The Molecular Taxonomy of Primary Prostate Cancer

Adam Abeshouse, Jaeil Ahn, Rehan Akbani, Adrian Ally, Samirkumar Amin, Christopher D. Andry, Matti Annala, Armen Aprikian, Joshua Armenia, Arshi Arora, J. Todd Auman, Miruna Balasundaram, Saianand Balu, Christopher E. Barbieri, Thomas Bauer, Christopher C. Benz, Alain Bergeron, Rameen Beroukhim, Mario Berrios, Adrian BivolTom Bodenheimer, Lori Boice, Moiz S. Bootwalla, Rodolfo Borges Dos Reis, Paul C. Boutros, Jay Bowen, Reanne Bowlby, Jeffrey Boyd, Robert K. Bradley, Anne Breggia, Fadi Brimo, Christopher A. Bristow, Denise Brooks, Bradley M. Broom, Alan H. Bryce, Glenn Bubley, Eric Burks, Yaron S N Butterfield, Michael Button, David Canes, Carlos G. Carlotti, Rebecca Carlsen, Michel Carmel, Peter R. Carroll, Scott L. Carter, Richard Cartun, Brett S. Carver, June M. Chan, Matthew T. Chang, Yu Chen, Andrew D. Cherniack, Simone Chevalier, Lynda Chin, Juok Cho, Andy Chu, Eric Chuah, Sudha Chudamani, Kristian Cibulskis, Giovanni Ciriello, Amanda Clarke, Matthew R. Cooperberg, Niall M. Corcoran, Anthony J. Costello, Janet Cowan, Daniel Crain, Erin Curley, Kerstin David, John A. Demchok, Francesca Demichelis, Noreen Dhalla, Rajiv Dhir, Alexandre Doueik, Bettina Drake, Heidi Dvinge, Natalya Dyakova, Ina Felau, Martin L. Ferguson, Scott Frazer, Stephen Freedland, Yao Fu, Stacey B. Gabriel, Jianjiong Gao, Johanna Gardner, Julie M. Gastier-Foster, Nils Gehlenborg, Mark Gerken, Mark B. Gerstein, Gad Getz, Andrew K. Godwin, Anuradha Gopalan, Markus Graefen, Kiley Graim, Thomas Gribbin, Ranabir Guin, Manaswi Gupta, Angela Hadjipanayis, Syed Haider, Lucie Hamel, D. Neil Hayes, David I. Heiman, Julian Hess, Katherine A. Hoadley, Andrea H. Holbrook, Robert A. Holt, Antonia Holway, Christopher M. Hovens, Alan P. Hoyle, Mei Huang, Carolyn M. Hutter, Michael Ittmann, Lisa Iype, Stuart R. Jefferys, Corbin D. Jones, Steven J M Jones, Hartmut Juhl, Andre Kahles, Christopher J. Kane, Katayoon Kasaian, Michael Kerger, Ekta Khurana, Jaegil Kim, Robert J. Klein, Raju Kucherlapati, Louis Lacombe, Marc Ladanyi, Phillip H. Lai, Peter W. Laird, Eric S. Lander, Mathieu Latour, Michael S. Lawrence, Kevin Lau, Tucker Lebien, Darlene Lee, Semin Lee, Kjong Van Lehmann, Kristen M. Leraas, Ignaty Leshchiner, Robert Leung, John A. Libertino, Tara M. Lichtenberg, Pei Lin, W. Marston Linehan, Shiyun Ling, Scott M. Lippman, Jia Liu, Wenbin Liu, Lucas Lochovsky, Massimo Loda, Christopher Logothetis, Laxmi Lolla, Teri Longacre, Yiling Lu, Jianhua Luo, Yussanne Ma, Harshad S. Mahadeshwar, David Mallery, Armaz Mariamidze, Marco A. Marra, Michael Mayo, Shannon McCall, Ginette McKercher, Shaowu Meng, Anne Marie Mes-Masson, Maria J. Merino, Matthew Meyerson, Piotr A. Mieczkowski, Gordon B. Mills, Kenna R Mills Shaw, Sarah Minner, Alireza Moinzadeh, Richard A. Moore, Scott Morris, Carl Morrison, Lisle E. Mose, Andrew J. Mungall, Bradley A. Murray, Jerome B. Myers, Rashi Naresh, Joel Nelson, Mark A. Nelson, Peter S. Nelson, Yulia Newton, Michael S. Noble, Houtan Noushmehr, Matti Nykter, Angeliki Pantazi, Michael Parfenov, Peter J. Park, Joel S. Parker, Joseph Paulauskis, Robert Penny, Charles M. Perou, Alain Piché, Todd Pihl, Peter A. Pinto, Davide Prandi, Alexei Protopopov, Nilsa C. Ramirez, Arvind Rao, W. Kimryn Rathmell, Gunnar Rätsch, Xiaojia Ren, Victor E. Reuter, Sheila M. Reynolds, Suhn K. Rhie, Kimberly Rieger-Christ, Jeffrey Roach, A. Gordon Robertson, Brian Robinson, Mark A. Rubin, Fred Saad, Sara Sadeghi, Gordon Saksena, Charles Saller, Andrew Salner, Francisco Sanchez-Vega, Chris Sander, George Sandusky, Guido Sauter, Andrea Sboner, Peter T. Scardino, Eleonora Scarlata, Jacqueline E. Schein, Thorsten Schlomm, Laura S. Schmidt, Nikolaus Schultz, Steven E. Schumacher, Jonathan Seidman, Luciano Neder, Sahil Seth, Alexis Sharp, Candace Shelton, Troy Shelton, Hui Shen, Ronglai Shen, Mark Sherman, Margi Sheth, Yan Shi, Juliann Shih, Ilya Shmulevich, Jeffry Simko, Ronald Simon, Janae V. Simons, Payal Sipahimalani, Tara Skelly, Heidi J. Sofia, Matthew G. Soloway, Xingzhi Song, Andrea Sorcini, Carrie Sougnez, Serghei Stepa, Chip Stewart, John Stewart, Joshua M. Stuart, Travis B. Sullivan, Charlie Sun, Huandong Sun, Angela Tam, Donghui Tan, Jiabin Tang, Roy Tarnuzzer, Katherine Tarvin, Barry S. Taylor, Patrick Teebagy, Imelda Tenggara, Bernard Têtu, Ashutosh Tewari, Nina Thiessen, Timothy Thompson, Leigh B. Thorne, Daniela P. Tirapelli, Scott A. Tomlins, Felipe Amstalden Trevisan, Patricia Troncoso, Lawrence D. True, Maria Christina Tsourlakis, Svitlana Tyekucheva, Eliezer Van Allen, David J. Van Den Berg, Umadevi Veluvolu, Roel Verhaak, Cathy D. Vocke, Doug Voet, Yunhu Wan, Qingguo Wang, Wenyi Wang, Zhining Wang, Nils Weinhold, John N. Weinstein, Daniel J. Weisenberger, Matthew D. Wilkerson, Lisa Wise, John Witte, Chia Chin Wu, Junyuan Wu, Ye Wu, Andrew W. Xu, Shalini S. Yadav, Liming Yang, Lixing Yang, Christina Yau, Huihui Ye, Peggy Yena, Thomas Zeng, Jean C. Zenklusen, Hailei Zhang, Jianhua Zhang, Jiashan Zhang, Wei Zhang, Yi Zhong, Kelsey Zhu, Erik Zmuda

Research output: Contribution to journalArticlepeer-review

1132 Scopus citations

Abstract

Summary There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects.

Original languageEnglish (US)
Pages (from-to)1011-1025
Number of pages15
JournalCell
Volume163
Issue number4
DOIs
StatePublished - Nov 5 2015

Bibliographical note

Funding Information:
We are grateful to all the affected individuals and families who contributed to this study. We thank Margi Sheth and Ina Felau for project management. This work was supported by the following grants from the NIH: 5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, U54HG003273, and P30CA16672. D.J.W. is a consultant for Zymo Research Corporation. S.A.T., M.A.R., and F.D. are coauthors on a patent issued to the University of Michigan and the Brigham and Women’s Hospital regarding ETS gene fusions in prostate cancer. The diagnostic field of use has been licensed to Hologic/Gen-Probe, Inc., who has sub-licensed some rights to Ventana Medical Systems. S.A.T. is a coauthor on a patent filed by the University of Michigan regarding SPINK1 in prostate cancer. The diagnostic field of use has been licensed to Hologic/Gen-Probe, Inc., who has sub-licensed some rights to Ventana Medical Systems. S.A.T. has served as a consultant and received honoraria from Ventana Medical Systems. M.A.R. is a co-inventor of the patent for the detection and therapeutic field of SPOP mutations in prostate cancer filed by Cornell University. E.V.A. is a consultant for Syapse and Ventana Medical Systems and owns equity in Syapse and Microsoft. A.D.C. has received research support from Bayer, AG. M.B.G. serves on the SAB of BINA. R. Beroukhim is a consultant for and received grant funding from Novartis. M. Meyerson received research support from Bayer and has equity in and is a consultant for Foundation Medicine.

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