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

Author

Listed:
  • Sia Viborg Lindskrog

    (Aarhus University Hospital
    Aarhus University)

  • Frederik Prip

    (Aarhus University Hospital
    Aarhus University)

  • Philippe Lamy

    (Aarhus University Hospital)

  • Ann Taber

    (Aarhus University Hospital
    Aarhus University)

  • Clarice S. Groeneveld

    (Ligue Nationale Contre le Cancer
    Oncologie Moleculaire, UMR144, Institut Curie)

  • Karin Birkenkamp-Demtröder

    (Aarhus University Hospital
    Aarhus University)

  • Jørgen Bjerggaard Jensen

    (Aarhus University
    Aarhus University Hospital)

  • Trine Strandgaard

    (Aarhus University Hospital
    Aarhus University)

  • Iver Nordentoft

    (Aarhus University Hospital)

  • Emil Christensen

    (Aarhus University Hospital
    Aarhus University)

  • Mateo Sokac

    (Aarhus University Hospital
    Aarhus University)

  • Nicolai J. Birkbak

    (Aarhus University Hospital
    Aarhus University)

  • Lasse Maretty

    (Aarhus University Hospital
    Aarhus University)

  • 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
    Malteser Hospital St. Josephshospital, Krefeld Uerdingen)

  • 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
    University Medical Center Hamburg-Eppendorf)

  • 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)
    Universitat Pompeu Fabra, CIBERONC)

  • Lars Dyrskjøt

    (Aarhus University Hospital
    Aarhus University)

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.

Suggested Citation

  • Sia Viborg Lindskrog & Frederik Prip & Philippe Lamy & Ann Taber & Clarice S. Groeneveld & Karin Birkenkamp-Demtröder & Jørgen Bjerggaard Jensen & Trine Strandgaard & Iver Nordentoft & Emil Christense, 2021. "An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22465-w
    DOI: 10.1038/s41467-021-22465-w
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    Cited by:

    1. F. A. Tucci & R. Pennisi & D. C. Rigiracciolo & M. G. Filippone & R. Bonfanti & F. Romeo & S. Freddi & E. Guerrera & C. Soriani & S. Rodighiero & R. H. Gunby & G. Jodice & F. Sanguedolce & G. Renne & , 2024. "Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis," Nature Communications, Nature, vol. 15(1), pages 1-24, December.

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