

AU - Gentry, Jeff

AU - Ardlie, Kristin

AU - Meyerson, Matthew

AU - Chun, Hye Jung E.

AU - Mungall, Andrew J.

AU - Sipahimalani, Payal

AU - Stoll, Dominik

AU - Ally, Adrian

AU - Balasundaram, Miruna

AU - Butterfield, Yaron S.N.

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PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84879890360&partnerID=8YFLogxK

U2 - 10.1038/nature12222

DO - 10.1038/nature12222

M3 - Article

AN - SCOPUS:84879890360

SN - 0028-0836

VL - 499

SP - 43

EP - 49

JO - Nature

JF - Nature

IS - 7456

ER -

Comprehensivemolecular characterization of clear cell renal cell carcinoma

Abstract

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