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

Clarice S Groeneveld,Roman Nawroth,David J Degraff,Ankit Goel ,Marc Oliver Grimm ,Marcus Horstmann,Astrid Petersen ,Joshua I Warrick,Karin Mogensen,Nicolai J Birkbak,Danijel Sikic,Richard T Bryan,Dejan Dragičević ,Frederik Prip,Núria Malats,Jay D Raman,Sia V Lindskrog ,Trine Strandgaard,Kim E.m Van Kessel ,Tatjana Simić ,Aurélien De Reyniès,Philippe Lamy,Douglas G Ward,Ann Taber,Arndt Hartmann,Carolyn D Hurst,Joshua J Meeks,Mattias Höglund,Per Uno Malmström ,Margaret A Knowles,Lasse Maretty,Karin Birkenkamp‐Demtröder ,Brian J Jordan ,Gottfrid Sjödahl,Gregers G Hermann,Jørgen Bjerggaard Jensen,Veronika Weyerer,Tobias Maurer,Emil Christensen,Xiaoqi Lin,Ulrika Segersten,Iver Nordentoft,Lars Dyrskjøt,Mateo Sokač ,Ellen C Zwarthoff,Torben Steiniche,Francisco X Real

doi:10.1038/s41467-021-22465-w

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.

Highlights

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes
Utilizing integrative multi-omics analysis, we demonstrated that disease aggressiveness in NMIBC patients was associated with genomic alterations, transcriptomic classes, and immune cell infiltration
We described the development and validation of a single-sample transcriptomic classifier for NMIBC, and identified patients with high chromosomal instability and poor outcome, denoted as class 2a

Summary

Introduction

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. 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. P53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. Patients with NMIBC experience a high likelihood of disease recurrence (50–70%) and progression to muscle-invasive bladder cancer (MIBC; up to 20%, depending on stage and grade)[1]. In a more recent study of 460 NMIBC patients, we reported three gene expression-based classes (class 1–3; UROMOL2016 classification system) with different clinical outcomes and molecular characteristics[8].

Methods

Results

Conclusion