Comprehensive molecular characterization of urothelial bladder carcinoma

John N. Weinstein, Rehan Akbani, Bradley M. Broom, Wenyi Wang, Roeland G.W. Verhaak, David McConkey, Seth Lerner, Margaret Morgan, Chad J. Creighton, Carolyn Smith, Andrew D. Cherniack, Jaegil Kim, Chandra Sekhar Pedamallu, Michael S. Noble, Hikmat A. Al-Ahmadie, Victor E. Reuter, Jonathan E. Rosenberg, Dean F.Bajorin, Bernard H. Bochner, David B. SolitTheresa Koppie, Brian Robinson, Dmitry A. Gordenin, David Fargo, Leszek J. Klimczak, Steven A. Roberts, Jessie Au, Peter W. Laird, Toshinori Hinoue, Nikolaus Schultz, Ricardo Ramirez, Donna Hansel, Katherine A. Hoadley, William Y. Kim, Jeffrey S. Damrauer, Stephen B. Baylin, Andrew J. Mungall, A. Gordon Robertson, Andy Chu, David J. Kwiatkowski, Carrie Sougnez, Kristian Cibulskis, Lee Lichtenstein, Andrey Sivachenko, Chip Stewart, Michael S. Lawrence, Gad Getz, Eric Lander, Stacey B. Gabrie, Lawrence Donehower, Scott L. Carter, Gordon Saksena, Steven E. Schumacher, Samuel S. Freeman, Joonil Jung, Ami S. Bhatt, Trevor Pugh, Rameen Beroukhim, Matthew Meyerson, Adrian Ally, Miruna Balasundaram, Yaron S.N. Butterfield, Noreen Dhalla, Carrie Hirst, Robert A. Holt, Steven J.M. Jones, Darlene Lee, Haiyan I. Li, Marco A. Marra, Michael Mayo, Richard A. Moore, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Tina Wong, Natasja Wye, Reanne Bowlby, Eric Chuah, Ranabir Guin, Hui Shen, Moiz S. Bootwalla, Timothy Triche, Phillip H. Lai, David J. Van Den Berg, Daniel J. Weisenberger, Saianand Balu, Tom Bodenheimer, Alan P. Hoyle, Stuart R. Jefferys, Shaowu Meng, Lisle E. Mose, Janae V. Simons, Mathew G. Soloway, Junyuan Wu, Joel S. Parker, D. Neil Hayes, Jeffrey Roach, Elizabeth Buda, Corbin D. Jones, Piotr A. Mieczkowski, Donghui Tan, Umadevi Veluvolu, Scot Waring, J. Todd Auman, Charles M. Perou, Matthew D. Wilkerson, Netty Santoso, Michael Parfenov, Xiaojia Ren, Angeliki Pantazi, Angela Hadjipanayis, Jonathan Seidman, Raju Kucherlapati, Semin Lee, Lixing Yang, Peter J. Park, Andrew Wei Xu, Alexei Protopopov, Jianhua Zhang, Christopher Bristow, Harshad S. Mahadeshwar, Sahil Seth, Xingzhi Song, Jiabin Tang, Dong Zeng, Lynda Chin, Charles Guo, Tod D. Casasent, Wenbin Liu, Zhenlin Ju, Thomas Motter, Bo Peng, Michael Ryan, Xiaoping Su, Ji Yeon Yang, Philip L. Lorenzi, Hui Yao, Nianxiang Zhang, Jiexin Zhang, Gordon B. Mills, Juok Cho, Daniel DiCara, Scott Frazer, Nils Gehlenborg, David I. Heiman, Pei Lin, Yingchun Liu, Petar Stojanov, Doug Voet, Hailei Zhang, Lihua Zou, Brady Bernard, Dick Kreisberg, Sheila Reynolds, Hector Rovira, Ilya Shmulevich, Jianjiong Gao, Anders Jacobsen, B. Arman Aksoy, Yevgeniy Antipin, Giovanni Ciriello, Gideon Dresdner, Benjamin Gross, William Lee, Boris Reva, Ronglai Shen, Rileen Sinha, S. Onur Sumer, Nils Weinhold, Marc Ladanyi, Chris Sander, Christopher Benz, Daniel Carlin, David Haussler, Sam Ng, Evano Paull, Joshua Stuart, Jing Zhu, Yuexin Liu, Wei Zhang, Barry S. Taylor, Tara M. Lichtenberg, Erik Zmuda, Thomas Barr, Aaron D. Black, Myra George, Benjamin Hanf, Carmen Helsel, Cynthia McAllister, Nilsa C. Ramirez, Teresa R. Tabler, Stephanie Weaver, Lisa Wise, Jay Bowen, Julie M. Gastier-Foster, Weiguo Jian, Sebrina Tello, Michael Ittman, Patricia Castro, Whitney D. McClenden, Richard Gibbs, Charles Saller, Katherine Tarvin, Jennifer M. DiPiero, Jennifer Owens, Roni Bollag, Qiang Li, Paul Weinberger, Christine Czerwinski, Lori Huelsenbeck-Dill, Mary Iacocca, Nicholas Petrelli, Brenda Rabeno, Pat Swanson, Troy Shelton, Erin Curley, Johanna Gardner, David Mallery, Robert Penny, Nguyen Van Bang, Phan Thi Hanh, Bernard Kohl, Xuan Van Le, Bui Duc Phu, Richard Thorp, Nguyen Viet Tien, Le Quang Vinh, George Sandusky, Eric Burks, Kimberly Christ, Jason Gee, Antonia Holway, Alireza Moinzadeh, Andrea Sorcini, Travis Sullivan, Ilana R. Garcia-Grossman, Ashley M. Regazzi, Lori Boice, Wendy Kimryn Rathmell, Leigh Thorne, Sheldon Bastacky, Benjamin Davies, Rajiv Dhir, Jeffrey Gingrich, Ronald Hrebinko, Jodi Maranchie, Joel Nelson, Anil Parwani, Wiam Bshara, Carmelo Gaudioso, Carl Morrison, Vina Alexopoulou, John Bartlett, Jay Engel, Sugy Kodeeswaran, Tatjana Antic, Peter H. O'Donnell, Norm D. Smith, Gary D. Steinberg, Sophie Egea, Carmen Gomez-Fernandez, Lynn Herbert, Merce Jorda, Mark Soloway, Allison Beaver, Suzie Carter, Payal Kapur, Cheryl Lewis, Yair Lotan, Jolanta Bondaruk, Bogdan Czerniak, Eila Skinner, Kenneth Aldape, Mark A. Jensen, Ari B. Kahn, Todd D. Pihl, David A. Pot, Deepak Srinivasan, Yunhu Wan, Martin L. Ferguson, Jean Claude Zenklusen, Tanja Davidsen, John A. Demchok, Kenna R.Mills Shaw, Margi Sheth, Roy Tarnuzzer, Zhining Wang, Liming Yang, Carolyn Hutter, Bradley A. Ozenberger, Heidi J. Sofia, Greg Eley

Research output: Contribution to journalArticle

Abstract

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.

Original languageEnglish (US)
Pages (from-to)315-322
Number of pages8
JournalNature
Volume507
Issue number7492
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

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    Weinstein, J. N., Akbani, R., Broom, B. M., Wang, W., Verhaak, R. G. W., McConkey, D., Lerner, S., Morgan, M., Creighton, C. J., Smith, C., Cherniack, A. D., Kim, J., Pedamallu, C. S., Noble, M. S., Al-Ahmadie, H. A., Reuter, V. E., Rosenberg, J. E., F.Bajorin, D., Bochner, B. H., ... Eley, G. (2014). Comprehensive molecular characterization of urothelial bladder carcinoma. Nature, 507(7492), 315-322. https://doi.org/10.1038/nature12965