An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer

Sia Viborg Lindskrog, Frederik Prip, Philippe Lamy, Ann Taber, Clarice S. Groeneveld, Karin Birkenkamp-Demtröder, Jørgen Bjerggaard Jensen, Trine Strandgaard, Iver Nordentoft, Emil Christensen, Mateo Sokac, Nicolai J. Birkbak, Lasse Maretty, Gregers G. Hermann, Astrid C. Petersen, Veronika Weyerer, Marc-Oliver Grimm, Marcus Horstmann, Gottfrid Sjödahl, Mattias Höglund, Torben Steiniche, Karin Mogensen, Aurélien Reyniès, Roman Nawroth, Brian Jordan, Xiaoqi Lin, Dejan Dragicevic, Douglas G. Ward, Anshita Goel, Carolyn D. Hurst, Jay D. Raman, Joshua I. Warrick, Ulrika Segersten, Danijel Sikic, Kim E. M. Kessel, Tobias Maurer, Joshua J. Meeks, David J. DeGraff, Richard T. Bryan, Margaret A. Knowles, Tatjana Simic, Arndt Hartmann, Ellen C. Zwarthoff, Per-Uno Malmström, Núria Malats, Francisco X. Real and Lars Dyrskjøt ()
Additional contact information
Sia Viborg Lindskrog: Aarhus University Hospital
Frederik Prip: Aarhus University Hospital
Philippe Lamy: Aarhus University Hospital
Ann Taber: Aarhus University Hospital
Clarice S. Groeneveld: Ligue Nationale Contre le Cancer
Karin Birkenkamp-Demtröder: Aarhus University Hospital
Jørgen Bjerggaard Jensen: Aarhus University
Trine Strandgaard: Aarhus University Hospital
Iver Nordentoft: Aarhus University Hospital
Emil Christensen: Aarhus University Hospital
Mateo Sokac: Aarhus University Hospital
Nicolai J. Birkbak: Aarhus University Hospital
Lasse Maretty: Aarhus University Hospital
Gregers G. Hermann: Copenhagen University
Astrid C. Petersen: Aalborg University Hospital
Veronika Weyerer: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg
Marc-Oliver Grimm: Jena University Hospital
Marcus Horstmann: Jena University Hospital
Gottfrid Sjödahl: Lund University, Skåne University Hospital
Mattias Höglund: Lund University
Torben Steiniche: Aarhus University Hospital
Karin Mogensen: Copenhagen University
Aurélien Reyniès: Ligue Nationale Contre le Cancer
Roman Nawroth: Technical University of Munich, Klinikum rechts der Isar
Brian Jordan: Northwestern University School of Medicine
Xiaoqi Lin: Northwestern University School of Medicine
Dejan Dragicevic: University of Belgrade
Douglas G. Ward: University of Birmingham
Anshita Goel: University of Birmingham
Carolyn D. Hurst: University of Leeds
Jay D. Raman: Pennsylvania State University
Joshua I. Warrick: Pennsylvania State University
Ulrika Segersten: Uppsala University
Danijel Sikic: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg
Kim E. M. Kessel: Erasmus University Medical Center
Tobias Maurer: Technical University of Munich, Klinikum rechts der Isar
Joshua J. Meeks: Northwestern University School of Medicine
David J. DeGraff: Pennsylvania State University
Richard T. Bryan: University of Birmingham
Margaret A. Knowles: University of Leeds
Tatjana Simic: University of Belgrade
Arndt Hartmann: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg
Ellen C. Zwarthoff: Erasmus University Medical Center
Per-Uno Malmström: Uppsala University
Núria Malats: Spanish National Cancer Research Center (CNIO), CIBERONC
Francisco X. Real: Epithelial Carcinogenesis Group, Spanish National Cancer Research Center (CNIO)
Lars Dyrskjøt: Aarhus University Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.

Date: 2021
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DOI: 10.1038/s41467-021-22465-w

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