1. An integrated multi-omics analysis identifies clinically relevant molecular subtypes of non-muscle-invasive bladder cancer
- Author
-
Lars Dyrskjøt, Sia Viborg Lindskrog, Mattias Höglund, Emil Christensen, Margaret A. Knowles, Xiaoqi Lin, Mateo Sokac, Gregers G. Hermann, Danijel Sikic, Francisco X. Real, Jørgen Bjerggaard Jensen, Dejan Dragicevic, Núria Malats, Joshua I. Warrick, Anshita Goel, Ulrika Segersten, Marcus Horstmann, Gottfrid Sjödahl, Veronika Weyerer, Arndt Hartmann, Ellen C. Zwarthoff, Tatjana Simic, Carolyn D. Hurst, Douglas G. Ward, Iver Nordentoft, Ann Taber, Marc-Oliver Grimm, Aurélien de Reyniès, Roman Nawroth, Kim E.M. van Kessel, Per-Uno Malmström, Philippe Lamy, Karin Birkenkamp-Demtröder, Astrid Christine Petersen, Nicolai Juul Birkbak, Frederik Prip, Trine Strandgaard, Brian J. Jordan, Richard T. Bryan, Torben Steiniche, Karin Mogensen, Tobias Maurer, David J. DeGraff, Jay D. Raman, Clarice S. Groeneveld, Lasse Maretty, and Joshua J. Meeks
- Subjects
Oncology ,0303 health sciences ,medicine.medical_specialty ,Bladder cancer ,business.industry ,Disease ,Proteomics ,medicine.disease ,Subtyping ,3. Good health ,Clinical trial ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Chromosome instability ,medicine ,Biomarker discovery ,business ,030304 developmental biology - Abstract
The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we performed a large integrative multi-omics analysis of patients diagnosed with NMIBC (n=834). Transcriptomic analysis identified four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provided independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations were significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration was associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirmed the higher infiltration of class 2b tumors and demonstrated an association between higher immune cell infiltration and lower recurrence rates. Finally, a single-sample classification tool was built and the independent prognostic value of the transcriptomic classes was documented in 1306 validation samples. The classifier provides a framework for novel biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
- Published
- 2020