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Nature DOI:10.1038/nature12222

Comprehensive molecular characterization of clear cell renal cell carcinoma.

Publication TypeJournal Article
Year of Publication2013
AuthorsThe Cancer Genome Atlas Research, N, Analysis working group: Baylor College of, M, Creighton, CJ, Morgan, M, Gunaratne, PH, Wheeler, DA, Gibbs, RA, BC Cancer, A, Gordon Robertson, A, Chu, A, Broad, I, Beroukhim, R, Cibulskis, K, Brigham & Women’s, H, Signoretti, S, Brown, U, Vandin Hsin-Ta Wu, F, Raphael, BJ, The University of Texas MD Anderson Cancer, C, Verhaak, RG, Tamboli, P, Torres-Garcia, W, Akbani, R, Weinstein, JN, Memorial Sloan-Kettering Cancer, C, Reuter, V, Hsieh, JJ, Rose Brannon, A, Ari Hakimi, A, Jacobsen, A, Ciriello, G, Reva, B, National Cancer, I, Ricketts, CJ, Marston Linehan, W, University of California Santa, C, Stuart, JM, University of North Carolina, Chapel, H, Kimryn Rathmell, W, University of Southern, C, Shen, H, Laird, PW, Genome sequencing centres: Baylor College of, M, Muzny, D, Davis, C, Morgan, M, Xi, L, Chang, K, Kakkar, N, Treviño, LR, Benton, S, Reid, JG, Morton, D, Doddapaneni, H, Han, Y, Lewis, L, Dinh, H, Kovar, C, Zhu, Y, Santibanez, J, Wang, M, Hale, W, Kalra, D, Creighton, CJ, Wheeler, DA, Gibbs, RA, Broad, I, Getz, G, Cibulskis, K, Lawrence, MS, Sougnez, C, Carter, SL, Sivachenko, A, Lichtenstein, L, Stewart, C, Voet, D, Fisher, S, Gabriel, SB, Lander, E, Genome characterization centres: Broad, I, Beroukhim, R, Schumacher, SE, Tabak, B, Saksena, G, Onofrio, RC, Carter, SL, Cherniack, AD, Gentry, J, Ardlie, K, Sougnez, C, Getz, G, Gabriel, SB, Meyerson, M, BC Cancer, A, Gordon Robertson, A, Chu, A, Chun, HJ, Mungall, AJ, Sipahimalani, P, Stoll, D, Ally, A, Balasundaram, M, Butterfield, YS, Carlsen, R, Carter, C, Chuah, E, Coope, RJ, 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, SJ, Marra, MA, University of North Carolina, Chapel, H, Auman, JT, Tan, D, Jones, CD, Hoadley, KA, Mieczkowski, PA, Mose, LE, Jefferys, SR, Topal, MD, Liquori, C, Turman, YJ, Shi, Y, Waring, S, Buda, E, Walsh, J, Wu, J, Bodenheimer, T, Hoyle, AP, Simons, JV, Soloway, MG, Balu, S, Parker, JS, Neil Hayes, D, Perou, CM, Harvard Medical, S, Kucherlapati, R, Park, P, University of Southern California & Johns Hopkins, U, Shen, H, Triche Jr, T, Weisenberger, DJ, Lai, PH, Bootwalla, MS, Maglinte, DT, Mahurkar, S, Berman, BP, Van Den Berg, DJ, Cope, L, Baylin, SB, Laird, PW, Genome data analysis: Baylor College of, M, Creighton, CJ, Wheeler, DA, Broad, I, Getz, G, Noble, MS, Dicara, D, Zhang, H, Cho, J, Heiman, DI, Gehlenborg, N, Voet, D, Mallard, W, Lin, P, Frazer, S, Stojanov, P, Liu, Y, Zhou, L, Kim, J, Lawrence, MS, Chin, L, Brown, U, Vandin, F, Wu, HT, Raphael, BJ, Buck Institute for Research on, A, Benz, C, Yau, C, Institute for Systems, B, Reynolds, SM, Shmulevich, I, The University of Texas MD Anderson Cancer, C, Verhaak, RG, Torres-Garcia, W, Vegesna, R, Im, HK, Zhang, W, Cogdell, D, Jonasch, E, Ding, Z, Lu, Y, Akbani, R, Zhang, N, Unruh, AK, Casasent, TD, Wakefield, C, Tsavachidou, D, Chin, L, Mills, GB, Weinstein, JN, Memorial Sloan-Kettering Cancer, C, Jacobsen, A, Rose Brannon, A, Ciriello, G, Schultz, N, Ari Hakimi, A, Reva, B, Antipin, Y, Gao, J, Cerami, E, Gross, B, Arman Aksoy, B, Sinha, R, Weinhold, N, Onur Sumer, S, Taylor, BS, Shen, R, Ostrovnaya, I, Hsieh, JJ, Berger, MF, Ladanyi, M, Sander, C, Oregon Health & Science, U, Fei, SS, Stout, A, Spellman, PT, Stanford, U, Rubin, DL, Liu, TT, University of California Santa, C, Stuart, JM, Ng, S, Paull, EO, Carlin, D, Goldstein, T, Waltman, P, Ellrott, K, Zhu, J, Haussler, D, University of, H, Gunaratne, PH, Xiao, W, Biospecimen core resource: International Genomics, C, Shelton, C, Gardner, J, Penny, R, Sherman, M, Mallery, D, Morris, S, Paulauskis, J, Burnett, K, Shelton, T, Tissue source sites: Brigham & Women’s, H, Signoretti, S, Dana-Farber Cancer, I, Kaelin, WG, Choueiri, T, Georgetown, U, Atkins, MB, International Genomics, C, Penny, R, Burnett, K, Mallery, D, Curley, E, Memorial Sloan-Kettering Cancer, C, Tickoo, S, Reuter, V, University of North Carolina at Chapel, H, Kimryn Rathmell, W, Thorne, L, Boice, L, Huang, M, Fisher, JC, National Cancer, I, Marston Linehan, W, Vocke, CD, Peterson, J, Worrell, R, Merino, MJ, Schmidt, LS, The University of Texas MD Anderson Cancer, C, Tamboli, P, Czerniak, BA, Aldape, KD, Wood, CG, Fox Chase Cancer, C, Boyd, J, Weaver, J, Helen F Graham Cancer Center at Christiana, C, Iacocca, MV, Petrelli, N, Witkin, G, Brown, J, Czerwinski, C, Huelsenbeck-Dill, L, Rabeno, B, Penrose-St. Francis Health, S, Myers, J, Morrison, C, Bergsten, J, Eckman, J, Harr, J, Smith, C, Tucker, K, Anne Zach, L, Roswell Park Cancer, I, Bshara, W, Gaudioso, C, Morrison, C, University of, P, Dhir, R, Maranchie, J, Nelson, J, Parwani, A, , C, Potapova, O, St. Petersburg City Clinical Oncology, D, Fedosenko, K, Mayo, C, Cheville, JC, Houston Thompson, R, Disease working group: Brigham & Women’s, H, Signoretti, S, Dana-Farber Cancer, I, Kaelin, WG, Georgetown, U, Atkins, MB, Memorial Sloan-Kettering Cancer, C, Tickoo, S, Reuter, V, National Cancer, I, Marston Linehan, W, Vocke, CD, Peterson, J, Merino, MJ, Schmidt, LS, The University of Texas MD Anderson Cancer, C, Tamboli, P, Weill Cornell Medical, C, Mosquera, JM, Rubin, MA, Massachusetts General, H, Blute, ML, University of North Carolina, Chapel, H, Kimryn Rathmell, W, centre Data coordination, , 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, Project team: National Cancer, I, Sheth, M, Demchok, JA, Davidsen, T, Wang, Z, Yang, L, Tarnuzzer, RW, Zhang, J, Eley, G, Ferguson, ML, Mills Shaw, KR, National Human Genome Research, I, Guyer, MS, Ozenberger, BA, Sofia, HJ
JournalNature
Date Published2013/06/23
ISSN0028-0836
Abstract

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.

URLhttp://dx.doi.org/10.1038/nature12222
DOI10.1038/nature12222
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23792563?dopt=Abstract