Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer

A Gordon Robertson; Jaegil Kim; Hikmat Al-Ahmadie; Joaquim Bellmunt; Guangwu Guo; Andrew D Cherniack; Toshinori Hinoue; Peter W Laird; Katherine A Hoadley; Rehan Akbani; Mauro A A Castro; Ewan A Gibb; Rupa S Kanchi; Dmitry A Gordenin; Sachet A Shukla; Francisco Sanchez-Vega; Donna E Hansel; Bogdan A Czerniak; Victor E Reuter; Xiaoping Su; Benilton de Sa Carvalho; Vinicius S Chagas; Karen L Mungall; Sara Sadeghi; Chandra Sekhar Pedamallu; Yiling Lu; Leszek J Klimczak; Jiexin Zhang; Caleb Choo; Akinyemi I Ojesina; Susan Bullman; Kristen M Leraas; Tara M Lichtenberg; Catherine J Wu; Nicholaus Schultz; Gad Getz; Matthew Meyerson; Gordon B Mills; David J McConkey; TCGA Research Network; John N Weinstein; David J Kwiatkowski; Seth P Lerner

doi:10.1016/j.cell.2017.09.007

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer

Cell. 2017 Oct 19;171(3):540-556.e25. doi: 10.1016/j.cell.2017.09.007. Epub 2017 Oct 5.

Authors

A Gordon Robertson¹, Jaegil Kim², Hikmat Al-Ahmadie³, Joaquim Bellmunt⁴, Guangwu Guo⁵, Andrew D Cherniack², Toshinori Hinoue⁶, Peter W Laird⁶, Katherine A Hoadley⁷, Rehan Akbani⁸, Mauro A A Castro⁹, Ewan A Gibb¹, Rupa S Kanchi⁸, Dmitry A Gordenin¹⁰, Sachet A Shukla⁵, Francisco Sanchez-Vega¹¹, Donna E Hansel¹², Bogdan A Czerniak¹³, Victor E Reuter³, Xiaoping Su⁸, Benilton de Sa Carvalho¹⁴, Vinicius S Chagas⁹, Karen L Mungall¹, Sara Sadeghi¹, Chandra Sekhar Pedamallu², Yiling Lu¹⁵, Leszek J Klimczak¹⁶, Jiexin Zhang⁸, Caleb Choo¹, Akinyemi I Ojesina¹⁷, Susan Bullman², Kristen M Leraas¹⁸, Tara M Lichtenberg¹⁸, Catherine J Wu¹⁹, Nicholaus Schultz¹¹, Gad Getz², Matthew Meyerson²⁰, Gordon B Mills¹⁵, David J McConkey²¹; TCGA Research Network; John N Weinstein²², David J Kwiatkowski²³, Seth P Lerner²⁴

Collaborators

TCGA Research Network:
Rehan Akbani, Hikmat Al-Ahmadie, Monique Albert, Iakovina Alexopoulou, Adrian Ally, Tatjana Antic, Manju Aron, Miruna Balasundaram, John Bartlett, Stephen B Baylin, Allison Beaver, Joaquim Bellmunt, Inanc Birol, Lori Boice, Moiz S Bootwalla, Jay Bowen, Reanne Bowlby, Denise Brooks, Bradley M Broom, Wiam Bshara, Susan Bullman, Eric Burks, Flavio M Cárcano, Rebecca Carlsen, Benilton S Carvalho, Andre L Carvalho, Eric P Castle, Mauro A A Castro, Patricia Castro, James W Catto, Vinicius S Chagas, Andrew D Cherniack, David W Chesla, Caleb Choo, Eric Chuah, Sudha Chudamani, Victoria K Cortessis, Sandra L Cottingham, Daniel Crain, Erin Curley, Bogdan A Czerniak, Siamak Daneshmand, John A Demchok, Noreen Dhalla, Hooman Djaladat, John Eckman, Sophie C Egea, Jay Engel, Ina Felau, Martin L Ferguson, Johanna Gardner, Julie M Gastier-Foster, Mark Gerken, Gad Getz, Ewan A Gibb, Carmen R Gomez-Fernandez, Dmitry A Gordenin, Guangwu Guo, Donna E Hansel, Jodi Harr, Arndt Hartmann, Lynn M Herbert, Toshinori Hinoue, Thai H Ho, Katherine A Hoadley, Robert A Holt, Carolyn M Hutter, Steven J M Jones, Merce Jorda, Richard J Kahnoski, Rupa S Kanchi, Katayoon Kasaian, Jaegil Kim, Leszek J Klimczak, David J Kwiatkowski, Phillip H Lai, Peter W Laird, Brian R Lane, Kristen M Leraas, Seth P Lerner, Tara M Lichtenberg, Jia Liu, Laxmi Lolla, Yair Lotan, Yiling Lu, Fabiano R Lucchesi, Yussanne Ma, Roberto D Machado, Dennis T Maglinte, David Mallery, Marco A Marra, Sue E Martin, Michael Mayo, David J McConkey, Anoop Meraney, Matthew Meyerson, Gordon B Mills, Alireza Moinzadeh, Richard A Moore, Edna M Mora Pinero, Scott Morris, Carl Morrison, Karen L Mungall, Andrew J Mungall, Jerome B Myers, Rashi Naresh, Peter H O'Donnell, Akinyemi I Ojesina, Dipen J Parekh, Jeremy Parfitt, Joseph D Paulauskis, Chandra Sekhar Pedamallu, Robert J Penny, Todd Pihl, Sima Porten, Mario E Quintero-Aguilo, Nilsa C Ramirez, W Kimryn Rathmell, Victor E Reuter, Kimberly Rieger-Christ, A Gordon Robertson, Sara Sadeghi, Charles Saller, Andrew Salner, Francisco Sanchez-Vega, George Sandusky, Cristovam Scapulatempo-Neto, Jacqueline E Schein, Anne K Schuckman, Nikolaus Schultz, Candace Shelton, Troy Shelton, Sachet A Shukla, Jeff Simko, Parminder Singh, Payal Sipahimalani, Norm D Smith, Heidi J Sofia, Andrea Sorcini, Melissa L Stanton, Gary D Steinberg, Robert Stoehr, Xiaoping Su, Travis Sullivan, Qiang Sun, Angela Tam, Roy Tarnuzzer, Katherine Tarvin, Helge Taubert, Nina Thiessen, Leigh Thorne, Kane Tse, Kelinda Tucker, David J Van Den Berg, Kim E van Kessel, Sven Wach, Yunhu Wan, Zhining Wang, John N Weinstein, Daniel J Weisenberger, Lisa Wise, Tina Wong, Ye Wu, Catherine J Wu, Liming Yang, Leigh Anne Zach, Jean C Zenklusen, Jiashan Julia Zhang, Jiexin Zhang, Erik Zmuda, Ellen C Zwarthoff

Affiliations

¹ Canada's Michael Smith Genome Sciences Center, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
² Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁴ PSMAR-IMIM Lab, Bladder Cancer Center, Department of Medicine, Dana-Farber Cancer Institute and Harvard University, Boston, MA 02215, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard University, Boston, MA 02115, USA.
⁶ Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
⁷ Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
⁸ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Bioinformatics and Systems Biology Laboratory, Federal University of Paraná Polytechnic Center, Curitiba, PR CEP 80.060-000, Brazil.
¹⁰ Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
¹¹ Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹² Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
¹³ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁴ Biostatistics and Computational Biology Laboratory, Department of Statistics, University of Campinas, São Paulo, 13.083-859, Brazil.
¹⁵ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁶ Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
¹⁷ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
¹⁸ Biospecimen Core Resource, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
¹⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
²⁰ Pathology and Medical Oncology, Dana-Farber Cancer Institute and Harvard University, Boston, MA 02115, USA.
²¹ Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD 21218, USA.
²² Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA. Electronic address: jweinste@mdanderson.org.
²³ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: dk@rics.bwh.harvard.edu.
²⁴ Scott Department of Urology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: slerner@bcm.edu.

Abstract

We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.

Keywords: APOBEC mutation; DNA methylation; basal mRNA subtype; lncRNA transcriptome; luminal mRNA subtype; microRNA; muscle-invasive bladder cancer; neoantigen; neuronal subtype; regulon.

MeSH terms

Aged
Cluster Analysis
DNA Methylation
Humans
MicroRNAs / genetics
Middle Aged
Muscle, Smooth / pathology
RNA, Long Noncoding / genetics
Survival Analysis
Urinary Bladder / pathology
Urinary Bladder Neoplasms / epidemiology
Urinary Bladder Neoplasms / genetics*
Urinary Bladder Neoplasms / pathology*
Urinary Bladder Neoplasms / therapy

Substances

MicroRNAs
RNA, Long Noncoding

Abstract

MeSH terms

Substances

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