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 | |
State | Published - 2013 |
Externally published | Yes |
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In: Nature, Vol. 499, No. 7456, 2013, p. 43-49.
Research output: Contribution to journal › Article › peer-review
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
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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.
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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
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AU - Muzny, Donna
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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.
AU - Carlsen, Rebecca
AU - Carter, Candace
AU - Chuah, Eric
AU - Coope, Robin J.N.
AU - Dhalla, Noreen
AU - Gorski, Sharon
AU - Guin, Ranabir
AU - Hirst, Carrie
AU - Hirst, Martin
AU - Holt, Robert A.
AU - Lebovitz, Chandra
AU - Lee, Darlene
AU - Li, Haiyan I.
AU - Mayo, Michael
AU - Moore, Richard A.
AU - Pleasance, Erin
AU - Plettner, Patrick
AU - Schein, Jacqueline E.
AU - Shafiei, Arash
AU - Slobodan, Jared R.
AU - Tam, Angela
AU - Thiessen, Nina
AU - Varhol, Richard J.
AU - Wye, Natasja
AU - Zhao, Yongjun
AU - Birol, Inanc
AU - Jones, Steven J.M.
AU - Marra, Marco A.
AU - Auman, J. Todd
AU - Tan, Donghui
AU - Jones, Corbin D.
AU - Hoadley, Katherine A.
AU - Mieczkowski, Piotr A.
AU - Mose, Lisle E.
AU - Jefferys, Stuart R.
AU - Topal, Michael D.
AU - Liquori, Christina
AU - Turman, Yidi J.
AU - Yan, Shi
AU - Waring, Scot
AU - Buda, Elizabeth
AU - Walsh, Jesse
AU - Wu, Junyuan
AU - Bodenheimer, Tom
AU - Hoyle, Alan P.
AU - Simons, Janae V.
AU - Soloway, Mathew G.
AU - Balu, Saianand
AU - Parker, Joel S.
AU - Hayes, D. Neil
AU - Perou, Charles M.
AU - Kucherlapati, Raju
AU - Park, Peter
AU - Triche, Timothy
AU - Weisenberger, Daniel J.
AU - Lai, Phillip H.
AU - Bootwalla, Moiz S.
AU - Maglinte, Dennis T.
AU - Mahurkar, Swapna
AU - Berman, Benjamin P.
AU - Van Den Berg, David J.
AU - Cope, Leslie
AU - Baylin, Stephen B.
AU - Noble, Michael S.
AU - DiCara, Daniel
AU - Zhang, Hailei
AU - Cho, Juok
AU - Heiman, David I.
AU - Gehlenborg, Nils
AU - Mallard, William
AU - Pei, Lin
AU - Frazer, Scott
AU - Stojanov, Petar
AU - Liu, Yingchun
AU - Zhou, Lihua
AU - Kim, Jaegil
AU - Chin, Lynda
AU - Benz, Christopher
AU - Yau, Christina
AU - Reynolds, Sheila M.
AU - Shmulevich, Ilya
AU - Vegesna, Rahul
AU - Kim, Hoon
AU - Wei, Zhang
AU - Cogdell, David
AU - Jonasch, Eric
AU - Ding, Zhiyong
AU - Lu, Yiling
AU - Zhang, Nianxiang
AU - Unruh, Anna K.
AU - Casasent, Tod D.
AU - Wakefield, Chris
AU - Tsavachidou, Dimitra
AU - Mills, Gordon B.
AU - Gao, Jianjiong
AU - Cerami, Ethan
AU - Gross, Benjamin
AU - Aksoy, B. Arman
AU - Sinha, Rileen
AU - Weinhold, Nils
AU - Sumer, S. Onur
AU - Taylor, Barry S.
AU - Shen, Ronglai
AU - Ostrovnaya, Irina
AU - Berger, Michael F.
AU - Ladanyi, Marc
AU - Sander, Chris
AU - Fei, Suzanne S.
AU - Stout, Andrew
AU - Spellman, Paul T.
AU - Rubin, Daniel L.
AU - Liu, Tiffany T.
AU - Sam, Ng
AU - Paull, Evan O.
AU - Carlin, Daniel
AU - Goldstein, Theodore
AU - Waltman, Peter
AU - Ellrott, Kyle
AU - Jing, Zhu
AU - Haussler, David
AU - Xiao, Weimin
AU - Shelton, Candace
AU - Gardner, Johanna
AU - Penny, Robert
AU - Sherman, Mark
AU - Mallery, David
AU - Morris, Scott
AU - Paulauskis, Joseph
AU - Burnett, Ken
AU - Shelton, Troy
AU - Kaelin, William G.
AU - Choueiri, Toni
AU - Atkins, Michael B.
AU - Curley, Erin
AU - Tickoo, Satish
AU - Thorne, Leigh
AU - Boice, Lori
AU - Mei, Huang
AU - Fisher, Jennifer C.
AU - Vocke, Cathy D.
AU - Peterson, James
AU - Worrell, Robert
AU - Merino, Maria J.
AU - Schmidt, Laura S.
AU - Czerniak, Bogdan A.
AU - Aldape, Kenneth D.
AU - Wood, Christopher G.
AU - Boyd, Jeff
AU - Weaver, Jo Ellen
AU - Iacocca, Mary V.
AU - Petrelli, Nicholas
AU - Witkin, Gary
AU - Brown, Jennifer
AU - Czerwinski, Christine
AU - Huelsenbeck-Dill, Lori
AU - Rabeno, Brenda
AU - Myers, Jerome
AU - Morrison, Carl
AU - Bergsten, Julie
AU - Eckman, John
AU - Harr, Jodi
AU - Smith, Christine
AU - Tucker, Kelinda
AU - Zach, Leigh Anne
AU - Bshara, Wiam
AU - Gaudioso, Carmelo
AU - Dhir, Rajiv
AU - Maranchie, Jodi
AU - Nelson, Joel
AU - Parwani, Anil
AU - Potapova, Cureline Olga
AU - Fedosenko, Konstantin
AU - Cheville, John C.
AU - Thompson, R. Houston
AU - Mosquera, Juan M.
AU - Rubin, Mark A.
AU - Blute, Michael L.
AU - Pihl, Todd
AU - Jensen, Mark
AU - Sfeir, Robert
AU - Kahn, Ari
AU - Chu, Anna
AU - Kothiyal, Prachi
AU - Snyder, Eric
AU - Pontius, Joan
AU - Ayala, Brenda
AU - Backus, Mark
AU - Walton, Jessica
AU - Baboud, Julien
AU - Berton, Dominique
AU - Nicholls, Matthew
AU - Srinivasan, Deepak
AU - Raman, Rohini
AU - Girshik, Stanley
AU - Kigonya, Peter
AU - Alonso, Shelley
AU - Sanbhadti, Rashmi
AU - Barletta, Sean
AU - Pot, David
AU - Sheth, Margi
AU - Demchok, John A.
AU - Davidsen, Tanja
AU - Wang, Zhining
AU - Yang, Liming
AU - Tarnuzzer, Roy W.
AU - Zhang, Jiashan
AU - Eley, Greg
AU - Ferguson, Martin L.
AU - Mills Shaw, Kenna R.
AU - Guyer, Mark S.
AU - Ozenberger, Bradley A.
AU - Sofia, Heidi J.
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 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
AN - SCOPUS:84879890360
SN - 0028-0836
VL - 499
SP - 43
EP - 49
JO - Nature
JF - Nature
IS - 7456
ER -