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 SuBenilton 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, Monique Albert, Iakovina Alexopoulou, Adrian Ally, Tatjana Antic, Manju Aron, Miruna Balasundaram, John Bartlett, Stephen B. Baylin, Allison Beaver, Inanc Birol, Lori Boice, Moiz S. Bootwalla, Jay Bowen, Reanne Bowlby, Denise Brooks, Bradley M. Broom, Wiam Bshara, Eric Burks, Flavio M. Cárcano, Rebecca Carlsen, Benilton S. Carvalho, Andre L. Carvalho, Eric P. Castle, Patricia Castro, James W. Catto, David W. Chesla, Eric Chuah, Sudha Chudamani, Victoria K. Cortessis, Sandra L. Cottingham, Daniel Crain, Erin Curley, 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, Carmen R. Gomez-Fernandez, Jodi Harr, Arndt Hartmann, Lynn M. Herbert, Thai H. Ho, Robert A. Holt, Carolyn M. Hutter, Steven J.M. Jones, Merce Jorda, Richard J. Kahnoski, Katayoon Kasaian, David J. Kwiatkowski, Phillip H. Lai, Brian R. Lane, Seth P. Lerner, Jia Liu, Laxmi Lolla, Yair Lotan, Fabiano R. Lucchesi, Yussanne Ma, Roberto D. Machado, Dennis T. Maglinte, David Mallery, Marco A. Marra, Sue E. Martin, Michael Mayo, Anoop Meraney, Alireza Moinzadeh, Richard A. Moore, Edna M. Mora Pinero, Scott Morris, Carl Morrison, Andrew J. Mungall, Jerome B. Myers, Rashi Naresh, Peter H. O'Donnell, 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, Kimberly Rieger-Christ, Charles Saller, Andrew Salner, George Sandusky, Cristovam Scapulatempo-Neto, Jacqueline E. Schein, Anne K. Schuckman, Candace Shelton, Troy Shelton, 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, Liming Yang, Leigh Anne Zach, Jean C. Zenklusen, Jiashan (Julia) Zhang, Erik Zmuda, Ellen C. Zwarthoff

Research output: Contribution to journalArticle

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. A multiplatform analysis of 412 muscle-invasive bladder cancer patients provides insights into mutational profiles with prognostic value and establishes a framework associating distinct tumor subtypes with clinical options.

Original languageEnglish (US)
Pages (from-to)540-556.e25
JournalCell
Volume171
Issue number3
DOIs
StatePublished - Oct 19 2017

Keywords

  • APOBEC mutation
  • DNA methylation
  • basal mRNA subtype
  • lncRNA transcriptome
  • luminal mRNA subtype
  • microRNA
  • muscle-invasive bladder cancer
  • neoantigen
  • neuronal subtype
  • regulon

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Robertson, A. G., Kim, J., Al-Ahmadie, H., Bellmunt, J., Guo, G., Cherniack, A. D., Hinoue, T., Laird, P. W., Hoadley, K. A., Akbani, R., Castro, M. A. A., Gibb, E. A., Kanchi, R. S., Gordenin, D. A., Shukla, S. A., Sanchez-Vega, F., Hansel, D. E., Czerniak, B. A., Reuter, V. E., ... Zwarthoff, E. C. (2017). Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell, 171(3), 540-556.e25. https://doi.org/10.1016/j.cell.2017.09.007