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.
Nature communications. 2021 Apr 16*** epublish ***
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 de 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 van 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, Lars Dyrskjøt
Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark., Cartes d'Identité des Tumeurs (CIT) Program, Ligue Nationale Contre le Cancer, Paris, France., Department of Clinical Medicine, Aarhus University, Aarhus, Denmark., Department of Urology, Herlev hospital, Copenhagen University, Copenhagen, Denmark., Department of Pathology, Aalborg University Hospital, Aalborg, Denmark., Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany., Department of Urology, Jena University Hospital, Jena, Germany., Division of Urological Research, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden., Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden., Department of Pathology, Aarhus University Hospital, Aarhus N, Denmark., Department of Urology, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany., Departments of Pathology, Urology, Biochemistry and Molecular Genetics, Northwestern University School of Medicine, Chicago, IL, USA., Clinic of Urology, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia., Bladder Cancer Research Centre, Institute of Cancer and Genomic Sciences, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, UK., Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK., Department of Surgery, Division of Urology, Pennsylvania State University, Hershey, PA, USA., Department of Pathology and Laboratory Medicine, Division of Urology, Department of Biochemistry and Molecular Biology, Pennsylvania State University, Hershey, PA, USA., Department of Surgical Sciences, Uppsala University, Uppsala, Sweden., Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany., Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands., Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia., Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), CIBERONC, Madrid, Spain., Epithelial Carcinogenesis Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain., Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark. .