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Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma

2015; Massachusetts Medical Society; Volume: 374; Issue: 2 Linguagem: Inglês

10.1056/nejmoa1505917

1533-4406

W. Marston Linehan, Paul T. Spellman, Christopher J. Ricketts, Chad J. Creighton, Suzanne S. Fei, Caleb Davis, David A. Wheeler, Bradley A. Murray, Laura S. Schmidt, Cathy D. Vocke, Myron Peto, Abu Amar M. Al Mamun, Eve Shinbrot, Anurag Sethi, Samira A. Brooks, W. Kimryn Rathmell, Angela N. Brooks, Katherine A. Hoadley, A. Gordon Robertson, Denise Brooks, Reanne Bowlby, Sara Sadeghi, Hui Shen, Daniel J. Weisenberger, Arnoud Boot, Stephen B. Baylin, Peter W. Laird, Andrew D. Cherniack, Gordon Saksena, Scott M. Haake, Jun Li, Liang Han, Yiling Lu, Gordon B. Mills, Rehan Akbani, Mark D.M. Leiserson, Benjamin J. Raphael, Pavana Anur, Donald P. Bottaro, Laurence Albigès, Nandita Barnabas, Toni K. Choueiri, Bogdan Czerniak, Andrew K. Godwin, A. Ari Hakimi, Thai H. Ho, James J. Hsieh, Michael Ittmann, William Y. Kim, Bhavani Krishnan, Maria J. Merino, Kenna Shaw, Victor E. Reuter, Ed Reznik, Carl Simon Shelley, Hai Hu, Sabina Signoretti, Ramaprasad Srinivasan, Pheroze Tamboli, George Thomas, Satish K. Tickoo, Kenneth Burnett, Daniel Crain, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, W. Troy Shelton, Mark E. Sherman, Eric Thompson, Peggy Yena, Melissa Avedon, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Tracie Santos, Lisa Wise, Erik Zmuda, John A. Demchok, Ina Felau, Carolyn M. Hutter, Margi Sheth, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan Zhang, Brenda Ayala, Julien Baboud, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Adrian Ally, Miruna Balasundaram, Saianand Balu, Rameen Beroukhim, Tom Bodenheimer, Christian Buhay, Yaron S.N. Butterfield, Rebecca Carlsen, Scott L. Carter, Hsu Chao, Eric Chuah, Amanda Clarke, Kyle Covington, Mahmoud Dahdouli, Ninad Dewal, Noreen Dhalla, HarshaVardhan Doddapaneni, Jennifer Drummond, Stacey Gabriel, Richard A. Gibbs, Ranabir Guin, Walker Hale, Alicia Hawes, D. Neil Hayes, Robert A. Holt, Alan P. Hoyle, Joshua M. Stuart, Steven J.M. Jones, Corbin D. Jones, Divya Kalra, Christie Kovar, Lora Lewis, Jie Li, Yussanne Ma, Marco A. Marra, Michael Mayo, Shaowu Meng, Matthew Meyerson, Piotr A. Mieczkowski, Richard A. Moore, Donna Morton, Lisle E. Mose, Andrew J. Mungall, Donna M. Muzny, Joel S. Parker, Charles M. Perou, Jeffrey Roach, Jacqueline E. Schein, Steven E. Schumacher, Yan Shi, Janae V. Simons, Payal Sipahimalani, Tara Skelly, Matthew G. Soloway, Carrie Sougnez, Angela Tam, Donghui Tan, Nina Thiessen, Umadevi Veluvolu, Min Wang, Matthew D. Wilkerson, Tina Wong, Junyuan Wu, Xi Liu, Jane H. Zhou, Jason Bedford, Fengju Chen, Yao Fu, Mark Gerstein, David Haussler, L. Sylvia, Phillip H. Lai, Shiyun Ling, Amie Radenbaugh, David Van Den Berg, John N. Weinstein, Jingchun Zhu, Monique Albert, Iakovina Alexopoulou, Jeremiah J. Andersen, J. Todd Auman, John M.S. Bartlett, Sheldon Bastacky, Julie Bergsten, Michael L. Blute, Lori Boice, Roni J. Bollag, Jeff Boyd, Erik P. Castle, Ying‐Bei Chen, John C. Cheville, Erin Curley, Benjamin Davies, April DeVolk, Rajiv Dhir, Laura Dike, John Eckman, Jay Engel, Jodi Harr, Ronald L. Hrebinko, Mei Huang, Lori Huelsenbeck-Dill, Mary Iacocca, Bruce L. Jacobs, Michael Lobis, Jodi K. Maranchie, Scott McMeekin, Jerome Myers, Joel B. Nelson, Jeremy Parfitt, A.V. Parwani, Nicholas J. Petrelli, Brenda Rabeno, Somak Roy, Andrew L. Salner, Joel W. Slaton, Melissa L. Stanton, R. Houston Thompson, Leigh B. Thorne, Kelinda Tucker, Paul Weinberger, Cynthia Winemiller, Leigh Anne Zach, Rosemary E. Zuna,

Epigenetics and DNA Methylation

Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis.Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH).Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).