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

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.

Collaborators (171)

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.

Author information

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

PMID:
28988769
PMCID:
PMC5687509
DOI:
10.1016/j.cell.2017.09.007
[Indexed for MEDLINE]
Free PMC Article

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