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; 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; 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

doi:10.1016/j.cell.2017.09.007

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, 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 journal › Article › peer-review

1160 Scopus citations

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 language	English (US)
Pages (from-to)	540-556.e25
Journal	Cell
Volume	171
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2017.09.007
State	Published - Oct 19 2017
Externally published	Yes

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)

Access to Document

10.1016/j.cell.2017.09.007

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

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, Albert, M, Alexopoulou, I, Ally, A, Antic, T, Aron, M, Balasundaram, M, Bartlett, J, Baylin, SB, Beaver, A, Birol, I, Boice, L, Bootwalla, MS, Bowen, J, Bowlby, R, Brooks, D, Broom, BM, Bshara, W, Burks, E, Cárcano, FM, Carlsen, R, Carvalho, AL, Castle, EP, Castro, P, Catto, JW, Chesla, DW, Chuah, E, Chudamani, S, Cortessis, VK, Cottingham, SL, Crain, D, Curley, E, 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, Gomez-Fernandez, CR, Harr, J, Hartmann, A, Herbert, LM, Ho, TH, Holt, RA, Hutter, CM, Jones, SJM, Jorda, M, Kahnoski, RJ, Kasaian, K, Kwiatkowski, DJ, Lai, PH, Lane, BR, Lerner, SP, Liu, J, Lolla, L, Lotan, Y, Lucchesi, FR, Ma, Y, Machado, RD, Maglinte, DT, Mallery, D, Marra, MA, Martin, SE, Mayo, M, Meraney, A, Moinzadeh, A, Moore, RA, Mora Pinero, EM, Morris, S, Morrison, C, Mungall, AJ, Myers, JB, Naresh, R, O'Donnell, PH, Parekh, DJ, Parfitt, J, Paulauskis, JD, Sekhar Pedamallu, C, Penny, RJ, Pihl, T, Porten, S, Quintero-Aguilo, ME, Ramirez, NC, Rathmell, WK, Rieger-Christ, K, Saller, C, Salner, A, Sandusky, G, Scapulatempo-Neto, C, Schein, JE, Schuckman, AK, Shelton, C, Shelton, T, 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, Yang, L, Zach, LA, Zenklusen, JC, Zhang, J, Zmuda, E & Zwarthoff, EC 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

@article{95f587f685854581974034975be0aa17,

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, DNA methylation, basal mRNA subtype, 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 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 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 Eric Burks and C{\'a}rcano, {Flavio M.} and Rebecca Carlsen and Carvalho, {Andre L.} and Castle, {Eric P.} and Patricia Castro and Catto, {James W.} and Chesla, {David W.} and Eric Chuah and Sudha Chudamani and Cortessis, {Victoria K.} and Cottingham, {Sandra L.} and Daniel Crain and Erin Curley 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 Gomez-Fernandez, {Carmen R.} and Jodi Harr and Arndt Hartmann and Herbert, {Lynn M.} and Ho, {Thai H.} and Holt, {Robert A.} and Hutter, {Carolyn M.} and Jones, {Steven J.M.} and Merce Jorda and Kahnoski, {Richard J.} and Katayoon Kasaian and Kwiatkowski, {David J.} and Lai, {Phillip H.} and Lane, {Brian R.} and Lerner, {Seth P.} and Jia Liu and Laxmi Lolla and Yair Lotan 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 Anoop Meraney and Alireza Moinzadeh and Moore, {Richard A.} and {Mora Pinero}, {Edna M.} and Scott Morris and Carl Morrison and Mungall, {Andrew J.} and Myers, {Jerome B.} and Rashi Naresh and O'Donnell, {Peter H.} 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 Kimberly Rieger-Christ and Charles Saller and Andrew Salner and George Sandusky and Cristovam Scapulatempo-Neto and Schein, {Jacqueline E.} and Schuckman, {Anne K.} and Candace Shelton and Troy Shelton 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 Liming Yang and Zach, {Leigh Anne} and Zenklusen, {Jean C.} and Zhang, {Jiashan (Julia)} and Erik Zmuda and Zwarthoff, {Ellen C.}",

note = "Funding Information: We are grateful to all of the patients and families who contributed to this study and for the support of the TCGA Program Office and Steering Committee members Neil Hayes and Paul Spellman for their detailed and thoughtful review of the manuscript. We thank the peer reviewers, whose thoughtful and detailed questions, comments, and requests very substantially improved the manuscript. We appreciate the dedication of Ina Felau for her administrative support throughout this project and of Lee Ann Chastain for her invaluable organizational skills in final manuscript preparation. This project has been funded in part with federal funds from the US Department of Health and Human Services and through the NIH, under various contracts (shown below). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor its member agencies, nor does any mention of trade names, commercial products, or organizations imply endorsement by the US Government. NIH/NCI, TCGA grant U24 CA143866 (A.G.R., K.L.M., S.S., C.C., and E.A.G.); NIH/NCI HHSN 261201000021l, HHSN261201000032I, TCGA Project (B.A.C.); NIH/NCI HHSN261200800001E (K.E.L. and T.M.L.); NIH/NCI U24 CA143883 (J.N.W., G.B.M., R.A., and R.K.); NIH/NCI U24 CA143867 (A.D.C. and M.M.); NIH/NCI U24CA210950 (R.A., J.N.W., and G.B.M.), U24CA209851, U01CA168394 (G.B.M. and Y.L.); NIH/NCI U24 CA199461 (J.N.W., B.M.B., and R.A.), CA210949 (J.N.W., R.A., and G.B.M.), CA210950; NIH/NCI P50 CA100632; NIH/NCI 4UL1 TR000371 (J.N.W.); NIH/NCI U24 CA143882 (P.W.L.); NIH/NCI P50 CA91846 (B.A.C., D.J.M., and X.S.); NCI CCSG P30 CA016672 (X.S.) for MD Anderson's Sequencing and Microarray Facility; NIH/NCI P30 CA008748 (H.A.); NIH/NCI P30 CA016672 Bioinformatics Shared Resources (J.N.W. and R.A.); NIH Intramural Research Program Project, Z1AES103266 (D.A.G.); NIH/NCI 1P01CA120964 (D.J.K.); NIH/NCI R01CA178744 (B.A.C.); NIH/NCI R01CA155010 (C.J.W.); NCI PAR-16-025 (S.A.S.); and DoD Lung Cancer Development (LC150174) (J.N.W.). This work was also partially funded by the Partnership for Bladder Cancer Research, Scott Department of Urology, Baylor College of Medicine (S.P.L.); Leukemia and Lymphoma Society Scholar Award (C.J.W.); Mary K. Chapman Foundation (80-107216-19); Michael and Susan Dell Foundation (J.N.W.); National Research Council (CNPq) of Brazil (M.A.A.C.); Pr{\'o}-Reitoria de Pesquisa / UNICAMP, FAEPEX 2885/16, FAEPEX 2803/16 (B.S.); Federal Agency for Support and Evaluation of Graduate Education (CAPES) of Brazil (V.S.C.). We acknowledge additional TCGA Network funding: U54 HG003273 (R. Gibbs), U54 HG003067 (S. Gabriel), U54 HG003079 (R. Wilson), U24 CA143799 (T. Speed), U24 CA143835 (I. Shmulevich), U24 CA143840 (M. Ladanyi), U24 CA143843 (R Gibbs), U24 CA143845 (G. Getz), U24 CA143848 (D. Hayes), U24 CA143858 (J. Stuart), and U24 CA144025 (R. Kucherlapati). S.P.L. has received investigator-initiated research funding from Endo Pharmaceuticals and support for a clinical trial from FKD and Viventia and is a consultant for UroGen, Vaxiion, Nucleix, and BioCancell. A.D.C., G.G., and M.M. have received research funding from Bayer AG. E.A.G. is now employed by GenomeDx Biosciences. M.M. was previously an equity holder in and consultant for Foundation Medicine. G.B.M. is a member of the scientific advisory board and receives research support from AstraZeneca. D.J.M. has stock options in ApoCell, Inc. J.B. has a paid consultancy with Pfizer, has received advisory board and lecture fees from Merck, has received advisory board fees from Genentech, and has given uncompensated presentations at Genentech. C.J.W. is a cofounder and advisory board member of Neon Therapeutics. Funding Information: We are grateful to all of the patients and families who contributed to this study and for the support of the TCGA Program Office and Steering Committee members Neil Hayes and Paul Spellman for their detailed and thoughtful review of the manuscript. We thank the peer reviewers, whose thoughtful and detailed questions, comments, and requests very substantially improved the manuscript. We appreciate the dedication of Ina Felau for her administrative support throughout this project and of Lee Ann Chastain for her invaluable organizational skills in final manuscript preparation. This project has been funded in part with federal funds from the US Department of Health and Human Services and through the NIH , under various contracts (shown below). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor its member agencies, nor does any mention of trade names, commercial products, or organizations imply endorsement by the US Government. NIH/NCI , TCGA grant U24 CA143866 (A.G.R., K.L.M., S.S., C.C., and E.A.G.); NIH/NCI HHSN 261201000021l , HHSN261201000032I , TCGA Project (B.A.C.); NIH/NCI HHSN261200800001E (K.E.L. and T.M.L.); NIH/NCI U24 CA143883 (J.N.W., G.B.M., R.A., and R.K.); NIH/NCI U24 CA143867 (A.D.C. and M.M.); NIH/NCI U24CA210950 (R.A., J.N.W., and G.B.M.), U24CA209851 , U01CA168394 (G.B.M. and Y.L.); NIH/NCI U24 CA199461 (J.N.W., B.M.B., and R.A.), CA210949 (J.N.W., R.A., and G.B.M.), CA210950 ; NIH/NCI P50 CA100632 ; NIH/NCI 4UL1 TR000371 (J.N.W.); NIH/NCI U24 CA143882 (P.W.L.); NIH/NCI P50 CA91846 (B.A.C., D.J.M., and X.S.); NCI CCSG P30 CA016672 (X.S.) for MD Anderson{\textquoteright}s Sequencing and Microarray Facility ; NIH/NCI P30 CA008748 (H.A.); NIH/NCI P30 CA016672 Bioinformatics Shared Resources (J.N.W. and R.A.); NIH Intramural Research Program Project , Z1AES103266 (D.A.G.); NIH/NCI 1P01CA120964 (D.J.K.); NIH/NCI R01CA178744 (B.A.C.); NIH/NCI R01CA155010 (C.J.W.); NCI PAR-16-025 (S.A.S.); and DoD Lung Cancer Development ( LC150174 ) (J.N.W.). This work was also partially funded by the Partnership for Bladder Cancer Research, Scott Department of Urology, Baylor College of Medicine (S.P.L.); Leukemia and Lymphoma Society Scholar Award (C.J.W.); Mary K. Chapman Foundation ( 80-107216-19 ); Michael and Susan Dell Foundation (J.N.W.); National Research Council (CNPq) of Brazil (M.A.A.C.); Pr{\'o}-Reitoria de Pesquisa / UNICAMP , FAEPEX 2885/16 , FAEPEX 2803/16 (B.S.); Federal Agency for Support and Evaluation of Graduate Education (CAPES) of Brazil (V.S.C.). We acknowledge additional TCGA Network funding: U54 HG003273 (R. Gibbs), U54 HG003067 (S. Gabriel), U54 HG003079 (R. Wilson), U24 CA143799 (T. Speed), U24 CA143835 (I. Shmulevich), U24 CA143840 (M. Ladanyi), U24 CA143843 (R Gibbs), U24 CA143845 (G. Getz), U24 CA143848 (D. Hayes), U24 CA143858 (J. Stuart), and U24 CA144025 (R. Kucherlapati). S.P.L. has received investigator-initiated research funding from Endo Pharmaceuticals and support for a clinical trial from FKD and Viventia and is a consultant for UroGen, Vaxiion, Nucleix, and BioCancell. A.D.C., G.G., and M.M. have received research funding from Bayer AG. E.A.G. is now employed by GenomeDx Biosciences. M.M. was previously an equity holder in and consultant for Foundation Medicine. G.B.M. is a member of the scientific advisory board and receives research support from AstraZeneca. D.J.M. has stock options in ApoCell, Inc. J.B. has a paid consultancy with Pfizer, has received advisory board and lecture fees from Merck, has received advisory board fees from Genentech, and has given uncompensated presentations at Genentech. C.J.W. is a cofounder and advisory board member of Neon Therapeutics. Funding Information: We are grateful to all of the patients and families who contributed to this study and for the support of the TCGA Program Office and Steering Committee members Neil Hayes and Paul Spellman for their detailed and thoughtful review of the manuscript. We thank the peer reviewers, whose thoughtful and detailed questions, comments, and requests very substantially improved the manuscript. We appreciate the dedication of Ina Felau for her administrative support throughout this project and of Lee Ann Chastain for her invaluable organizational skills in final manuscript preparation. This project has been funded in part with federal funds from the US Department of Health and Human Services and through the NIH, under various contracts (shown below). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor its member agencies, nor does any mention of trade names, commercial products, or organizations imply endorsement by the US Government. NIH/NCI, TCGA grant U24 CA143866 (A.G.R., K.L.M., S.S., C.C., and E.A.G.); NIH/NCI HHSN 261201000021l, HHSN261201000032I, TCGA Project (B.A.C.); NIH/NCI HHSN261200800001E (K.E.L. and T.M.L.); NIH/NCI U24 CA143883 (J.N.W., G.B.M., R.A., and R.K.); NIH/NCI U24 CA143867 (A.D.C. and M.M.); NIH/NCI U24CA210950 (R.A., J.N.W., and G.B.M.), U24CA209851, U01CA168394 (G.B.M. and Y.L.); NIH/NCI U24 CA199461 (J.N.W., B.M.B., and R.A.), CA210949 (J.N.W., R.A., and G.B.M.), CA210950; NIH/NCI P50 CA100632; NIH/NCI 4UL1 TR000371 (J.N.W.); NIH/NCI U24 CA143882 (P.W.L.); NIH/NCI P50 CA91846 (B.A.C., D.J.M., and X.S.); NCI CCSG P30 CA016672 (X.S.) for MD Anderson's Sequencing and Microarray Facility; NIH/NCI P30 CA008748 (H.A.); NIH/NCI P30 CA016672 Bioinformatics Shared Resources (J.N.W. and R.A.); NIH Intramural Research Program Project, Z1AES103266 (D.A.G.); NIH/NCI 1P01CA120964 (D.J.K.); NIH/NCI R01CA178744 (B.A.C.); NIH/NCI R01CA155010 (C.J.W.); NCI PAR-16-025 (S.A.S.); and DoD Lung Cancer Development (LC150174) (J.N.W.). This work was also partially funded by the Partnership for Bladder Cancer Research, Scott Department of Urology, Baylor College of Medicine (S.P.L.); Leukemia and Lymphoma Society Scholar Award (C.J.W.); Mary K. Chapman Foundation (80-107216-19); Michael and Susan Dell Foundation (J.N.W.); National Research Council (CNPq) of Brazil (M.A.A.C.); Pr?-Reitoria de Pesquisa / UNICAMP, FAEPEX 2885/16, FAEPEX 2803/16 (B.S.); Federal Agency for Support and Evaluation of Graduate Education (CAPES) of Brazil (V.S.C.). We acknowledge additional TCGA Network funding: U54 HG003273 (R. Gibbs), U54 HG003067 (S. Gabriel), U54 HG003079 (R. Wilson), U24 CA143799 (T. Speed), U24 CA143835 (I. Shmulevich), U24 CA143840 (M. Ladanyi), U24 CA143843 (R Gibbs), U24 CA143845 (G. Getz), U24 CA143848 (D. Hayes), U24 CA143858 (J. Stuart), and U24 CA144025 (R. Kucherlapati). S.P.L. has received investigator-initiated research funding from Endo Pharmaceuticals and support for a clinical trial from FKD and Viventia and is a consultant for UroGen, Vaxiion, Nucleix, and BioCancell. A.D.C., G.G., and M.M. have received research funding from Bayer AG. E.A.G. is now employed by GenomeDx Biosciences. M.M. was previously an equity holder in and consultant for Foundation Medicine. G.B.M. is a member of the scientific advisory board and receives research support from AstraZeneca. D.J.M. has stock options in ApoCell, Inc. J.B. has a paid consultancy with Pfizer, has received advisory board and lecture fees from Merck, has received advisory board fees from Genentech, and has given uncompensated presentations at Genentech. C.J.W. is a cofounder and advisory board member of Neon Therapeutics. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = oct,

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",

}

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 - 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 - 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 - Burks, Eric

AU - Cárcano, Flavio M.

AU - Carlsen, Rebecca

AU - Carvalho, Andre L.

AU - Castle, Eric P.

AU - Castro, Patricia

AU - Catto, James W.

AU - Chesla, David W.

AU - Chuah, Eric

AU - Chudamani, Sudha

AU - Cortessis, Victoria K.

AU - Cottingham, Sandra L.

AU - Crain, Daniel

AU - Curley, Erin

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 - Gomez-Fernandez, Carmen R.

AU - Harr, Jodi

AU - Hartmann, Arndt

AU - Herbert, Lynn M.

AU - Ho, Thai H.

AU - Holt, Robert A.

AU - Hutter, Carolyn M.

AU - Jones, Steven J.M.

AU - Jorda, Merce

AU - Kahnoski, Richard J.

AU - Kasaian, Katayoon

AU - Kwiatkowski, David J.

AU - Lai, Phillip H.

AU - Lane, Brian R.

AU - Lerner, Seth P.

AU - Liu, Jia

AU - Lolla, Laxmi

AU - Lotan, Yair

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 - Meraney, Anoop

AU - Moinzadeh, Alireza

AU - Moore, Richard A.

AU - Mora Pinero, Edna M.

AU - Morris, Scott

AU - Morrison, Carl

AU - Mungall, Andrew J.

AU - Myers, Jerome B.

AU - Naresh, Rashi

AU - O'Donnell, Peter H.

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 - Rieger-Christ, Kimberly

AU - Saller, Charles

AU - Salner, Andrew

AU - Sandusky, George

AU - Scapulatempo-Neto, Cristovam

AU - Schein, Jacqueline E.

AU - Schuckman, Anne K.

AU - Shelton, Candace

AU - Shelton, Troy

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 - Yang, Liming

AU - Zach, Leigh Anne

AU - Zenklusen, Jean C.

AU - Zhang, Jiashan (Julia)

AU - Zmuda, Erik

AU - Zwarthoff, Ellen C.

N1 - Funding Information: We are grateful to all of the patients and families who contributed to this study and for the support of the TCGA Program Office and Steering Committee members Neil Hayes and Paul Spellman for their detailed and thoughtful review of the manuscript. We thank the peer reviewers, whose thoughtful and detailed questions, comments, and requests very substantially improved the manuscript. We appreciate the dedication of Ina Felau for her administrative support throughout this project and of Lee Ann Chastain for her invaluable organizational skills in final manuscript preparation. This project has been funded in part with federal funds from the US Department of Health and Human Services and through the NIH, under various contracts (shown below). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor its member agencies, nor does any mention of trade names, commercial products, or organizations imply endorsement by the US Government. NIH/NCI, TCGA grant U24 CA143866 (A.G.R., K.L.M., S.S., C.C., and E.A.G.); NIH/NCI HHSN 261201000021l, HHSN261201000032I, TCGA Project (B.A.C.); NIH/NCI HHSN261200800001E (K.E.L. and T.M.L.); NIH/NCI U24 CA143883 (J.N.W., G.B.M., R.A., and R.K.); NIH/NCI U24 CA143867 (A.D.C. and M.M.); NIH/NCI U24CA210950 (R.A., J.N.W., and G.B.M.), U24CA209851, U01CA168394 (G.B.M. and Y.L.); NIH/NCI U24 CA199461 (J.N.W., B.M.B., and R.A.), CA210949 (J.N.W., R.A., and G.B.M.), CA210950; NIH/NCI P50 CA100632; NIH/NCI 4UL1 TR000371 (J.N.W.); NIH/NCI U24 CA143882 (P.W.L.); NIH/NCI P50 CA91846 (B.A.C., D.J.M., and X.S.); NCI CCSG P30 CA016672 (X.S.) for MD Anderson's Sequencing and Microarray Facility; NIH/NCI P30 CA008748 (H.A.); NIH/NCI P30 CA016672 Bioinformatics Shared Resources (J.N.W. and R.A.); NIH Intramural Research Program Project, Z1AES103266 (D.A.G.); NIH/NCI 1P01CA120964 (D.J.K.); NIH/NCI R01CA178744 (B.A.C.); NIH/NCI R01CA155010 (C.J.W.); NCI PAR-16-025 (S.A.S.); and DoD Lung Cancer Development (LC150174) (J.N.W.). This work was also partially funded by the Partnership for Bladder Cancer Research, Scott Department of Urology, Baylor College of Medicine (S.P.L.); Leukemia and Lymphoma Society Scholar Award (C.J.W.); Mary K. Chapman Foundation (80-107216-19); Michael and Susan Dell Foundation (J.N.W.); National Research Council (CNPq) of Brazil (M.A.A.C.); Pró-Reitoria de Pesquisa / UNICAMP, FAEPEX 2885/16, FAEPEX 2803/16 (B.S.); Federal Agency for Support and Evaluation of Graduate Education (CAPES) of Brazil (V.S.C.). We acknowledge additional TCGA Network funding: U54 HG003273 (R. Gibbs), U54 HG003067 (S. Gabriel), U54 HG003079 (R. Wilson), U24 CA143799 (T. Speed), U24 CA143835 (I. Shmulevich), U24 CA143840 (M. Ladanyi), U24 CA143843 (R Gibbs), U24 CA143845 (G. Getz), U24 CA143848 (D. Hayes), U24 CA143858 (J. Stuart), and U24 CA144025 (R. Kucherlapati). S.P.L. has received investigator-initiated research funding from Endo Pharmaceuticals and support for a clinical trial from FKD and Viventia and is a consultant for UroGen, Vaxiion, Nucleix, and BioCancell. A.D.C., G.G., and M.M. have received research funding from Bayer AG. E.A.G. is now employed by GenomeDx Biosciences. M.M. was previously an equity holder in and consultant for Foundation Medicine. G.B.M. is a member of the scientific advisory board and receives research support from AstraZeneca. D.J.M. has stock options in ApoCell, Inc. J.B. has a paid consultancy with Pfizer, has received advisory board and lecture fees from Merck, has received advisory board fees from Genentech, and has given uncompensated presentations at Genentech. C.J.W. is a cofounder and advisory board member of Neon Therapeutics. Funding Information: We are grateful to all of the patients and families who contributed to this study and for the support of the TCGA Program Office and Steering Committee members Neil Hayes and Paul Spellman for their detailed and thoughtful review of the manuscript. We thank the peer reviewers, whose thoughtful and detailed questions, comments, and requests very substantially improved the manuscript. We appreciate the dedication of Ina Felau for her administrative support throughout this project and of Lee Ann Chastain for her invaluable organizational skills in final manuscript preparation. This project has been funded in part with federal funds from the US Department of Health and Human Services and through the NIH , under various contracts (shown below). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor its member agencies, nor does any mention of trade names, commercial products, or organizations imply endorsement by the US Government. NIH/NCI , TCGA grant U24 CA143866 (A.G.R., K.L.M., S.S., C.C., and E.A.G.); NIH/NCI HHSN 261201000021l , HHSN261201000032I , TCGA Project (B.A.C.); NIH/NCI HHSN261200800001E (K.E.L. and T.M.L.); NIH/NCI U24 CA143883 (J.N.W., G.B.M., R.A., and R.K.); NIH/NCI U24 CA143867 (A.D.C. and M.M.); NIH/NCI U24CA210950 (R.A., J.N.W., and G.B.M.), U24CA209851 , U01CA168394 (G.B.M. and Y.L.); NIH/NCI U24 CA199461 (J.N.W., B.M.B., and R.A.), CA210949 (J.N.W., R.A., and G.B.M.), CA210950 ; NIH/NCI P50 CA100632 ; NIH/NCI 4UL1 TR000371 (J.N.W.); NIH/NCI U24 CA143882 (P.W.L.); NIH/NCI P50 CA91846 (B.A.C., D.J.M., and X.S.); NCI CCSG P30 CA016672 (X.S.) for MD Anderson’s Sequencing and Microarray Facility ; NIH/NCI P30 CA008748 (H.A.); NIH/NCI P30 CA016672 Bioinformatics Shared Resources (J.N.W. and R.A.); NIH Intramural Research Program Project , Z1AES103266 (D.A.G.); NIH/NCI 1P01CA120964 (D.J.K.); NIH/NCI R01CA178744 (B.A.C.); NIH/NCI R01CA155010 (C.J.W.); NCI PAR-16-025 (S.A.S.); and DoD Lung Cancer Development ( LC150174 ) (J.N.W.). This work was also partially funded by the Partnership for Bladder Cancer Research, Scott Department of Urology, Baylor College of Medicine (S.P.L.); Leukemia and Lymphoma Society Scholar Award (C.J.W.); Mary K. Chapman Foundation ( 80-107216-19 ); Michael and Susan Dell Foundation (J.N.W.); National Research Council (CNPq) of Brazil (M.A.A.C.); Pró-Reitoria de Pesquisa / UNICAMP , FAEPEX 2885/16 , FAEPEX 2803/16 (B.S.); Federal Agency for Support and Evaluation of Graduate Education (CAPES) of Brazil (V.S.C.). We acknowledge additional TCGA Network funding: U54 HG003273 (R. Gibbs), U54 HG003067 (S. Gabriel), U54 HG003079 (R. Wilson), U24 CA143799 (T. Speed), U24 CA143835 (I. Shmulevich), U24 CA143840 (M. Ladanyi), U24 CA143843 (R Gibbs), U24 CA143845 (G. Getz), U24 CA143848 (D. Hayes), U24 CA143858 (J. Stuart), and U24 CA144025 (R. Kucherlapati). S.P.L. has received investigator-initiated research funding from Endo Pharmaceuticals and support for a clinical trial from FKD and Viventia and is a consultant for UroGen, Vaxiion, Nucleix, and BioCancell. A.D.C., G.G., and M.M. have received research funding from Bayer AG. E.A.G. is now employed by GenomeDx Biosciences. M.M. was previously an equity holder in and consultant for Foundation Medicine. G.B.M. is a member of the scientific advisory board and receives research support from AstraZeneca. D.J.M. has stock options in ApoCell, Inc. J.B. has a paid consultancy with Pfizer, has received advisory board and lecture fees from Merck, has received advisory board fees from Genentech, and has given uncompensated presentations at Genentech. C.J.W. is a cofounder and advisory board member of Neon Therapeutics. Funding Information: We are grateful to all of the patients and families who contributed to this study and for the support of the TCGA Program Office and Steering Committee members Neil Hayes and Paul Spellman for their detailed and thoughtful review of the manuscript. We thank the peer reviewers, whose thoughtful and detailed questions, comments, and requests very substantially improved the manuscript. We appreciate the dedication of Ina Felau for her administrative support throughout this project and of Lee Ann Chastain for her invaluable organizational skills in final manuscript preparation. This project has been funded in part with federal funds from the US Department of Health and Human Services and through the NIH, under various contracts (shown below). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor its member agencies, nor does any mention of trade names, commercial products, or organizations imply endorsement by the US Government. NIH/NCI, TCGA grant U24 CA143866 (A.G.R., K.L.M., S.S., C.C., and E.A.G.); NIH/NCI HHSN 261201000021l, HHSN261201000032I, TCGA Project (B.A.C.); NIH/NCI HHSN261200800001E (K.E.L. and T.M.L.); NIH/NCI U24 CA143883 (J.N.W., G.B.M., R.A., and R.K.); NIH/NCI U24 CA143867 (A.D.C. and M.M.); NIH/NCI U24CA210950 (R.A., J.N.W., and G.B.M.), U24CA209851, U01CA168394 (G.B.M. and Y.L.); NIH/NCI U24 CA199461 (J.N.W., B.M.B., and R.A.), CA210949 (J.N.W., R.A., and G.B.M.), CA210950; NIH/NCI P50 CA100632; NIH/NCI 4UL1 TR000371 (J.N.W.); NIH/NCI U24 CA143882 (P.W.L.); NIH/NCI P50 CA91846 (B.A.C., D.J.M., and X.S.); NCI CCSG P30 CA016672 (X.S.) for MD Anderson's Sequencing and Microarray Facility; NIH/NCI P30 CA008748 (H.A.); NIH/NCI P30 CA016672 Bioinformatics Shared Resources (J.N.W. and R.A.); NIH Intramural Research Program Project, Z1AES103266 (D.A.G.); NIH/NCI 1P01CA120964 (D.J.K.); NIH/NCI R01CA178744 (B.A.C.); NIH/NCI R01CA155010 (C.J.W.); NCI PAR-16-025 (S.A.S.); and DoD Lung Cancer Development (LC150174) (J.N.W.). This work was also partially funded by the Partnership for Bladder Cancer Research, Scott Department of Urology, Baylor College of Medicine (S.P.L.); Leukemia and Lymphoma Society Scholar Award (C.J.W.); Mary K. Chapman Foundation (80-107216-19); Michael and Susan Dell Foundation (J.N.W.); National Research Council (CNPq) of Brazil (M.A.A.C.); Pr?-Reitoria de Pesquisa / UNICAMP, FAEPEX 2885/16, FAEPEX 2803/16 (B.S.); Federal Agency for Support and Evaluation of Graduate Education (CAPES) of Brazil (V.S.C.). We acknowledge additional TCGA Network funding: U54 HG003273 (R. Gibbs), U54 HG003067 (S. Gabriel), U54 HG003079 (R. Wilson), U24 CA143799 (T. Speed), U24 CA143835 (I. Shmulevich), U24 CA143840 (M. Ladanyi), U24 CA143843 (R Gibbs), U24 CA143845 (G. Getz), U24 CA143848 (D. Hayes), U24 CA143858 (J. Stuart), and U24 CA144025 (R. Kucherlapati). S.P.L. has received investigator-initiated research funding from Endo Pharmaceuticals and support for a clinical trial from FKD and Viventia and is a consultant for UroGen, Vaxiion, Nucleix, and BioCancell. A.D.C., G.G., and M.M. have received research funding from Bayer AG. E.A.G. is now employed by GenomeDx Biosciences. M.M. was previously an equity holder in and consultant for Foundation Medicine. G.B.M. is a member of the scientific advisory board and receives research support from AstraZeneca. D.J.M. has stock options in ApoCell, Inc. J.B. has a paid consultancy with Pfizer, has received advisory board and lecture fees from Merck, has received advisory board fees from Genentech, and has given uncompensated presentations at Genentech. C.J.W. is a cofounder and advisory board member of Neon Therapeutics. Publisher Copyright: © 2017 Elsevier Inc.

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 - DNA methylation

KW - basal mRNA subtype

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

SN - 0092-8674

VL - 171

SP - 540-556.e25

JO - Cell

JF - Cell

IS - 3

ER -

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer

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