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, 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, John N. Weinstein, David J. Kwiatkowski, Seth P. Lerner

Research output: Contribution to journalArticle

367 Citations (Scopus)

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

Fingerprint

Urinary Bladder Neoplasms
Cluster Analysis
Muscle
Tumors
Long Noncoding RNA
Muscles
Mutagenesis
Messenger RNA
Histology
MicroRNAs
Survival
Genes
Neuroendocrine Cells
Mutation
Epithelial-Mesenchymal Transition
Carcinoma in Situ
Neoplasms
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Robertson, A. G., Kim, J., Al-Ahmadie, H., Bellmunt, J., Guo, G., Cherniack, A. D., ... Lerner, S. P. (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

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

In: Cell, Vol. 171, No. 3, 19.10.2017, p. 540-556.e25.

Research output: Contribution to journalArticle

Robertson, AG, Kim, J, Al-Ahmadie, H, Bellmunt, J, Guo, G, Cherniack, AD, Hinoue, T, Laird, PW, Hoadley, KA, Akbani, R, Castro, MAA, Gibb, EA, Kanchi, RS, Gordenin, DA, Shukla, SA, Sanchez-Vega, F, Hansel, DE, Czerniak, BA, Reuter, VE, Su, X, de Sa Carvalho, B, Chagas, VS, Mungall, KL, Sadeghi, S, Pedamallu, CS, Lu, Y, Klimczak, LJ, Zhang, J, Choo, C, Ojesina, AI, Bullman, S, Leraas, KM, Lichtenberg, TM, Wu, CJ, Schultz, N, Getz, G, Meyerson, M, Mills, GB, McConkey, DJ, Akbani, R, Al-Ahmadie, H, Albert, M, Alexopoulou, I, Ally, A, Antic, T, Aron, M, Balasundaram, M, Bartlett, J, Baylin, SB, Beaver, A, Bellmunt, J, Birol, I, Boice, L, Bootwalla, MS, Bowen, J, Bowlby, R, Brooks, D, Broom, BM, Bshara, W, Bullman, S, Burks, E, Cárcano, FM, Carlsen, R, Carvalho, BS, Carvalho, AL, Castle, EP, Castro, MAA, Castro, P, Catto, JW, Chagas, VS, Cherniack, AD, Chesla, DW, Choo, C, Chuah, E, Chudamani, S, Cortessis, VK, Cottingham, SL, Crain, D, Curley, E, Czerniak, BA, Daneshmand, S, Demchok, JA, Dhalla, N, Djaladat, H, Eckman, J, Egea, SC, Engel, J, Felau, I, Ferguson, ML, Gardner, J, Gastier-Foster, JM, Gerken, M, Getz, G, Gibb, EA, Gomez-Fernandez, CR, Gordenin, DA, Guo, G, Hansel, DE, Harr, J, Hartmann, A, Herbert, LM, Hinoue, T, Ho, TH, Hoadley, KA, Holt, RA, Hutter, CM, Jones, SJM, Jorda, M, Kahnoski, RJ, Kanchi, RS, Kasaian, K, Kim, J, Klimczak, LJ, Kwiatkowski, DJ, Lai, PH, Laird, PW, Lane, BR, Leraas, KM, Lerner, SP, Lichtenberg, TM, Liu, J, Lolla, L, Lotan, Y, Lu, Y, Lucchesi, FR, Ma, Y, Machado, RD, Maglinte, DT, Mallery, D, Marra, MA, Martin, SE, Mayo, M, McConkey, DJ, Meraney, A, Meyerson, M, Mills, GB, Moinzadeh, A, Moore, RA, Mora Pinero, EM, Morris, S, Morrison, C, Mungall, KL, Mungall, AJ, Myers, JB, Naresh, R, O'Donnell, PH, Ojesina, AI, Parekh, DJ, Parfitt, J, Paulauskis, JD, Sekhar Pedamallu, C, Penny, RJ, Pihl, T, Porten, S, Quintero-Aguilo, ME, Ramirez, NC, Rathmell, WK, Reuter, VE, Rieger-Christ, K, Robertson, AG, Sadeghi, S, Saller, C, Salner, A, Sanchez-Vega, F, Sandusky, G, Scapulatempo-Neto, C, Schein, JE, Schuckman, AK, Schultz, N, Shelton, C, Shelton, T, Shukla, SA, Simko, J, Singh, P, Sipahimalani, P, Smith, ND, Sofia, HJ, Sorcini, A, Stanton, ML, Steinberg, GD, Stoehr, R, Su, X, Sullivan, T, Sun, Q, Tam, A, Tarnuzzer, R, Tarvin, K, Taubert, H, Thiessen, N, Thorne, L, Tse, K, Tucker, K, Van Den Berg, DJ, van Kessel, KE, Wach, S, Wan, Y, Wang, Z, Weinstein, JN, Weisenberger, DJ, Wise, L, Wong, T, Wu, Y, Wu, CJ, Yang, L, Zach, LA, Zenklusen, JC, Zhang, JJ, Zhang, J, Zmuda, E, Zwarthoff, EC, Weinstein, JN, Kwiatkowski, DJ & Lerner, SP 2017, 'Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer', Cell, vol. 171, no. 3, pp. 540-556.e25. https://doi.org/10.1016/j.cell.2017.09.007
Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD et al. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell. 2017 Oct 19;171(3):540-556.e25. https://doi.org/10.1016/j.cell.2017.09.007
Robertson, A. Gordon ; Kim, Jaegil ; Al-Ahmadie, Hikmat ; Bellmunt, Joaquim ; Guo, Guangwu ; Cherniack, Andrew D. ; Hinoue, Toshinori ; Laird, Peter W. ; Hoadley, Katherine A. ; Akbani, Rehan ; Castro, Mauro A.A. ; Gibb, Ewan A. ; Kanchi, Rupa S. ; Gordenin, Dmitry A. ; Shukla, Sachet A. ; Sanchez-Vega, Francisco ; Hansel, Donna E. ; Czerniak, Bogdan A. ; Reuter, Victor E. ; Su, Xiaoping ; de Sa Carvalho, Benilton ; Chagas, Vinicius S. ; Mungall, Karen L. ; Sadeghi, Sara ; Pedamallu, Chandra Sekhar ; Lu, Yiling ; Klimczak, Leszek J. ; Zhang, Jiexin ; Choo, Caleb ; Ojesina, Akinyemi I. ; Bullman, Susan ; Leraas, Kristen M. ; Lichtenberg, Tara M. ; Wu, Catherine J. ; Schultz, Nicholaus ; Getz, Gad ; Meyerson, Matthew ; Mills, Gordon B. ; McConkey, David J. ; Akbani, Rehan ; Al-Ahmadie, Hikmat ; Albert, Monique ; Alexopoulou, Iakovina ; Ally, Adrian ; Antic, Tatjana ; Aron, Manju ; Balasundaram, Miruna ; Bartlett, John ; Baylin, Stephen B. ; Beaver, Allison ; Bellmunt, Joaquim ; Birol, Inanc ; Boice, Lori ; Bootwalla, Moiz S. ; Bowen, Jay ; Bowlby, Reanne ; Brooks, Denise ; Broom, Bradley M. ; Bshara, Wiam ; Bullman, Susan ; Burks, Eric ; Cárcano, Flavio M. ; Carlsen, Rebecca ; Carvalho, Benilton S. ; Carvalho, Andre L. ; Castle, Eric P. ; Castro, Mauro A.A. ; Castro, Patricia ; Catto, James W. ; Chagas, Vinicius S. ; Cherniack, Andrew D. ; Chesla, David W. ; Choo, Caleb ; Chuah, Eric ; Chudamani, Sudha ; Cortessis, Victoria K. ; Cottingham, Sandra L. ; Crain, Daniel ; Curley, Erin ; Czerniak, Bogdan A. ; Daneshmand, Siamak ; Demchok, John A. ; Dhalla, Noreen ; Djaladat, Hooman ; Eckman, John ; Egea, Sophie C. ; Engel, Jay ; Felau, Ina ; Ferguson, Martin L. ; Gardner, Johanna ; Gastier-Foster, Julie M. ; Gerken, Mark ; Getz, Gad ; Gibb, Ewan A. ; Gomez-Fernandez, Carmen R. ; Gordenin, Dmitry A. ; Guo, Guangwu ; Hansel, Donna E. ; Harr, Jodi ; Hartmann, Arndt ; Herbert, Lynn M. ; Hinoue, Toshinori ; Ho, Thai H. ; Hoadley, Katherine A. ; Holt, Robert A. ; Hutter, Carolyn M. ; Jones, Steven J.M. ; Jorda, Merce ; Kahnoski, Richard J. ; Kanchi, Rupa S. ; Kasaian, Katayoon ; Kim, Jaegil ; Klimczak, Leszek J. ; Kwiatkowski, David J. ; Lai, Phillip H. ; Laird, Peter W. ; Lane, Brian R. ; Leraas, Kristen M. ; Lerner, Seth P. ; Lichtenberg, Tara M. ; Liu, Jia ; Lolla, Laxmi ; Lotan, Yair ; Lu, Yiling ; Lucchesi, Fabiano R. ; Ma, Yussanne ; Machado, Roberto D. ; Maglinte, Dennis T. ; Mallery, David ; Marra, Marco A. ; Martin, Sue E. ; Mayo, Michael ; McConkey, David J. ; Meraney, Anoop ; Meyerson, Matthew ; Mills, Gordon B. ; Moinzadeh, Alireza ; Moore, Richard A. ; Mora Pinero, Edna M. ; Morris, Scott ; Morrison, Carl ; Mungall, Karen L. ; Mungall, Andrew J. ; Myers, Jerome B. ; Naresh, Rashi ; O'Donnell, Peter H. ; Ojesina, Akinyemi I. ; Parekh, Dipen J. ; Parfitt, Jeremy ; Paulauskis, Joseph D. ; Sekhar Pedamallu, Chandra ; Penny, Robert J. ; Pihl, Todd ; Porten, Sima ; Quintero-Aguilo, Mario E. ; Ramirez, Nilsa C. ; Rathmell, W. Kimryn ; Reuter, Victor E. ; Rieger-Christ, Kimberly ; Robertson, A. Gordon ; Sadeghi, Sara ; Saller, Charles ; Salner, Andrew ; Sanchez-Vega, Francisco ; Sandusky, George ; Scapulatempo-Neto, Cristovam ; Schein, Jacqueline E. ; Schuckman, Anne K. ; Schultz, Nikolaus ; Shelton, Candace ; Shelton, Troy ; Shukla, Sachet A. ; Simko, Jeff ; Singh, Parminder ; Sipahimalani, Payal ; Smith, Norm D. ; Sofia, Heidi J. ; Sorcini, Andrea ; Stanton, Melissa L. ; Steinberg, Gary D. ; Stoehr, Robert ; Su, Xiaoping ; Sullivan, Travis ; Sun, Qiang ; Tam, Angela ; Tarnuzzer, Roy ; Tarvin, Katherine ; Taubert, Helge ; Thiessen, Nina ; Thorne, Leigh ; Tse, Kane ; Tucker, Kelinda ; Van Den Berg, David J. ; van Kessel, Kim E. ; Wach, Sven ; Wan, Yunhu ; Wang, Zhining ; Weinstein, John N. ; Weisenberger, Daniel J. ; Wise, Lisa ; Wong, Tina ; Wu, Ye ; Wu, Catherine J. ; Yang, Liming ; Zach, Leigh Anne ; Zenklusen, Jean C. ; Zhang, Jiashan (Julia) ; Zhang, Jiexin ; Zmuda, Erik ; Zwarthoff, Ellen C. ; Weinstein, John N. ; Kwiatkowski, David J. ; Lerner, Seth P. / Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. In: Cell. 2017 ; Vol. 171, No. 3. pp. 540-556.e25.
@article{ed21f45e7ef1490c95abe6ade912295c,
title = "Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer",
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.",
keywords = "APOBEC mutation, basal mRNA subtype, DNA methylation, lncRNA transcriptome, luminal mRNA subtype, microRNA, muscle-invasive bladder cancer, neoantigen, neuronal subtype, regulon",
author = "Robertson, {A. Gordon} and Jaegil Kim and Hikmat Al-Ahmadie and Joaquim Bellmunt and Guangwu Guo and Cherniack, {Andrew D.} and Toshinori Hinoue and Laird, {Peter W.} and Hoadley, {Katherine A.} and Rehan Akbani and Castro, {Mauro A.A.} and Gibb, {Ewan A.} and Kanchi, {Rupa S.} and Gordenin, {Dmitry A.} and Shukla, {Sachet A.} and Francisco Sanchez-Vega and Hansel, {Donna E.} and Czerniak, {Bogdan A.} and Reuter, {Victor E.} and Xiaoping Su and {de Sa Carvalho}, Benilton and Chagas, {Vinicius S.} and Mungall, {Karen L.} and Sara Sadeghi and Pedamallu, {Chandra Sekhar} and Yiling Lu and Klimczak, {Leszek J.} and Jiexin Zhang and Caleb Choo and Ojesina, {Akinyemi I.} and Susan Bullman and Leraas, {Kristen M.} and Lichtenberg, {Tara M.} and Wu, {Catherine J.} and Nicholaus Schultz and Gad Getz and Matthew Meyerson and Mills, {Gordon B.} and McConkey, {David J.} and Rehan Akbani and Hikmat Al-Ahmadie and Monique Albert and Iakovina Alexopoulou and Adrian Ally and Tatjana Antic and Manju Aron and Miruna Balasundaram and John Bartlett and Baylin, {Stephen B.} and Allison Beaver and Joaquim Bellmunt and Inanc Birol and Lori Boice and Bootwalla, {Moiz S.} and Jay Bowen and Reanne Bowlby and Denise Brooks and Broom, {Bradley M.} and Wiam Bshara and Susan Bullman and Eric Burks and C{\'a}rcano, {Flavio M.} and Rebecca Carlsen and Carvalho, {Benilton S.} and Carvalho, {Andre L.} and Castle, {Eric P.} and Castro, {Mauro A.A.} and Patricia Castro and Catto, {James W.} and Chagas, {Vinicius S.} and Cherniack, {Andrew D.} and Chesla, {David W.} and Caleb Choo and Eric Chuah and Sudha Chudamani and Cortessis, {Victoria K.} and Cottingham, {Sandra L.} and Daniel Crain and Erin Curley and Czerniak, {Bogdan A.} and Siamak Daneshmand and Demchok, {John A.} and Noreen Dhalla and Hooman Djaladat and John Eckman and Egea, {Sophie C.} and Jay Engel and Ina Felau and Ferguson, {Martin L.} and Johanna Gardner and Gastier-Foster, {Julie M.} and Mark Gerken and Gad Getz and Gibb, {Ewan A.} and Gomez-Fernandez, {Carmen R.} and Gordenin, {Dmitry A.} and Guangwu Guo and Hansel, {Donna E.} and Jodi Harr and Arndt Hartmann and Herbert, {Lynn M.} and Toshinori Hinoue and Ho, {Thai H.} and Hoadley, {Katherine A.} and Holt, {Robert A.} and Hutter, {Carolyn M.} and Jones, {Steven J.M.} and Merce Jorda and Kahnoski, {Richard J.} and Kanchi, {Rupa S.} and Katayoon Kasaian and Jaegil Kim and Klimczak, {Leszek J.} and Kwiatkowski, {David J.} and Lai, {Phillip H.} and Laird, {Peter W.} and Lane, {Brian R.} and Leraas, {Kristen M.} and Lerner, {Seth P.} and Lichtenberg, {Tara M.} and Jia Liu and Laxmi Lolla and Yair Lotan and Yiling Lu and Lucchesi, {Fabiano R.} and Yussanne Ma and Machado, {Roberto D.} and Maglinte, {Dennis T.} and David Mallery and Marra, {Marco A.} and Martin, {Sue E.} and Michael Mayo and McConkey, {David J.} and Anoop Meraney and Matthew Meyerson and Mills, {Gordon B.} and Alireza Moinzadeh and Moore, {Richard A.} and {Mora Pinero}, {Edna M.} and Scott Morris and Carl Morrison and Mungall, {Karen L.} and Mungall, {Andrew J.} and Myers, {Jerome B.} and Rashi Naresh and O'Donnell, {Peter H.} and Ojesina, {Akinyemi I.} and Parekh, {Dipen J.} and Jeremy Parfitt and Paulauskis, {Joseph D.} and {Sekhar Pedamallu}, Chandra and Penny, {Robert J.} and Todd Pihl and Sima Porten and Quintero-Aguilo, {Mario E.} and Ramirez, {Nilsa C.} and Rathmell, {W. Kimryn} and Reuter, {Victor E.} and Kimberly Rieger-Christ and Robertson, {A. Gordon} and Sara Sadeghi and Charles Saller and Andrew Salner and Francisco Sanchez-Vega and George Sandusky and Cristovam Scapulatempo-Neto and Schein, {Jacqueline E.} and Schuckman, {Anne K.} and Nikolaus Schultz and Candace Shelton and Troy Shelton and Shukla, {Sachet A.} and Jeff Simko and Parminder Singh and Payal Sipahimalani and Smith, {Norm D.} and Sofia, {Heidi J.} and Andrea Sorcini and Stanton, {Melissa L.} and Steinberg, {Gary D.} and Robert Stoehr and Xiaoping Su and Travis Sullivan and Qiang Sun and Angela Tam and Roy Tarnuzzer and Katherine Tarvin and Helge Taubert and Nina Thiessen and Leigh Thorne and Kane Tse and Kelinda Tucker and {Van Den Berg}, {David J.} and {van Kessel}, {Kim E.} and Sven Wach and Yunhu Wan and Zhining Wang and Weinstein, {John N.} and Weisenberger, {Daniel J.} and Lisa Wise and Tina Wong and Ye Wu and Wu, {Catherine J.} and Liming Yang and Zach, {Leigh Anne} and Zenklusen, {Jean C.} and Zhang, {Jiashan (Julia)} and Jiexin Zhang and Erik Zmuda and Zwarthoff, {Ellen C.} and Weinstein, {John N.} and Kwiatkowski, {David J.} and Lerner, {Seth P.}",
year = "2017",
month = "10",
day = "19",
doi = "10.1016/j.cell.2017.09.007",
language = "English (US)",
volume = "171",
pages = "540--556.e25",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",

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TY - JOUR

T1 - Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer

AU - Robertson, A. Gordon

AU - Kim, Jaegil

AU - Al-Ahmadie, Hikmat

AU - Bellmunt, Joaquim

AU - Guo, Guangwu

AU - Cherniack, Andrew D.

AU - Hinoue, Toshinori

AU - Laird, Peter W.

AU - Hoadley, Katherine A.

AU - Akbani, Rehan

AU - Castro, Mauro A.A.

AU - Gibb, Ewan A.

AU - Kanchi, Rupa S.

AU - Gordenin, Dmitry A.

AU - Shukla, Sachet A.

AU - Sanchez-Vega, Francisco

AU - Hansel, Donna E.

AU - Czerniak, Bogdan A.

AU - Reuter, Victor E.

AU - Su, Xiaoping

AU - de Sa Carvalho, Benilton

AU - Chagas, Vinicius S.

AU - Mungall, Karen L.

AU - Sadeghi, Sara

AU - Pedamallu, Chandra Sekhar

AU - Lu, Yiling

AU - Klimczak, Leszek J.

AU - Zhang, Jiexin

AU - Choo, Caleb

AU - Ojesina, Akinyemi I.

AU - Bullman, Susan

AU - Leraas, Kristen M.

AU - Lichtenberg, Tara M.

AU - Wu, Catherine J.

AU - Schultz, Nicholaus

AU - Getz, Gad

AU - Meyerson, Matthew

AU - Mills, Gordon B.

AU - McConkey, David J.

AU - Akbani, Rehan

AU - Al-Ahmadie, Hikmat

AU - Albert, Monique

AU - Alexopoulou, Iakovina

AU - Ally, Adrian

AU - Antic, Tatjana

AU - Aron, Manju

AU - Balasundaram, Miruna

AU - Bartlett, John

AU - Baylin, Stephen B.

AU - Beaver, Allison

AU - Bellmunt, Joaquim

AU - Birol, Inanc

AU - Boice, Lori

AU - Bootwalla, Moiz S.

AU - Bowen, Jay

AU - Bowlby, Reanne

AU - Brooks, Denise

AU - Broom, Bradley M.

AU - Bshara, Wiam

AU - Bullman, Susan

AU - Burks, Eric

AU - Cárcano, Flavio M.

AU - Carlsen, Rebecca

AU - Carvalho, Benilton S.

AU - Carvalho, Andre L.

AU - Castle, Eric P.

AU - Castro, Mauro A.A.

AU - Castro, Patricia

AU - Catto, James W.

AU - Chagas, Vinicius S.

AU - Cherniack, Andrew D.

AU - Chesla, David W.

AU - Choo, Caleb

AU - Chuah, Eric

AU - Chudamani, Sudha

AU - Cortessis, Victoria K.

AU - Cottingham, Sandra L.

AU - Crain, Daniel

AU - Curley, Erin

AU - Czerniak, Bogdan A.

AU - Daneshmand, Siamak

AU - Demchok, John A.

AU - Dhalla, Noreen

AU - Djaladat, Hooman

AU - Eckman, John

AU - Egea, Sophie C.

AU - Engel, Jay

AU - Felau, Ina

AU - Ferguson, Martin L.

AU - Gardner, Johanna

AU - Gastier-Foster, Julie M.

AU - Gerken, Mark

AU - Getz, Gad

AU - Gibb, Ewan A.

AU - Gomez-Fernandez, Carmen R.

AU - Gordenin, Dmitry A.

AU - Guo, Guangwu

AU - Hansel, Donna E.

AU - Harr, Jodi

AU - Hartmann, Arndt

AU - Herbert, Lynn M.

AU - Hinoue, Toshinori

AU - Ho, Thai H.

AU - Hoadley, Katherine A.

AU - Holt, Robert A.

AU - Hutter, Carolyn M.

AU - Jones, Steven J.M.

AU - Jorda, Merce

AU - Kahnoski, Richard J.

AU - Kanchi, Rupa S.

AU - Kasaian, Katayoon

AU - Kim, Jaegil

AU - Klimczak, Leszek J.

AU - Kwiatkowski, David J.

AU - Lai, Phillip H.

AU - Laird, Peter W.

AU - Lane, Brian R.

AU - Leraas, Kristen M.

AU - Lerner, Seth P.

AU - Lichtenberg, Tara M.

AU - Liu, Jia

AU - Lolla, Laxmi

AU - Lotan, Yair

AU - Lu, Yiling

AU - Lucchesi, Fabiano R.

AU - Ma, Yussanne

AU - Machado, Roberto D.

AU - Maglinte, Dennis T.

AU - Mallery, David

AU - Marra, Marco A.

AU - Martin, Sue E.

AU - Mayo, Michael

AU - McConkey, David J.

AU - Meraney, Anoop

AU - Meyerson, Matthew

AU - Mills, Gordon B.

AU - Moinzadeh, Alireza

AU - Moore, Richard A.

AU - Mora Pinero, Edna M.

AU - Morris, Scott

AU - Morrison, Carl

AU - Mungall, Karen L.

AU - Mungall, Andrew J.

AU - Myers, Jerome B.

AU - Naresh, Rashi

AU - O'Donnell, Peter H.

AU - Ojesina, Akinyemi I.

AU - Parekh, Dipen J.

AU - Parfitt, Jeremy

AU - Paulauskis, Joseph D.

AU - Sekhar Pedamallu, Chandra

AU - Penny, Robert J.

AU - Pihl, Todd

AU - Porten, Sima

AU - Quintero-Aguilo, Mario E.

AU - Ramirez, Nilsa C.

AU - Rathmell, W. Kimryn

AU - Reuter, Victor E.

AU - Rieger-Christ, Kimberly

AU - Robertson, A. Gordon

AU - Sadeghi, Sara

AU - Saller, Charles

AU - Salner, Andrew

AU - Sanchez-Vega, Francisco

AU - Sandusky, George

AU - Scapulatempo-Neto, Cristovam

AU - Schein, Jacqueline E.

AU - Schuckman, Anne K.

AU - Schultz, Nikolaus

AU - Shelton, Candace

AU - Shelton, Troy

AU - Shukla, Sachet A.

AU - Simko, Jeff

AU - Singh, Parminder

AU - Sipahimalani, Payal

AU - Smith, Norm D.

AU - Sofia, Heidi J.

AU - Sorcini, Andrea

AU - Stanton, Melissa L.

AU - Steinberg, Gary D.

AU - Stoehr, Robert

AU - Su, Xiaoping

AU - Sullivan, Travis

AU - Sun, Qiang

AU - Tam, Angela

AU - Tarnuzzer, Roy

AU - Tarvin, Katherine

AU - Taubert, Helge

AU - Thiessen, Nina

AU - Thorne, Leigh

AU - Tse, Kane

AU - Tucker, Kelinda

AU - Van Den Berg, David J.

AU - van Kessel, Kim E.

AU - Wach, Sven

AU - Wan, Yunhu

AU - Wang, Zhining

AU - Weinstein, John N.

AU - Weisenberger, Daniel J.

AU - Wise, Lisa

AU - Wong, Tina

AU - Wu, Ye

AU - Wu, Catherine J.

AU - Yang, Liming

AU - Zach, Leigh Anne

AU - Zenklusen, Jean C.

AU - Zhang, Jiashan (Julia)

AU - Zhang, Jiexin

AU - Zmuda, Erik

AU - Zwarthoff, Ellen C.

AU - Weinstein, John N.

AU - Kwiatkowski, David J.

AU - Lerner, Seth P.

PY - 2017/10/19

Y1 - 2017/10/19

N2 - 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.

AB - 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.

KW - APOBEC mutation

KW - basal mRNA subtype

KW - DNA methylation

KW - lncRNA transcriptome

KW - luminal mRNA subtype

KW - microRNA

KW - muscle-invasive bladder cancer

KW - neoantigen

KW - neuronal subtype

KW - regulon

UR - http://www.scopus.com/inward/record.url?scp=85030652738&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030652738&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2017.09.007

DO - 10.1016/j.cell.2017.09.007

M3 - Article

C2 - 28988769

AN - SCOPUS:85030652738

VL - 171

SP - 540-556.e25

JO - Cell

JF - Cell

SN - 0092-8674

IS - 3

ER -