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Nature. 2013 Jul 4;499(7456):43-9. doi: 10.1038/nature12222. Epub 2013 Jun 23.

Comprehensive molecular characterization of clear cell renal cell carcinoma.

Collaborators (346)

Creighton CJ, Morgan M, Gunaratne PH, Wheeler DA, Gibbs RA, Robertson A, Chu A, Beroukhim R, Cibulskis K, Signoretti S, Vandin F, Wu HT, Raphael BJ, Verhaak RG, Tamboli P, Torres-Garcia W, Akbani R, Weinstein JN, Reuter V, Hsieh JJ, Brannon A, Hakimi A, Jacobsen A, Ciriello G, Reva B, Ricketts CJ, Linehan W, Stuart JM, Rathmell W, Shen H, Laird PW, 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, Getz G, Cibulskis K, Lawrence MS, Sougnez C, Carter SL, Sivachenko A, Lichtenstein L, Stewart C, Voet D, Fisher S, Gabriel SB, Lander E, 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, 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, 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, Hayes D, Perou CM, Kucherlapati R, Park P, Shen H, Triche T Jr, Weisenberger DJ, Lai PH, Bootwalla MS, Maglinte DT, Mahurkar S, Berman BP, Van Den Berg DJ, Cope L, Baylin SB, Laird PW, Creighton CJ, Wheeler DA, 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, Vandin F, Wu HT, Raphael BJ, Benz C, Yau C, Reynolds SM, Shmulevich I, Verhaak RG, Torres-Garcia W, Vegesna R, Kim H, 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, Jacobsen A, Brannon R, Ciriello G, Schultz N, Hakimi A, Reva B, Antipin Y, Gao J, Cerami E, Gross B, Aksoy BA, Sinha R, Weinhold N, Sumer S, Taylor BS, Shen R, Ostrovnaya I, Hsieh JJ, Berger MF, Ladanyi M, Sander C, Fei SS, Stout A, Spellman PT, Rubin DL, Liu TT, Stuart JM, Ng S, Paull EO, Carlin D, Goldstein T, Waltman P, Ellrott K, Zhu J, Haussler D, Gunaratne PH, Xiao W, Shelton C, Gardner J, Penny R, Sherman M, Mallery D, Morris S, Paulauskis J, Burnett K, Shelton T, Signoretti S, Kaelin WG, Choueiri T, Atkins MB, Penny R, Burnett K, Mallery D, Curley E, Tickoo S, Reuter V, Rathmell W, Thorne L, Boice L, Huang M, Fisher JC, Linehan WM, Vocke CD, Peterson J, Worrell R, Merino MJ, Schmidt LS, Tamboli P, Czerniak BA, Aldape KD, Wood CG, Boyd J, Weaver J, 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, Morrison C, Dhir R, Maranchie J, Nelson J, Parwani A, Potapova O, Fedosenko K, Cheville JC, Thompson RH, Signoretti S, Kaelin WG, Atkins MB, Tickoo S, Reuter V, Linehan WM, Vocke CD, Peterson J, Merino MJ, Schmidt LS, Tamboli P, Mosquera JM, Rubin MA, Blute ML, Rathmell W, 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.

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.

PMID:
23792563
PMCID:
PMC3771322
DOI:
10.1038/nature12222
[Indexed for MEDLINE]
Free PMC Article

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