Comprehensive molecular characterization of urothelial bladder carcinoma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-01-29

AUTHORS

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, David J. Kwiatkowski, 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. Solit, Theresa 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. Gabriel., Chad J. Creighton, Lawrence Donehower, Andrew D. Cherniack, Jaegil Kim, Scott L. Carter, Gordon Saksena, Steven E. Schumacher, Carrie Sougnez, Samuel S. Freeman, Joonil Jung, Chandra Sekhar Pedamallu, Ami S. Bhatt, Trevor Pugh, Gad Getz, Rameen Beroukhim, Stacey B. Gabriel, Matthew Meyerson, Andrew J. Mungall, A. Gordon Robertson, Andy Chu, 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, Steven J. M. Jones, Marco A. Marra, Toshinori Hinoue, Hui Shen, Moiz S. Bootwalla, Timothy Triche, Phillip H. Lai, David J. Van Den Berg, Daniel J. Weisenberger, Peter W. Laird, Donna Hansel, Katherine A. Hoadley, Saianand Balu, Tom Bodenheimer, Jeffrey S. Damrauer Alan P. Hoyle, Stuart R. Jefferys, Shaowu Meng, Lisle E. Mose, Janae V. Simons, Mathew G. Soloway, Junyuan Wu, William Y. Kim, 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, Stephen B. Baylin, Andrew Wei Xu, Alexei Protopopov, Jianhua Zhang, Christopher Bristow, Harshad S. Mahadeshwar, Sahil Seth, Xingzhi Song, Jiabin Tang, Dong Zeng, Lynda Chin, Charles Guo, John N. Weinstein, Rehan Akbani, Bradley M. Broom, David McConkey, Tod D. Casasent, Wenbin Liu, Zhenlin Ju, Thomas Motter, Bo Peng, Michael Ryan, Wenyi Wang, Roeland G. W. Verhaak, Xiaoping Su, Ji-Yeon Yang, Philip L. Lorenzi, Hui Yao, Nianxiang Zhang, Jiexin Zhang, Gordon B. Mills, Jaegil Kim, Michael S. Noble, Juok Cho, Daniel DiCara, Scott Frazer, Nils Gehlenborg, David I. Heiman, Pei Lin, Yingchun Liu, Petar Stojanov, Doug Voet, Hailei Zhang, Lihua Zou, Lynda Chin, Gad Getz, Brady Bernard, Dick Kreisberg, Sheila Reynolds, Hector Rovira, Ilya Shmulevich, Ricardo Ramirez, Nikolaus Schultz, 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, Evan O. 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, John N. Weinstein, Seth Lerner, Weiguo Jian, Sebrina Tello, Michael Ittman, Patricia Castro, Whitney D. McClenden, Margaret Morgan, Richard Gibbs, Yingchun Liu, 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, Hikmat A. Al-Ahmadie, Dean F. Bajorin, Bernard H. Bochner, Ilana R. Garcia-Grossman, Ashley M. Regazzi, David B. Solit, Jonathan E. Rosenberg, Victor E. Reuter, Theresa Koppie, 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, Brian Robinson, Donna Hansel, Charles Guo, Jolanta Bondaruk, Bogdan Czerniak, Rehan Akbani, Bradley M. Broom, Yuexin Liu, Wei Zhang, John N. Weinstein, Seth Lerner, Margaret Morgan, Jaegil Kim, Andrew D. Cherniack, Samuel S. Freeman, Chandra Sekhar Pedamallu, Michael S. Noble, David J. Kwiatkowski, Hikmat A. Al-Ahmadie, Dean F. Bajorin, Bernard H. Bochner, David B. Solit, Jonathan E. Rosenberg, Victor E. Reuter, Theresa Koppie, Brian Robinson, Eila Skinner, Ricardo Ramirez, Nikolaus Schultz, Donna Hansel, William Y. Kim, Charles Guo, Jolanta Bondaruk, Kenneth Aldape, Bogdan Czerniak, 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

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. More... »

PAGES

315-322

Journal

TITLE

Nature

ISSUE

7492

VOLUME

507

Author Affiliations

  • Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, 77030 Texas USA
  • Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, 77030 Texas USA
  • The University of Texas MD Anderson Cancer Center, Houston, 77030 Texas USA
  • Texas Cancer Research Biobank (TCRB), Baylor College of Medicine, Houston, 77030 Texas USA
  • Human Genome Sequencing Center at Baylor College of Medicine, Houston, 77030 Texas USA
  • Dan L. Duncan Cancer Center, Human Genome Sequencing Center, Baylor College of Medicine, Houston, 77030 Texas USA
  • Baylor College of Medicine, Houston, 77030 Texas USA
  • Harvard Medical School, Boston, 02115 Massachusetts USA
  • The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, 02142 Massachusetts USA
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 02215 Massachusetts USA
  • Memorial Sloan-Kettering Cancer Center, New York, 10065 New York USA
  • Department of Urology, Oregon Health and Science University, 3303 SW Bond Avenue, CHH10U, Portland, Oregon 97239, USA.,
  • Weill Medical College of Cornell University, New York, 10065 New York USA
  • National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, Research Triangle Park, North Carolina 27709, USA.,
  • Optimum Therapeutics LLC, 9363 Towne Centre Drive, San Diego, California 92121, USA.,
  • University of Southern California Epigenome Center, University of Southern California, Los Angeles, 90033 California USA
  • Computational Biology Center, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.,
  • UCSD Department of Pathology 9500 Gilman Drive, La Jolla, California 92093, USA.,
  • Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599 North Carolina USA
  • Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.,
  • Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.,
  • Cancer Biology Division, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, 21231 Maryland USA
  • Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.,
  • Cancer Center and Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.,
  • Department of Molecular Virology and Microbiology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA.,
  • Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02215 Massachusetts USA
  • Department of Medicine, Harvard Medical School, Boston, 02215 Massachusetts USA
  • Department of Pathology, Harvard Medical School, Boston, 02215 Massachusetts USA
  • Department of Internal Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, 27599 North Carolina USA
  • Research Computing Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599 North Carolina USA
  • Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, 27599 North Carolina USA
  • Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.,
  • Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.,
  • Department of Genetics, Harvard Medical School, Boston, 02115 Massachusetts USA
  • Division of Genetics, Brigham and Women’s Hospital, Boston, 02115 Massachusetts USA
  • The Center for Biomedical Informatics, Harvard Medical School, Boston, 02115 Massachusetts USA
  • Informatics Program, Children’s Hospital, Boston, 02115 Massachusetts USA
  • Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, 77030 Texas USA
  • Holcombe Boulevard, Houston, 77030 Texas USA
  • Brigham and Women’s Hospital, 75 Francis St, Boston, Massachusetts 02115, USA.,
  • Institute for Systems Biology, 401 Terry Ave N, Seattle, Washington 98109, USA.,
  • Redwood Blvd, Novato, California 94945, USA.,
  • University California Santa Cruz, 1156 High Street, Santa Cruz, California 95064, USA.,
  • Department of Pathology, MD Anderson Cancer Center, Houston, 77030 Texas USA
  • Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 94158 California USA
  • The Research Institute at Nationwide Children’s Hospital, Columbus, 43205 Ohio USA
  • The Ohio State University, Columbus, 43210 Ohio USA
  • Department of Pathology, Baylor College of Medicine, Houston, 77030 Texas USA
  • Analytical Biological Services, Inc., 701 Cornell Drive, Wilmington, Delaware 19801, USA.,
  • Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.,
  • Georgia Regents University Cancer Center, Augusta, 30912 Georgia USA
  • Helen F. Graham Cancer Center at Christiana Care, 4701 Ogletown Stanton Road, Newark, Delaware 19713, USA.,
  • International Genomics Consortium, 445 N. Fifth Street, Phoenix, Arizona 85004, USA.,
  • Hue Central Hospital, Hue City, Vietnam
  • ILSbio, LLC 100 Radcliffe Drive, Chestertown, Maryland 21620, USA.,
  • IU School of Medicine, Med Science Bldg, Room 128A, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA.,
  • Lahey Hospital and Medical Center, Burlington, 01805 Massachusetts USA
  • University of North Carolina, Lineberger Cancer Center, 450 West Drive, Chapel Hill, North Carolina 27599, USA.,
  • University of Pittsburgh, Pittsburgh, 15213 Pennsylvania USA
  • Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14063, USA.,
  • Ontario Tumour Bank—Hamilton site, St Joseph’s Healthcare Hamilton, Hamilton, Ontario L8N 3Z5, Canada.,
  • The University of Chicago, Chicago, 60637 Illinois USA
  • University of Miami, Sylvester Comprehensive Cancer Center, 1550 NW 10th Avenue, Miami, Florida 33136, USA.,
  • UT Southwestern Medical Center 5323 Harry Hines Blvd, Dallas, 75390-9110 Texas USA
  • Department of Urology, Stanford University, 300 Pasteur Drive, Suite S287, Stanford, California 94305, USA.,
  • SRA International, Fairfax, 22033 Virginia USA
  • MLF Consulting, Arlington, 02474 Massachusetts USA
  • National Cancer Institute, 31 Center Drive, 3A20, Bethesda, Maryland 20892, USA.,
  • National Human Genome Research Institute, 5635 Fishers Lane, Rockville, Maryland 20852, USA.,
  • Scimentis, LLC, Atlanta, Georgia 30666, USA.,
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature12965

    DOI

    http://dx.doi.org/10.1038/nature12965

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1032218108

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/24476821


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    36 schema:description 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.
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    43 schema:keywords AKT/mTOR pathway
    44 Atlas project
    45 Cancer Genome Atlas (TCGA) project
    46 FGFR3-TACC3 fusions
    47 Genome Atlas project
    48 MAPK pathway
    49 RNA sequencing
    50 RTK/MAPK pathway
    51 abnormalities
    52 agents
    53 alterations
    54 analysis
    55 bladder
    56 bladder carcinoma
    57 cancer
    58 carcinoma
    59 cell cycle regulation
    60 characterization
    61 chromatin abnormalities
    62 chromatin regulation
    63 chromatin regulatory genes
    64 common cancer
    65 common malignancy
    66 comprehensive landscape
    67 comprehensive molecular characterization
    68 data
    69 death
    70 disease
    71 expression
    72 expression subtypes
    73 frame
    74 fusion
    75 future possibilities
    76 gene inactivation
    77 genes
    78 inactivation
    79 integration
    80 kinase/AKT/mTOR pathway
    81 landscape
    82 mTOR pathway
    83 malignancy
    84 microRNA sequencing
    85 molecular alterations
    86 molecular characterization
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    91 phosphatidylinositol-3-OH kinase/AKT/mTOR pathway
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    94 project
    95 protein data
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    98 regulation
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    100 sequencing
    101 significant recurrent mutations
    102 subtypes
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    105 therapeutic target
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    113 schema:name Comprehensive molecular characterization of urothelial bladder carcinoma
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