A Consensus Molecular Classification of Muscle-invasive Bladder Cancer

Aurélie Kamoun; Aurélien de Reyniès; Yves Allory; Gottfrid Sjödahl; A Gordon Robertson; Roland Seiler; Katherine A Hoadley; Clarice S Groeneveld; Hikmat Al-Ahmadie; Woonyoung Choi; Mauro A A Castro; Jacqueline Fontugne; Pontus Eriksson; Qianxing Mo; Jordan Kardos; Alexandre Zlotta; Arndt Hartmann; Colin P Dinney; Joaquim Bellmunt; Thomas Powles; Núria Malats; Keith S Chan; William Y Kim; David J McConkey; Peter C Black; Lars Dyrskjøt; Mattias Höglund; Seth P Lerner; Francisco X Real; François Radvanyi; Bladder Cancer Molecular Taxonomy Group

doi:10.1016/j.eururo.2019.09.006

A Consensus Molecular Classification of Muscle-invasive Bladder Cancer

Eur Urol. 2020 Apr;77(4):420-433. doi: 10.1016/j.eururo.2019.09.006. Epub 2019 Sep 26.

Authors

Aurélie Kamoun¹, Aurélien de Reyniès², Yves Allory³, Gottfrid Sjödahl⁴, A Gordon Robertson⁵, Roland Seiler⁶, Katherine A Hoadley⁷, Clarice S Groeneveld⁸, Hikmat Al-Ahmadie⁹, Woonyoung Choi¹⁰, Mauro A A Castro¹¹, Jacqueline Fontugne³, Pontus Eriksson¹², Qianxing Mo¹³, Jordan Kardos⁷, Alexandre Zlotta¹⁴, Arndt Hartmann¹⁵, Colin P Dinney¹⁶, Joaquim Bellmunt¹⁷, Thomas Powles¹⁸, Núria Malats¹⁹, Keith S Chan²⁰, William Y Kim²¹, David J McConkey¹⁰, Peter C Black²², Lars Dyrskjøt²³, Mattias Höglund¹², Seth P Lerner²⁴, Francisco X Real²⁵, François Radvanyi²⁶; Bladder Cancer Molecular Taxonomy Group

Collaborators

Bladder Cancer Molecular Taxonomy Group:
Mattias Aine²⁷, Hikmat Al-Ahmadie²⁸, Yves Allory²⁹, Joaquim Bellmunt³⁰, Isabelle Bernard-Pierrot³¹, Peter C Black³², Mauro A A Castro¹¹, Keith S Chan³³, Woonyoung Choi¹⁰, Bogdan Czerniak³⁴, Colin P Dinney³⁵, Lars Dyrskjøt³⁶, Pontus Eriksson¹², Jacqueline Fontugne²⁹, Ewan A Gibb³⁷, Clarice S Groeneveld³⁸, Arndt Hartmann³⁹, Katherine A Hoadley⁴⁰, Mattias Höglund¹², Aurélie Kamoun⁴¹, Jordan Kardos⁷, Jaegil Kim⁴², William Y Kim⁴⁰, David J Kwiatkowski⁴³, Thierry Lebret⁴⁴, Seth P Lerner²⁴, Fredrik Liedberg⁴⁵, Núria Malats⁴⁶, David J McConkey¹⁰, Qianxing Mo⁴⁷, Thomas Powles¹⁸, François Radvanyi²⁶, Francisco X Real⁴⁸, Aurélien de Reyniès⁴¹, A Gordon Robertson⁴⁹, Arlene Siefker-Radtke⁵⁰, Nanor Sirab⁵¹, Roland Seiler⁵², Gottfrid Sjödahl⁵³, Ann Taber³⁶, John Weinstein⁵⁴, Alexandre Zlotta⁵⁵

Affiliations

¹ Cartes d'Identité des Tumeurs (CIT) Program, Ligue Nationale Contre le Cancer, Paris, France. Electronic address: aurelie.kamoun@ponts.org.
² Cartes d'Identité des Tumeurs (CIT) Program, Ligue Nationale Contre le Cancer, Paris, France.
³ Department of Pathology, Institut Curie, Saint-Cloud, France; Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue Contre le Cancer, Paris, France.
⁴ Division of Urological Research, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
⁵ Canada's Michael Smith Genome Sciences Center, BC Cancer Agency, Vancouver, BC, Canada.
⁶ Department of Urology, Bern University Hospital, Bern, Switzerland.
⁷ Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸ Cartes d'Identité des Tumeurs (CIT) Program, Ligue Nationale Contre le Cancer, Paris, France; Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue Contre le Cancer, Paris, France; Bioinformatics and Systems Biology Laboratory, Federal University of Paraná, Polytechnic Center, Curitiba, Brazil.
⁹ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰ Johns Hopkins Greenberg Bladder Cancer Institute and Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA.
¹¹ Bioinformatics and Systems Biology Laboratory, Federal University of Paraná, Polytechnic Center, Curitiba, Brazil.
¹² Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
¹³ Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
¹⁴ Division of Urology, Department of Surgery, University of Toronto, Mount Sinai Hospital and University Health Network, Toronto, ON, Canada.
¹⁵ Institute of Pathology, University Erlangen-Nürnberg, Erlangen, Germany.
¹⁶ Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁷ Bladder Cancer Center, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA.
¹⁸ Barts Cancer Institute ECMC, Barts Health and the Royal Free NHS Trust, Queen Mary University of London, London, UK.
¹⁹ Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), CIBERONC, Madrid, Spain.
²⁰ Cedars-Sinai Samuel Oschin Cancer Institute, Los Angeles, CA, USA.
²¹ Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²² Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
²³ Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
²⁴ Scott Department of Urology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
²⁵ Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), CIBERONC, Madrid, Spain.
²⁶ Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue Contre le Cancer, Paris, France.
²⁷ Division of Molecular Hematology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Lund, Sweden.
²⁸ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
²⁹ Department of Pathology, Institut Curie, Saint-Cloud, France; Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, Paris, France.
³⁰ Bladder Cancer Center, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA 02215, USA.
³¹ Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, Paris, France.
³² Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
³³ Cedars-Sinai Samuel Oschin Cancer Institute, Los Angeles, CA 90048, USA.
³⁴ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³⁵ Department of Urology and Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³⁶ Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
³⁷ GenomeDx Biosciences Inc., Vancouver, BC, Canada.
³⁸ Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, Paris, France; Bioinformatics and Systems Biology Laboratory, Federal University of Paraná, Polytechnic Center, Curitiba, Brazil; Cartes d'Identité des Tumeurs Program, Ligue Nationale Contre le Cancer, Paris, France.
³⁹ Institute of Pathology, University Erlangen-Nürnberg, Krankenhausstr 8-10, Erlangen, Germany.
⁴⁰ Department of Genetics, Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴¹ Cartes d'Identité des Tumeurs Program, Ligue Nationale Contre le Cancer, Paris, France.
⁴² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴³ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴⁴ Department of Urology, University of Versailles-Saint-Quentin-en-Yvelines, Foch Hospital, Suresnes, France.
⁴⁵ Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
⁴⁶ Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁴⁷ Department of Biostatistics & Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁴⁸ Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁴⁹ Canada's Michael Smith Genome Sciences Center, BC Cancer Agency, Vancouver, Canada.
⁵⁰ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵¹ Department of Pathology, Institut Curie Hospital Group, Paris, France.
⁵² Department of Urology, Bern University Hospital, Switzerland.
⁵³ Division of Urological Research, Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, Sweden.
⁵⁴ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁵⁵ Department of Surgery, Division of Urology, University of Toronto, Mount Sinai Hospital and University Health Network, Toronto, ON, Canada.

Abstract

Background: Muscle-invasive bladder cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, but the diversity of their subtype sets impedes their clinical application.

Objective: To achieve an international consensus on MIBC molecular subtypes that reconciles the published classification schemes.

Design, setting, and participants: We used 1750 MIBC transcriptomic profiles from 16 published datasets and two additional cohorts.

Outcome measurements and statistical analysis: We performed a network-based analysis of six independent MIBC classification systems to identify a consensus set of molecular classes. Association with survival was assessed using multivariable Cox models.

Results and limitations: We report the results of an international effort to reach a consensus on MIBC molecular subtypes. We identified a consensus set of six molecular classes: luminal papillary (24%), luminal nonspecified (8%), luminal unstable (15%), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics, including outcomes. We provide a single-sample classifier that assigns a consensus class label to a tumor sample's transcriptome. Limitations of the work are retrospective clinical data collection and a lack of complete information regarding patient treatment.

Conclusions: This consensus system offers a robust framework that will enable testing and validation of predictive biomarkers in future prospective clinical trials.

Patient summary: Bladder cancers are heterogeneous at the molecular level, and scientists have proposed several classifications into sets of molecular classes. While these classifications may be useful to stratify patients for prognosis or response to treatment, a consensus classification would facilitate the clinical use of molecular classes. Conducted by multidisciplinary expert teams in the field, this study proposes such a consensus and provides a tool for applying the consensus classification in the clinical setting.

Keywords: Consensus; Molecular taxonomy; Muscle-invasive bladder cancer; Transcriptomic classifier.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Consensus
Female
Humans
Male
Middle Aged
Neoplasm Invasiveness
Retrospective Studies
Urinary Bladder Neoplasms / classification*
Urinary Bladder Neoplasms / genetics*
Urinary Bladder Neoplasms / pathology

Abstract

Publication types

MeSH terms

Grants and funding