Comprehensive molecular characterization of clear cell renal cell carcinoma
David A. Wheeler(Baylor College of Medicine), Divya Kalra(Baylor College of Medicine), Chad J. Creighton(Baylor College of Medicine), Christie Kovar(Baylor College of Medicine), Donna Muzny(Baylor College of Medicine), Walker Hale(Baylor College of Medicine), Margaret Morgan(Baylor College of Medicine), Kyle Chang(Baylor College of Medicine), Harsha Doddapaneni(Baylor College of Medicine), Richard A. Gibbs(Baylor College of Medicine), Yi Han(Baylor College of Medicine), Lora Lewis(Baylor College of Medicine), Jireh Santibanez(Baylor College of Medicine), Caleb Davis(Baylor College of Medicine), David A. Wheeler (Baylor College of Medicine), Yiming Zhu(Baylor College of Medicine), Susan Benton(Baylor College of Medicine), Jeffrey G. Reid(Baylor College of Medicine), Donna Morton(Baylor College of Medicine), Preethi H. Gunaratne(University of Houston), Liu Xi(Baylor College of Medicine), Lisa R. Treviño(Baylor College of Medicine), Huyen Dinh(Baylor College of Medicine), Chad J. Creighton(Children's Cancer Center), Nipun Kakkar(Baylor College of Medicine), Min Wang(Baylor College of Medicine), Chad J. Creighton(Baylor College of Medicine), Chad J. Creighton(Children's Cancer Center), Chad J. Creighton (Baylor College of Medicine), Preethi H. Gunaratne(Baylor College of Medicine), Preethi H. Gunaratne (University of Houston), Weimin Xiao(University of Houston), Jacqueline E. Schein(Canada's Michael Smith Genome Sciences Centre), Patrick Plettner(Canada's Michael Smith Genome Sciences Centre), Darlene Lee(Canada's Michael Smith Genome Sciences Centre), Steven J. M. Jones (Canada's Michael Smith Genome Sciences Centre), Michael Mayo(Canada's Michael Smith Genome Sciences Centre), Yaron S. N. Butterfield(Canada's Michael Smith Genome Sciences Centre), Payal Sipahimalani(Canada's Michael Smith Genome Sciences Centre), A. Gordon Robertson(Canada's Michael Smith Genome Sciences Centre), Marco A. Marra(Canada's Michael Smith Genome Sciences Centre), Yongjun Zhao(Canada's Michael Smith Genome Sciences Centre), Adrian Ally(Canada's Michael Smith Genome Sciences Centre), Chandra Lebovitz(Canada's Michael Smith Genome Sciences Centre), Erin Pleasance(Canada's Michael Smith Genome Sciences Centre), Andrew J. Mungall(Canada's Michael Smith Genome Sciences Centre), Inanc Birol(Canada's Michael Smith Genome Sciences Centre), Natasja Wye(Canada's Michael Smith Genome Sciences Centre), Noreen Dhalla(Canada's Michael Smith Genome Sciences Centre), Richard A. Moore(Canada's Michael Smith Genome Sciences Centre), Dominik Stoll(Canada's Michael Smith Genome Sciences Centre), Rebecca Carlsen(Canada's Michael Smith Genome Sciences Centre), Robert A. Holt(Canada's Michael Smith Genome Sciences Centre), Angela Tam(Canada's Michael Smith Genome Sciences Centre), Andy Chu(Canada's Michael Smith Genome Sciences Centre), Nina Thiessen(Canada's Michael Smith Genome Sciences Centre), Carrie Hirst(Canada's Michael Smith Genome Sciences Centre), Haiyan I. Li(Canada's Michael Smith Genome Sciences Centre), Arash Shafiei(Canada's Michael Smith Genome Sciences Centre), Jared R. Slobodan(Canada's Michael Smith Genome Sciences Centre), Eric Chuah(Canada's Michael Smith Genome Sciences Centre), Candace Carter(Canada's Michael Smith Genome Sciences Centre), Miruna Balasundaram(Canada's Michael Smith Genome Sciences Centre), Hye-Jung E. Chun(Canada's Michael Smith Genome Sciences Centre), Richard J. Varhol(Canada's Michael Smith Genome Sciences Centre), Sharon Gorski(Canada's Michael Smith Genome Sciences Centre), A. Gordon Robertson(Canada's Michael Smith Genome Sciences Centre), Ranabir Guin(Canada's Michael Smith Genome Sciences Centre), Martin Hirst(Canada's Michael Smith Genome Sciences Centre), Robin J. N. Coope(Canada's Michael Smith Genome Sciences Centre), Rameen Beroukhim (Harvard University), Rameen Beroukhim(Dana-Farber Cancer Institute), Sheila Fisher(Broad Institute), Gordon Saksena(Eli and Edythe Broad Foundation), Lynda Chin(Broad Institute), Kristin Ardlie(Broad Institute), Lihua Zhou(Broad Institute), Chip Stewart(Broad Institute), Rameen Beroukhim(Dana-Farber Cancer Institute), Steve E. Schumacher(Dana-Farber Cancer Institute), Barbara Tabak(Dana-Farber Cancer Institute), David I. Heiman(Broad Institute), Pei Lin(Eli and Edythe Broad Foundation), Michael S. Noble(Eli and Edythe Broad Foundation), Michael S. Lawrence(Broad Institute), Stacey B. Gabriel(Eli and Edythe Broad Foundation), Andrey Sivachenko(Eli and Edythe Broad Foundation), Stacey B. Gabriel(Eli and Edythe Broad Foundation), William Mallard(Eli and Edythe Broad Foundation), Carrie Sougnez(Eli and Edythe Broad Foundation), Lynda Chin (Eli and Edythe Broad Foundation), Jaegil Kim(Eli and Edythe Broad Foundation), Nils Gehlenborg(Eli and Edythe Broad Foundation), Matthew Meyerson(Broad Institute), Eric Lander(Eli and Edythe Broad Foundation), Rameen Beroukhim(Dana-Farber Cancer Institute), Scott Frazer(Broad Institute), Petar Stojanov(Broad Institute), Robert C. Onofrio(Eli and Edythe Broad Foundation), Yingchun Liu(Broad Institute), Jeff Gentry(Broad Institute), Scott L. Carter(Eli and Edythe Broad Foundation), Hailei Zhang(Eli and Edythe Broad Foundation), Kristian Cibulskis(Broad Institute), Carrie Sougnez(Broad Institute), Daniel DiCara(Broad Institute), Lee Lichtenstein(Broad Institute), Gad Getz(Center for Cancer Research), Juok Cho(Eli and Edythe Broad Foundation), Doug Voet(Eli and Edythe Broad Foundation), Andrew D. Cherniack(Broad Institute), Sabina Signoretti(Harvard University), Matthew Meyerson(Eli and Edythe Broad Foundation), Sabina Signoretti (Harvard University), Sabina Signoretti(Brigham and Women's Hospital), Fabio Vandin Hsin-Ta Wu(Brown University), Benjamin J. Raphael(Brown University), Hsin-Ta Wu (Brown University), Fabio Vandin Hsin-Ta Wu(Brown University), Fabio Vandin(Brown University), Roel G.W. Verhaak(The University of Texas MD Anderson Cancer Center), Eric Jonasch(The University of Texas MD Anderson Cancer Center), Rahul Vegesna(The University of Texas MD Anderson Cancer Center), Tod D. Casasent(The University of Texas MD Anderson Cancer Center), Roel G. W. Verhaak(The University of Texas MD Anderson Cancer Center), Wandaliz Torres-Garcia(The University of Texas MD Anderson Cancer Center), Anna K. Unruh(The University of Texas MD Anderson Cancer Center), Nianxiang Zhang(The University of Texas MD Anderson Cancer Center), Hoon Kim(The University of Texas MD Anderson Cancer Center), Zhiyong Ding(The University of Texas MD Anderson Cancer Center), Chris Wakefield (The University of Texas MD Anderson Cancer Center), Rehan Akbani(The University of Texas MD Anderson Cancer Center), John N. Weinstein(The University of Texas MD Anderson Cancer Center), Bogdan A. Czerniak(The University of Texas MD Anderson Cancer Center), David Cogdell(The University of Texas MD Anderson Cancer Center), Pheroze Tamboli(The University of Texas MD Anderson Cancer Center), Kenneth D. Aldape (The University of Texas MD Anderson Cancer Center), Pheroze Tamboli(The University of Texas MD Anderson Cancer Center), Wei Zhang(The University of Texas MD Anderson Cancer Center), Satish Tickoo (Memorial Sloan Kettering Cancer Center), Victor Reuter(Memorial Sloan Kettering Cancer Center), Michael F. Berger(Memorial Sloan Kettering Cancer Center), Satish Tickoo(Memorial Sloan Kettering Cancer Center), Victor Reuter(Memorial Sloan Kettering Cancer Center), A. Rose Brannon(Memorial Sloan Kettering Cancer Center), Marc Ladanyi(Memorial Sloan Kettering Cancer Center), James J. Hsieh (Memorial Sloan Kettering Cancer Center), A. Ari Hakimi(Memorial Sloan Kettering Cancer Center), James J. Hsieh(Memorial Sloan Kettering Cancer Center), Giovanni Ciriello(Memorial Sloan Kettering Cancer Center), Yevgeniy Antipin(Memorial Sloan Kettering Cancer Center), Boris Reva(Memorial Sloan Kettering Cancer Center), Nikolaus Schultz(Memorial Sloan Kettering Cancer Center), Barry S. Taylor(Memorial Sloan Kettering Cancer Center), Nils Weinhold(Memorial Sloan Kettering Cancer Center), Chris Sander(Memorial Sloan Kettering Cancer Center), Anders Jacobsen(Memorial Sloan Kettering Cancer Center), Rileen Sinha(Memorial Sloan Kettering Cancer Center), S. Onur Sumer(Memorial Sloan Kettering Cancer Center), Benjamin Gross(Memorial Sloan Kettering Cancer Center), Ronglai Shen (Memorial Sloan Kettering Cancer Center), Ethan Cerami(Memorial Sloan Kettering Cancer Center), B. Arman Aksoy(Memorial Sloan Kettering Cancer Center), Jianjiong Gao(Memorial Sloan Kettering Cancer Center), Anders Jacobsen(Memorial Sloan Kettering Cancer Center), Christopher J. Ricketts(National Cancer Institute), Maria J. Merino(National Cancer Institute), W. Marston Linehan(National Cancer Institute), Cathy D. Vocke(National Cancer Institute), Maria J. Merino (National Cancer Institute), Robert Worrell(National Cancer Institute), James Peterson(National Cancer Institute), Laura S. Schmidt(National Cancer Institute), Joshua M. Stuart(University of California, Santa Cruz), Peter Waltman(University of California, Santa Cruz), Evan O. Paull(University of California, Santa Cruz), Joshua M. Stuart(University of California, Santa Cruz), Sam Ng(University of California, Santa Cruz), Theodore Goldstein(University of California, Santa Cruz), Daniel Carlin(University of California, Santa Cruz), Kyle Ellrott(University of California, Santa Cruz), David Haussler(Howard Hughes Medical Institute), Jing Zhu (University of California, Santa Cruz), Joel S. Parker(University of North Carolina at Chapel Hill), W. Kimryn Rathmell(University of North Carolina at Chapel Hill), W. Kimryn Rathmell(University of North Carolina at Chapel Hill), Alan P. Hoyle(University of North Carolina at Chapel Hill), Elizabeth Buda(University of North Carolina at Chapel Hill), Junyuan Wu(University of North Carolina at Chapel Hill), Saianand Balu(University of North Carolina at Chapel Hill), Jesse Walsh(University of North Carolina at Chapel Hill), Lori Boice(University of North Carolina at Chapel Hill), Mathew G. Soloway(University of North Carolina at Chapel Hill), Christina Liquori(University of North Carolina at Chapel Hill), Janae V. Simons(University of North Carolina at Chapel Hill), Mei Huang(University of North Carolina at Chapel Hill), Jennifer C. Fisher (University of North Carolina at Chapel Hill), Scot Waring(University of North Carolina at Chapel Hill), Leigh Thorne(University of North Carolina at Chapel Hill), Yan Shi(University of North Carolina at Chapel Hill), Katherine A. Hoadley(University of North Carolina at Chapel Hill), Yidi J. Turman(University of North Carolina at Chapel Hill), D. Neil Hayes(University of North Carolina at Chapel Hill), Tom Bodenheimer(University of North Carolina at Chapel Hill), Charles M. Perou(University of North Carolina at Chapel Hill), Hui Shen(University of Southern California), Daniel J. Weisenberger(University of Southern California), Hui Shen(University of Southern California), David J. Van Den Berg (University of Southern California), Phillip H. Lai(University of Southern California), Moiz S. Bootwalla(University of Southern California), Dennis T. Maglinte(University of Southern California), Benjamin P. Berman(University of Southern California), Swapna Mahurkar(University of Southern California), Timothy Triche Jr(University of Southern California), Peter W. Laird(University of Southern California), J.Todd Auman(University of North Carolina at Chapel Hill), Donghui Tan(University of North Carolina at Chapel Hill), Corbin D. Jones(University of North Carolina at Chapel Hill), Katherine A. Hoadley(University of North Carolina at Chapel Hill), Lisle E. Mose(University of North Carolina at Chapel Hill), Michael D. Topal (University of North Carolina at Chapel Hill), Charles M. Perou(University of North Carolina at Chapel Hill), Piotr A. Mieczkowski(University of North Carolina at Chapel Hill), Stuart R. Jefferys(University of North Carolina at Chapel Hill), Katherine A. Hoadley(University of North Carolina at Chapel Hill), Michael D. Topal (University of North Carolina at Chapel Hill), Charles M. Perou(University of North Carolina at Chapel Hill), D. Neil Hayes(University of North Carolina at Chapel Hill), Raju Kucherlapati(Brigham and Women's Hospital), Peter Park(Center for Systems Biology), Raju Kucherlapati (Harvard University), Nils Gehlenborg(Eli and Edythe Broad Foundation), Peter Park (Brigham and Women's Hospital), Peter Park(Brigham and Women's Hospital), Leslie Cope (Sidney Kimmel Comprehensive Cancer Center), Stephen B. Baylin(Sidney Kimmel Comprehensive Cancer Center), Sheila M. Reynolds (Institute for Systems Biology), Ilya Shmulevich(Institute for Systems Biology), Dimitra Tsavachidou (The University of Texas MD Anderson Cancer Center), Yiling Lu(The University of Texas MD Anderson Cancer Center), Gordon B. Mills(The University of Texas MD Anderson Cancer Center), Lynda Chin (Eli and Edythe Broad Foundation), Lynda Chin(Broad Institute), Irina Ostrovnaya(Memorial Sloan Kettering Cancer Center), Andrew Stout (Oregon Health & Science University), Suzanne S. Fei(Oregon Health & Science University), Paul T. Spellman(Oregon Health & Science University), Daniel L. Rubin (Stanford Medicine), Tiffany T. Liu(Stanford University), David Haussler(University of California, Santa Cruz), Robert Penny(Translational Genomics Research Institute), Johanna Gardner(Translational Genomics Research Institute), Ken Burnett(Translational Genomics Research Institute), Troy Shelton(Translational Genomics Research Institute), Candace Shelton(Translational Genomics Research Institute), David Mallery(Translational Genomics Research Institute), Joseph Paulauskis(Translational Genomics Research Institute), Mark Sherman(Translational Genomics Research Institute), David Mallery (Translational Genomics Research Institute), Erin Curley(Translational Genomics Research Institute), Scott Morris(Translational Genomics Research Institute), Michael B. Atkins(Georgetown University Medical Center), Michael B. Atkins (Georgetown University Medical Center), Laura S. Schmidt (National Cancer Institute), Laura S. Schmidt(National Cancer Institute), Christopher G. Wood(The University of Texas MD Anderson Cancer Center), Jeff Boyd (Fox Chase Cancer Center), JoEllen Weaver(Fox Chase Cancer Center), Gary Witkin(Christiana Care Health System), Lori Huelsenbeck-Dill (Christiana Care Health System), Jennifer Brown(Christiana Care Health System), Nicholas Petrelli(Christiana Care Health System), Christine Czerwinski(Christiana Care Health System), Mary V. Iacocca(Christiana Care Health System), Brenda Rabeno(Christiana Care Health System), Julie Bergsten(Penrose-St. Francis Health Services), Carl Morrison(Penrose-St. Francis Health Services), Jerome Myers(Penrose-St. Francis Health Services), Kelinda Tucker (Penrose-St. Francis Health Services), Christine Smith(Penrose-St. Francis Health Services), Leigh Anne Zach(Penrose-St. Francis Health Services), John Eckman(Penrose-St. Francis Health Services), Jodi Harr(Penrose-St. Francis Health Services), Carl Morrison(Roswell Park Comprehensive Cancer Center), Carmelo Gaudioso (Roswell Park Comprehensive Cancer Center), Wiam Bshara(Roswell Park Comprehensive Cancer Center), Anil Parwani(University of Pittsburgh), Joel Nelson (University of Pittsburgh), Jodi Maranchie(University of Pittsburgh), Rajiv Dhir(University of Pittsburgh), Olga Potapova(Sunesis (United States)), Konstantin Fedosenko(City Clinical Oncology Center), Juan M. Mosquera (Cornell University), Mark A. Rubin(Cornell University), Michael L. Blute(Massachusetts General Hospital), Ari Kahn(SRA International (United States)), Mark Backus(SRA International (United States)), Rohini Raman(SRA International (United States)), David Pot(SRA International (United States)), Shelley Alonso(SRA International (United States)), Sean Barletta (SRA International (United States)), Peter Kigonya(SRA International (United States)), Deepak Srinivasan(SRA International (United States)), Prachi Kothiyal(SRA International (United States)), Julien Baboud(SRA International (United States)), Eric Snyder(SRA International (United States)), Rashmi Sanbhadti(SRA International (United States)), Joan Pontius(SRA International (United States)), Robert Sfeir(SRA International (United States)), Stanley Girshik(SRA International (United States)), Todd Pihl(SRA International (United States)), Brenda Ayala(SRA International (United States)), Anna Chu(Canada's Michael Smith Genome Sciences Centre), Matthew Nicholls(SRA International (United States)), Jessica Walton(SRA International (United States)), Dominique Berton(SRA International (United States)), Mark Jensen(SRA International (United States)), Zhining Wang(National Cancer Institute), Jiashan Zhang (National Cancer Institute), Liming Yang(National Cancer Institute), Tanja Davidsen(National Cancer Institute), Roy W. Tarnuzzer(National Cancer Institute), Margi Sheth(National Cancer Institute), Kenna R. Mills Shaw(National Cancer Institute), John A. Demchok(National Cancer Institute), Greg Eley(Atlanta University Center), Martin L. Ferguson(FIT Consulting (Italy)), Mark S. Guyer(National Institutes of Health), Heidi J. Sofia.(National Institutes of Health), Bradley A. Ozenberger (National Institutes of Health), Rameen Beroukhim(Eli and Edythe Broad Foundation), William G. Kaelin(Howard Hughes Medical Institute), Sabina Signoretti(Dana-Farber Cancer Institute), Toni Choueiri(Dana-Farber Cancer Institute), Sabina Signoretti (Dana-Farber Cancer Institute), Matthew Meyerson(Dana-Farber Cancer Institute), Sabina Signoretti(Dana-Farber Cancer Institute), Petar Stojanov(Eli and Edythe Broad Foundation), Christopher Benz (Buck Institute for Research on Aging), Christina Yau(Buck Institute for Research on Aging), Barbara Tabak(Eli and Edythe Broad Foundation), Rameen Beroukhim(Broad Institute), Steve E. Schumacher (Eli and Edythe Broad Foundation), Gad Getz (Center for Cancer Research), Gad Getz(Eli and Edythe Broad Foundation), Gad Getz(Massachusetts General Hospital), John C. Cheville (Mayo Clinic), R. Houston Thompson(Mayo Clinic), Sabina Signoretti(Dana-Farber Cancer Institute), Sabina Signoretti (Brigham and Women's Hospital), Sabina Signoretti(Harvard University), William G. Kaelin (Dana-Farber Cancer Institute), William G. Kaelin(Dana-Farber Cancer Institute)
Cited by 3,524Open Access
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. The Cancer Genome Atlas Research Network reports an integrative analysis of more than 400 samples of clear cell renal cell carcinoma based on genomic, DNA methylation, RNA and proteomic characterisation; frequent mutations were identified in the PI(3)K/AKT pathway, suggesting this pathway might be a potential therapeutic target, among the findings is also a demonstration of metabolic remodelling which correlates with tumour stage and severity. The Cancer Genome Atlas consortium reports an integrative analysis of more than 400 samples of clear cell renal carcinoma on the basis of genomic, DNA methylation, RNA and proteomic characterization. The data reveal frequent mutations in the PI(3)K/AKT pathway, suggesting that this pathway might be a potential therapeutic target, in addition to an array of epigenetic alterations that are linked to specific mutations in chromatin-associated proteins. One notable finding is the presence of a metabolic shift in aggressive cancers, correlating with tumour stage and severity.