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

doi:10.1056/NEJMoa1505917

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 BrooksReanne 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

Research output: Contribution to journal › Article › peer-review

931 Scopus citations

Abstract

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 renalcell carcinoma consisted of at least three subtypes based on molecular and phenotypic features.

Original language	English (US)
Pages (from-to)	135-145
Number of pages	11
Journal	New England Journal of Medicine
Volume	374
Issue number	2
DOIs	https://doi.org/10.1056/NEJMoa1505917
State	Published - Jan 14 2016

ASJC Scopus subject areas

General Medicine

Access to Document

10.1056/NEJMoa1505917

Cite this

Linehan, W. M., Spellman, P. T., Ricketts, C. J., Creighton, C. J., Fei, S. S., Davis, C., Wheeler, D. A., Murray, B. A., Schmidt, L., Vocke, C. D., Peto, M., Al Mamun, A. A. M., Shinbrot, E., Sethi, A., Brooks, S., Rathmell, W. K., Brooks, A. N., Hoadley, K. A., Robertson, A. G., ... Zuna, R. (2016). Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. New England Journal of Medicine, 374(2), 135-145. https://doi.org/10.1056/NEJMoa1505917

Linehan, WM, Spellman, PT, Ricketts, CJ, Creighton, CJ, Fei, SS, Davis, C, Wheeler, DA, Murray, BA, Schmidt, L, Vocke, CD, Peto, M, Al Mamun, AAM, Shinbrot, E, Sethi, A, Brooks, S, Rathmell, WK, Brooks, AN, Hoadley, KA, Robertson, AG, Brooks, D, Bowlby, R, Sadeghi, S, Shen, H, Weisenberger, DJ, Bootwalla, M, Baylin, SB, Laird, PW, Cherniack, AD, Saksena, G, Haake, S, Li, J, Liang, H, Lu, Y, Mills, GB, Akbani, R, Leiserson, MDM, Raphael, BJ, Anur, P, Bottaro, D, Albiges, L, Barnabas, N, Choueiri, TK, Czerniak, B, Godwin, AK, Hakimi, AA, Ho, TH, Hsieh, J, Ittmann, M, Kim, WY, Krishnan, B, Merino, MJ, Shaw, KRM, Reuter, VE, Reznik, E, Shelley, CS, Shuch, B, Signoretti, S, Srinivasan, R, Tamboli, P, Thomas, G, Tickoo, S, Burnett, K, Crain, D, Gardner, J, Lau, K, Mallery, D, Morris, S, Paulauskis, JD, Penny, RJ, Shelton, C, Shelton, WT, Sherman, M, Thompson, E, Yena, P, Avedon, MT, Bowen, J, Gastier-Foster, JM, Gerken, M, Leraas, KM, Lichtenberg, TM, Ramirez, NC, Santos, T, Wise, L, Zmuda, E, Demchok, JA, Felau, I, Hutter, CM, Sheth, M, Sofia, HJ, Tarnuzzer, R, Wang, Z, Yang, L, Zenklusen, JC, Zhang, J, Ayala, B, Baboud, J, Chudamani, S, Liu, J, Lolla, L, Naresh, R, Pihl, T, Sun, Q, Wan, Y, Wu, Y, Ally, A, Balasundaram, M, Balu, S, Beroukhim, R, Bodenheimer, T, Buhay, C, Butterfield, YSN, Carlsen, R, Carter, SL, Chao, H, Chuah, E, Clarke, A, Covington, KR, Dahdouli, M, Dewal, N, Dhalla, N, Doddapaneni, HV, Drummond, JA, Gabriel, SB, Gibbs, RA, Guin, R, Hale, W, Hawes, A, Hayes, DN, Holt, RA, Hoyle, AP, Jefferys, SR, Jones, SJM, Jones, CD, Kalra, D, Kovar, C, Lewis, L, Li, J, Ma, Y, Marra, MA, Mayo, M, Meng, S, Meyerson, M, Mieczkowski, PA, Moore, RA, Morton, D, Mose, LE, Mungall, AJ, Muzny, D, Parker, JS, Perou, CM, Roach, J, Schein, JE, Schumacher, SE, Shi, Y, Simons, JV, Sipahimalani, P, Skelly, T, Soloway, MG, Sougnez, C, Tam, A, Tan, D, Thiessen, N, Veluvolu, U, Wang, M, Wilkerson, MD, Wong, T, Wu, J, Xi, L, Zhou, J, Bedford, J, Chen, F, Fu, Y, Gerstein, M, Haussler, D, Kasaian, K, Lai, P, Ling, S, Radenbaugh, A, Van Den Berg, D, Weinstein, JN, Zhu, J, Albert, M, Alexopoulou, I, Andersen, JJ, Auman, JT, Bartlett, J, Bastacky, S, Bergsten, J, Blute, ML, Boice, L, Bollag, RJ, Boyd, J, Castle, E, Chen, YB, Cheville, JC, Curley, E, Davies, B, DeVolk, A, Dhir, R, Dike, L, Eckman, J, Engel, J, Harr, J, Hrebinko, R, Huang, M, Huelsenbeck-Dill, L, Iacocca, M, Jacobs, B, Lobis, M, Maranchie, JK, McMeekin, S, Myers, J, Nelson, J, Parfitt, J, Parwani, A, Petrelli, N, Rabeno, B, Roy, S, Salner, AL, Slaton, J, Stanton, M, Thompson, RH, Thorne, L, Tucker, K, Weinberger, PM, Winemiller, C, Zach, LA & Zuna, R 2016, 'Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma', New England Journal of Medicine, vol. 374, no. 2, pp. 135-145. https://doi.org/10.1056/NEJMoa1505917

@article{27faa89f35594e8c8d0ba6be7d9a08ce,

title = "Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma",

abstract = "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 renalcell carcinoma consisted of at least three subtypes based on molecular and phenotypic features.",

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

note = "Publisher Copyright: {\textcopyright} 2015 Massachusetts Medical Society.",

year = "2016",

month = jan,

day = "14",

doi = "10.1056/NEJMoa1505917",

language = "English (US)",

volume = "374",

pages = "135--145",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "2",

}

TY - JOUR

T1 - Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma

AU - Linehan, W. Marston

AU - Spellman, Paul T.

AU - Ricketts, Christopher J.

AU - Creighton, Chad J.

AU - Fei, Suzanne S.

AU - Davis, Caleb

AU - Wheeler, David A.

AU - Murray, Bradley A.

AU - Schmidt, Laura

AU - Vocke, Cathy D.

AU - Peto, Myron

AU - Al Mamun, Abu Amar M.

AU - Shinbrot, Eve

AU - Sethi, Anurag

AU - Brooks, Samira

AU - Rathmell, W. Kimryn

AU - Brooks, Angela N.

AU - Hoadley, Katherine A.

AU - Robertson, A. Gordon

AU - Brooks, Denise

AU - Bowlby, Reanne

AU - Sadeghi, Sara

AU - Shen, Hui

AU - Weisenberger, Daniel J.

AU - Bootwalla, Moiz

AU - Baylin, Stephen B.

AU - Laird, Peter W.

AU - Cherniack, Andrew D.

AU - Saksena, Gordon

AU - Haake, Scott

AU - Li, Jun

AU - Liang, Han

AU - Lu, Yiling

AU - Mills, Gordon B.

AU - Akbani, Rehan

AU - Leiserson, Mark D.M.

AU - Raphael, Benjamin J.

AU - Anur, Pavana

AU - Bottaro, Donald

AU - Albiges, Laurence

AU - Barnabas, Nandita

AU - Choueiri, Toni K.

AU - Czerniak, Bogdan

AU - Godwin, Andrew K.

AU - Hakimi, A. Ari

AU - Ho, Thai H.

AU - Hsieh, James

AU - Ittmann, Michael

AU - Kim, William Y.

AU - Krishnan, Bhavani

AU - Merino, Maria J.

AU - Shaw, Kenna R.Mills

AU - Reuter, Victor E.

AU - Reznik, Ed

AU - Shelley, Carl S.

AU - Shuch, Brian

AU - Signoretti, Sabina

AU - Srinivasan, Ramaprasad

AU - Tamboli, Pheroze

AU - Thomas, George

AU - Tickoo, Satish

AU - Burnett, Kenneth

AU - Crain, Daniel

AU - Gardner, Johanna

AU - Lau, Kevin

AU - Mallery, David

AU - Morris, Scott

AU - Paulauskis, Joseph D.

AU - Penny, Robert J.

AU - Shelton, Candace

AU - Shelton, W. Troy

AU - Sherman, Mark

AU - Thompson, Eric

AU - Yena, Peggy

AU - Avedon, Melissa T.

AU - Bowen, Jay

AU - Gastier-Foster, Julie M.

AU - Gerken, Mark

AU - Leraas, Kristen M.

AU - Lichtenberg, Tara M.

AU - Ramirez, Nilsa C.

AU - Santos, Tracie

AU - Wise, Lisa

AU - Zmuda, Erik

AU - Demchok, John A.

AU - Felau, Ina

AU - Hutter, Carolyn M.

AU - Sheth, Margi

AU - Sofia, Heidi J.

AU - Tarnuzzer, Roy

AU - Wang, Zhining

AU - Yang, Liming

AU - Zenklusen, Jean C.

AU - Zhang, Jiashan

AU - Ayala, Brenda

AU - Baboud, Julien

AU - Chudamani, Sudha

AU - Liu, Jia

AU - Lolla, Laxmi

AU - Naresh, Rashi

AU - Pihl, Todd

AU - Sun, Qiang

AU - Wan, Yunhu

AU - Wu, Ye

AU - Ally, Adrian

AU - Balasundaram, Miruna

AU - Balu, Saianand

AU - Beroukhim, Rameen

AU - Bodenheimer, Tom

AU - Buhay, Christian

AU - Butterfield, Yaron S.N.

AU - Carlsen, Rebecca

AU - Carter, Scott L.

AU - Chao, Hsu

AU - Chuah, Eric

AU - Clarke, Amanda

AU - Covington, Kyle R.

AU - Dahdouli, Mahmoud

AU - Dewal, Ninad

AU - Dhalla, Noreen

AU - Doddapaneni, Harsha V.

AU - Drummond, Jennifer A.

AU - Gabriel, Stacey B.

AU - Gibbs, Richard A.

AU - Guin, Ranabir

AU - Hale, Walker

AU - Hawes, Alicia

AU - Hayes, D. Neil

AU - Holt, Robert A.

AU - Hoyle, Alan P.

AU - Jefferys, Stuart R.

AU - Jones, Steven J.M.

AU - Jones, Corbin D.

AU - Kalra, Divya

AU - Kovar, Christie

AU - Lewis, Lora

AU - Li, Jie

AU - Ma, Yussanne

AU - Marra, Marco A.

AU - Mayo, Michael

AU - Meng, Shaowu

AU - Meyerson, Matthew

AU - Mieczkowski, Piotr A.

AU - Moore, Richard A.

AU - Morton, Donna

AU - Mose, Lisle E.

AU - Mungall, Andrew J.

AU - Muzny, Donna

AU - Parker, Joel S.

AU - Perou, Charles M.

AU - Roach, Jeffrey

AU - Schein, Jacqueline E.

AU - Schumacher, Steven E.

AU - Shi, Yan

AU - Simons, Janae V.

AU - Sipahimalani, Payal

AU - Skelly, Tara

AU - Soloway, Matthew G.

AU - Sougnez, Carrie

AU - Tam, Angela

AU - Tan, Donghui

AU - Thiessen, Nina

AU - Veluvolu, Umadevi

AU - Wang, Min

AU - Wilkerson, Matthew D.

AU - Wong, Tina

AU - Wu, Junyuan

AU - Xi, Liu

AU - Zhou, Jane

AU - Bedford, Jason

AU - Chen, Fengju

AU - Fu, Yao

AU - Gerstein, Mark

AU - Haussler, David

AU - Kasaian, Katayoon

AU - Lai, Phillip

AU - Ling, Shiyun

AU - Radenbaugh, Amie

AU - Van Den Berg, David

AU - Weinstein, John N.

AU - Zhu, Jingchun

AU - Albert, Monique

AU - Alexopoulou, Iakovina

AU - Andersen, Jeremiah J.

AU - Auman, J. Todd

AU - Bartlett, John

AU - Bastacky, Sheldon

AU - Bergsten, Julie

AU - Blute, Michael L.

AU - Boice, Lori

AU - Bollag, Roni J.

AU - Boyd, Jeff

AU - Castle, Erik

AU - Chen, Ying Bei

AU - Cheville, John C.

AU - Curley, Erin

AU - Davies, Benjamin

AU - DeVolk, April

AU - Dhir, Rajiv

AU - Dike, Laura

AU - Eckman, John

AU - Engel, Jay

AU - Harr, Jodi

AU - Hrebinko, Ronald

AU - Huang, Mei

AU - Huelsenbeck-Dill, Lori

AU - Iacocca, Mary

AU - Jacobs, Bruce

AU - Lobis, Michael

AU - Maranchie, Jodi K.

AU - McMeekin, Scott

AU - Myers, Jerome

AU - Nelson, Joel

AU - Parfitt, Jeremy

AU - Parwani, Anil

AU - Petrelli, Nicholas

AU - Rabeno, Brenda

AU - Roy, Somak

AU - Salner, Andrew L.

AU - Slaton, Joel

AU - Stanton, Melissa

AU - Thompson, R. Houston

AU - Thorne, Leigh

AU - Tucker, Kelinda

AU - Weinberger, Paul M.

AU - Winemiller, Cynthia

AU - Zach, Leigh Anne

AU - Zuna, Rosemary

PY - 2016/1/14

Y1 - 2016/1/14

N2 - 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 renalcell carcinoma consisted of at least three subtypes based on molecular and phenotypic features.

AB - 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 renalcell carcinoma consisted of at least three subtypes based on molecular and phenotypic features.

UR - http://www.scopus.com/inward/record.url?scp=84954286974&partnerID=8YFLogxK

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U2 - 10.1056/NEJMoa1505917

DO - 10.1056/NEJMoa1505917

M3 - Article

C2 - 26536169

AN - SCOPUS:84954286974

SN - 0028-4793

VL - 374

SP - 135

EP - 145

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 2

ER -

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma

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