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 language | English |
|---|---|
| Pages (from-to) | 315-322 |
| Number of pages | 8 |
| Journal | Nature |
| Volume | 507 |
| Issue number | 7492 |
| DOIs | |
| State | Published - 2014 |
| Externally published | Yes |
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In: Nature, Vol. 507, No. 7492, 2014, p. 315-322.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Comprehensive molecular characterization of urothelial bladder carcinoma
AU - Weinstein, John N.
AU - Akbani, Rehan
AU - Broom, Bradley M.
AU - Wang, Wenyi
AU - Verhaak, Roeland G.W.
AU - McConkey, David
AU - Lerner, Seth
AU - Morgan, Margaret
AU - Creighton, Chad J.
AU - Smith, Carolyn
AU - Cherniack, Andrew D.
AU - Kim, Jaegil
AU - Pedamallu, Chandra Sekhar
AU - Noble, Michael S.
AU - Al-Ahmadie, Hikmat A.
AU - Reuter, Victor E.
AU - Rosenberg, Jonathan E.
AU - F.Bajorin, Dean
AU - Bochner, Bernard H.
AU - Solit, David B.
AU - Koppie, Theresa
AU - Robinson, Brian
AU - Gordenin, Dmitry A.
AU - Fargo, David
AU - Klimczak, Leszek J.
AU - Roberts, Steven A.
AU - Au, Jessie
AU - Laird, Peter W.
AU - Hinoue, Toshinori
AU - Schultz, Nikolaus
AU - Ramirez, Ricardo
AU - Hansel, Donna
AU - Hoadley, Katherine A.
AU - Kim, William Y.
AU - Damrauer, Jeffrey S.
AU - Baylin, Stephen B.
AU - Mungall, Andrew J.
AU - Robertson, A. Gordon
AU - Chu, Andy
AU - Kwiatkowski, David J.
AU - Sougnez, Carrie
AU - Cibulskis, Kristian
AU - Lichtenstein, Lee
AU - Sivachenko, Andrey
AU - Stewart, Chip
AU - Lawrence, Michael S.
AU - Getz, Gad
AU - Lander, Eric
AU - Gabrie, Stacey B.
AU - Donehower, Lawrence
AU - Carter, Scott L.
AU - Saksena, Gordon
AU - Schumacher, Steven E.
AU - Freeman, Samuel S.
AU - Jung, Joonil
AU - Bhatt, Ami S.
AU - Pugh, Trevor
AU - Beroukhim, Rameen
AU - Meyerson, Matthew
AU - Ally, Adrian
AU - Balasundaram, Miruna
AU - Butterfield, Yaron S.N.
AU - Dhalla, Noreen
AU - Hirst, Carrie
AU - Holt, Robert A.
AU - Jones, Steven J.M.
AU - Lee, Darlene
AU - Li, Haiyan I.
AU - Marra, Marco A.
AU - Mayo, Michael
AU - Moore, Richard A.
AU - Schein, Jacqueline E.
AU - Sipahimalani, Payal
AU - Tam, Angela
AU - Thiessen, Nina
AU - Wong, Tina
AU - Wye, Natasja
AU - Bowlby, Reanne
AU - Chuah, Eric
AU - Guin, Ranabir
AU - Shen, Hui
AU - Bootwalla, Moiz S.
AU - Triche, Timothy
AU - Lai, Phillip H.
AU - Van Den Berg, David J.
AU - Weisenberger, Daniel J.
AU - Balu, Saianand
AU - Bodenheimer, Tom
AU - Hoyle, Alan P.
AU - Jefferys, Stuart R.
AU - Meng, Shaowu
AU - Mose, Lisle E.
AU - Simons, Janae V.
AU - Soloway, Mathew G.
AU - Wu, Junyuan
AU - Parker, Joel S.
AU - Hayes, D. Neil
AU - Roach, Jeffrey
AU - Buda, Elizabeth
AU - Jones, Corbin D.
AU - Mieczkowski, Piotr A.
AU - Tan, Donghui
AU - Veluvolu, Umadevi
AU - Waring, Scot
AU - Auman, J. Todd
AU - Perou, Charles M.
AU - Wilkerson, Matthew D.
AU - Santoso, Netty
AU - Parfenov, Michael
AU - Ren, Xiaojia
AU - Pantazi, Angeliki
AU - Hadjipanayis, Angela
AU - Seidman, Jonathan
AU - Kucherlapati, Raju
AU - Lee, Semin
AU - Yang, Lixing
AU - Park, Peter J.
AU - Xu, Andrew Wei
AU - Protopopov, Alexei
AU - Zhang, Jianhua
AU - Bristow, Christopher
AU - Mahadeshwar, Harshad S.
AU - Seth, Sahil
AU - Song, Xingzhi
AU - Tang, Jiabin
AU - Zeng, Dong
AU - Chin, Lynda
AU - Guo, Charles
AU - Casasent, Tod D.
AU - Liu, Wenbin
AU - Ju, Zhenlin
AU - Motter, Thomas
AU - Peng, Bo
AU - Ryan, Michael
AU - Su, Xiaoping
AU - Yang, Ji Yeon
AU - Lorenzi, Philip L.
AU - Yao, Hui
AU - Zhang, Nianxiang
AU - Zhang, Jiexin
AU - Mills, Gordon B.
AU - Cho, Juok
AU - DiCara, Daniel
AU - Frazer, Scott
AU - Gehlenborg, Nils
AU - Heiman, David I.
AU - Lin, Pei
AU - Liu, Yingchun
AU - Stojanov, Petar
AU - Voet, Doug
AU - Zhang, Hailei
AU - Zou, Lihua
AU - Bernard, Brady
AU - Kreisberg, Dick
AU - Reynolds, Sheila
AU - Rovira, Hector
AU - Shmulevich, Ilya
AU - Gao, Jianjiong
AU - Jacobsen, Anders
AU - Aksoy, B. Arman
AU - Antipin, Yevgeniy
AU - Ciriello, Giovanni
AU - Dresdner, Gideon
AU - Gross, Benjamin
AU - Lee, William
AU - Reva, Boris
AU - Shen, Ronglai
AU - Sinha, Rileen
AU - Sumer, S. Onur
AU - Weinhold, Nils
AU - Ladanyi, Marc
AU - Sander, Chris
AU - Benz, Christopher
AU - Carlin, Daniel
AU - Haussler, David
AU - Ng, Sam
AU - Paull, Evano
AU - Stuart, Joshua
AU - Zhu, Jing
AU - Liu, Yuexin
AU - Zhang, Wei
AU - Taylor, Barry S.
AU - Lichtenberg, Tara M.
AU - Zmuda, Erik
AU - Barr, Thomas
AU - Black, Aaron D.
AU - George, Myra
AU - Hanf, Benjamin
AU - Helsel, Carmen
AU - McAllister, Cynthia
AU - Ramirez, Nilsa C.
AU - Tabler, Teresa R.
AU - Weaver, Stephanie
AU - Wise, Lisa
AU - Bowen, Jay
AU - Gastier-Foster, Julie M.
AU - Jian, Weiguo
AU - Tello, Sebrina
AU - Ittman, Michael
AU - Castro, Patricia
AU - McClenden, Whitney D.
AU - Gibbs, Richard
AU - Saller, Charles
AU - Tarvin, Katherine
AU - DiPiero, Jennifer M.
AU - Owens, Jennifer
AU - Bollag, Roni
AU - Li, Qiang
AU - Weinberger, Paul
AU - Czerwinski, Christine
AU - Huelsenbeck-Dill, Lori
AU - Iacocca, Mary
AU - Petrelli, Nicholas
AU - Rabeno, Brenda
AU - Swanson, Pat
AU - Shelton, Troy
AU - Curley, Erin
AU - Gardner, Johanna
AU - Mallery, David
AU - Penny, Robert
AU - Van Bang, Nguyen
AU - Hanh, Phan Thi
AU - Kohl, Bernard
AU - Van Le, Xuan
AU - Phu, Bui Duc
AU - Thorp, Richard
AU - Tien, Nguyen Viet
AU - Vinh, Le Quang
AU - Sandusky, George
AU - Burks, Eric
AU - Christ, Kimberly
AU - Gee, Jason
AU - Holway, Antonia
AU - Moinzadeh, Alireza
AU - Sorcini, Andrea
AU - Sullivan, Travis
AU - Garcia-Grossman, Ilana R.
AU - Regazzi, Ashley M.
AU - Boice, Lori
AU - Rathmell, Wendy Kimryn
AU - Thorne, Leigh
AU - Bastacky, Sheldon
AU - Davies, Benjamin
AU - Dhir, Rajiv
AU - Gingrich, Jeffrey
AU - Hrebinko, Ronald
AU - Maranchie, Jodi
AU - Nelson, Joel
AU - Parwani, Anil
AU - Bshara, Wiam
AU - Gaudioso, Carmelo
AU - Morrison, Carl
AU - Alexopoulou, Vina
AU - Bartlett, John
AU - Engel, Jay
AU - Kodeeswaran, Sugy
AU - Antic, Tatjana
AU - O'Donnell, Peter H.
AU - Smith, Norm D.
AU - Steinberg, Gary D.
AU - Egea, Sophie
AU - Gomez-Fernandez, Carmen
AU - Herbert, Lynn
AU - Jorda, Merce
AU - Soloway, Mark
AU - Beaver, Allison
AU - Carter, Suzie
AU - Kapur, Payal
AU - Lewis, Cheryl
AU - Lotan, Yair
AU - Bondaruk, Jolanta
AU - Czerniak, Bogdan
AU - Skinner, Eila
AU - Aldape, Kenneth
AU - Jensen, Mark A.
AU - Kahn, Ari B.
AU - Pihl, Todd D.
AU - Pot, David A.
AU - Srinivasan, Deepak
AU - Wan, Yunhu
AU - Ferguson, Martin L.
AU - Zenklusen, Jean Claude
AU - Davidsen, Tanja
AU - Demchok, John A.
AU - Shaw, Kenna R.Mills
AU - Sheth, Margi
AU - Tarnuzzer, Roy
AU - Wang, Zhining
AU - Yang, Liming
AU - Hutter, Carolyn
AU - Ozenberger, Bradley A.
AU - Sofia, Heidi J.
AU - Eley, Greg
N1 - Funding Information: Acknowledgements We are grateful to all of the patients and families who contributed to this study, as well as C. Gunter and L. Chastain for scientific editing and M. Sheth, J. Zhang and C. Ron Bouchard for administrative support. This work was supported by the following grants from the United States National Institutes of Health: U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025 and P01 CA120964. Additional personnel and funding sources are acknowledged in the Supplementary Information.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84897022815&partnerID=8YFLogxK
U2 - 10.1038/nature12965
DO - 10.1038/nature12965
M3 - Article
C2 - 24476821
AN - SCOPUS:84897022815
SN - 0028-0836
VL - 507
SP - 315
EP - 322
JO - Nature
JF - Nature
IS - 7492
ER -