Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma

W Marston Linehan, Paul T Spellman, Christopher J Ricketts, Chad J Creighton, Suzanne S Fei, Caleb Davis, David A Wheeler, Bradley A Murray, Laura Schmidt, Cathy D Vocke, Myron Peto, Abu Amar M Al Mamun, Eve Shinbrot, Anurag Sethi, Samira Brooks, W Kimryn Rathmell, Angela N Brooks, Katherine A Hoadley, A Gordon Robertson, Denise Brooks, Reanne Bowlby, Sara Sadeghi, Hui Shen, Daniel J Weisenberger, Moiz Bootwalla, Stephen B Baylin, Peter W Laird, Andrew D Cherniack, Gordon Saksena, Scott Haake, Jun Li, Han Liang, Yiling Lu, Gordon B Mills, Rehan Akbani, Mark D M Leiserson, Benjamin J Raphael, Pavana Anur, Donald Bottaro, Laurence Albiges, Nandita Barnabas, Toni K Choueiri, Bogdan Czerniak, Andrew K Godwin, A Ari Hakimi, Thai H Ho, James Hsieh, Michael Ittmann, William Y Kim, Bhavani Krishnan, Maria J Merino, Kenna R Mills Shaw, Victor E Reuter, Ed Reznik, Carl S Shelley, Brian Shuch, Sabina Signoretti, Ramaprasad Srinivasan, Pheroze Tamboli, George Thomas, Satish Tickoo, Kenneth Burnett, Daniel Crain, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph D Paulauskis, Robert J Penny, Candace Shelton, W Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Melissa T 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 R Covington, Mahmoud Dahdouli, Ninad Dewal, Noreen Dhalla, Harsha V Doddapaneni, Jennifer A Drummond, Stacey B Gabriel, Richard A Gibbs, Ranabir Guin, Walker Hale, Alicia Hawes, D Neil Hayes, Robert A Holt, Alan P Hoyle, Stuart R Jefferys, 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 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, Liu Xi, Jane Zhou, Jason Bedford, Fengju Chen, Yao Fu, Mark Gerstein, David Haussler, Katayoon Kasaian, Phillip 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 Bartlett, Sheldon Bastacky, Julie Bergsten, Michael L Blute, Lori Boice, Roni J Bollag, Jeff Boyd, Erik Castle, Ying-Bei Chen, John C Cheville, Erin Curley, Benjamin Davies, April DeVolk, Rajiv Dhir, Laura Dike, John Eckman, Jay Engel, Jodi Harr, Ronald Hrebinko, Mei Huang, Lori Huelsenbeck-Dill, Mary Iacocca, Bruce Jacobs, Michael Lobis, Jodi K Maranchie, Scott McMeekin, Jerome Myers, Joel Nelson, Jeremy Parfitt, Anil Parwani, Nicholas Petrelli, Brenda Rabeno, Somak Roy, Andrew L Salner, Joel Slaton, Melissa Stanton, R Houston Thompson, Leigh Thorne, Kelinda Tucker, Paul M Weinberger, Cynthia Winemiller, Leigh Anne Zach, Rosemary Zuna

Background 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. Methods 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. Results 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). Conclusions 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.).