Comprehensivemolecular characterization of clear cell renal cell carcinoma

被引：2372

作者：

Creighton, Chad J. ^{[1
]}

Morgan, Margaret ^{[1
]}

Gunaratne, Preethi H. ^{[1
]}

Wheeler, David A. ^{[1
]}

Gibbs, Richard A. ^{[1
]}

Robertson, A. Gordon ^{[3
]}

Chu, Andy ^{[3
]}

Beroukhim, Rameen ^{[4
,5
,6
,53
,55
]}

Cibulskis, Kristian ^{[5
]}

Signoretti, Sabina ^{[7
]}

Vandin, Fabio ^{[8
]}

Wu, Hsin-Ta ^{[8
]}

Raphael, Benjamin J. ^{[8
]}

Verhaak, Roel G. W. ^{[9
]}

Tamboli, Pheroze ^{[10
]}

Torres-Garcia, Wandaliz ^{[9
]}

Akbani, Rehan ^{[9
]}

Weinstein, John N. ^{[9
]}

Reuter, Victor ^{[11
]}

Hsieh, James J. ^{[12
]}

Brannon, A. Rose ^{[11
]}

Hakimi, A. Ari ^{[12
]}

Jacobsen, Anders ^{[13
]}

Ciriello, Giovanni ^{[13
]}

Reva, Boris ^{[13
]}

Ricketts, Christopher J. ^{[14
]}

Linehan, W. Marston ^{[14
]}

Stuart, Joshua M. ^{[15
]}

Rathmell, W. Kimryn ^{[17
]}

Shen, Hui ^{[18
]}

Laird, Peter W. ^{[18
]}

Muzny, Donna ^{[1
]}

Davis, Caleb ^{[1
]}

Morgan, Margaret ^{[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
]}

机构：

[1] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[2] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA

[3] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z, Canada

[4] Harvard Univ, Dept Med, Sch Med, Boston, MA 02215 USA

[5] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA

[6] Harvard Univ, Cambridge, MA 02142 USA

[7] Harvard Univ, Dept Pathol, Sch Med, Boston, MA 02215 USA

[8] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[11] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[12] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[13] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA

[14] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA

[15] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA

[16] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA

[17] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[18] Univ So Calif, USC Epigenome Ctr, Los Angeles, CA 90033 USA

[19] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA

[20] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA

[21] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA

[22] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA

[23] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[24] Univ N Carolina, Dept Internal Med, Div Med Oncol, Chapel Hill, NC 27599 USA

[25] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA

[26] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

[27] Harvard Univ, Ctr Biomed Informat, Sch Med, Boston, MA 02115 USA

[28] Childrens Hosp, Informat Program, Boston, MA 02115 USA

[29] Johns Hopkins Univ, Canc Biol Div, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA

[30] Inst Syst Biol, Seattle, WA 98109 USA

[31] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[32] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA

[33] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portand, OR 97239 USA

[34] Stanford Univ, Dept Radiol, Med Ctr, Stanford, CA 94305 USA

[35] Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA

[36] Int Genom Consortium, Phoenix, AZ 85004 USA

[37] Georgetown Univ, Georgetown Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA

[38] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA

[39] Fox Chase Canc Ctr, Canc Biol Program, Philadelphia, PA 19111 USA

[40] Christiana Care, Helen F Graham Canc Ctr, Newark, DC 19713 USA

[41] Penrose St Francis Hlth Serv, Colorado Springs, CO 80907 USA

[42] Roswell Pk Canc Inst, Dept Pathol, Buffalo, NY 14263 USA

[43] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA

[44] Cureline Inc, San Francisco, CA 94080 USA

[45] St Petersburg City Clin Oncol Dispensary, St Petersburg 198255, Russia

[46] Weill Cornell Coll Med, Dept Pathol & Lab Med, New York, NY 10065 USA

[47] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA

[48] SRA Int, Fairfax, VA 22033 USA

[49] NCI, Canc Genome Atlas Program Off, Ctr Canc Genom, Bethesda, MD 20892 USA

[50] TCGA Consultant Scimentis LLC, Atlanta, GA 30666 USA

来源：

NATURE | 2013年 / 499卷 / 7456期

基金：

美国国家科学基金会;

关键词：

KIDNEY CANCER; TUMOR-SUPPRESSOR; GENETIC-BASIS; METHYLATION; PROTEIN; ARM;

D O I：

10.1038/nature12222

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：43 / +

页数：7

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