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

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.

SUBMITTER: Lindskrog SV

PROVIDER: S-EPMC8052448 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Lindskrog Sia Viborg SV Prip Frederik F Lamy Philippe P Taber Ann A Groeneveld Clarice S CS Birkenkamp-Demtröder Karin K Jensen Jørgen Bjerggaard JB Strandgaard Trine T Nordentoft Iver I Christensen Emil E Sokac Mateo M Birkbak Nicolai J NJ Maretty Lasse L Hermann Gregers G GG Petersen Astrid C AC Weyerer Veronika V Grimm Marc-Oliver MO Horstmann Marcus M Sjödahl Gottfrid G Höglund Mattias M Steiniche Torben T Mogensen Karin K de Reyniès Aurélien A Nawroth Roman R Jordan Brian B Lin Xiaoqi X Dragicevic Dejan D Ward Douglas G DG Goel Anshita A Hurst Carolyn D CD Raman Jay D JD Warrick Joshua I JI Segersten Ulrika U Sikic Danijel D van Kessel Kim E M KEM Maurer Tobias T Meeks Joshua J JJ DeGraff David J DJ Bryan Richard T RT Knowles Margaret A MA Simic Tatjana T Hartmann Arndt A Zwarthoff Ellen C EC Malmström Per-Uno PU Malats Núria N Real Francisco X FX Dyrskjøt Lars L

Nature communications 20210416 1

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 establishe ...[more]

PMID: 33863885

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Project description:BackgroundBladder cancer is a urological carcinoma with high incidence, among which muscle invasive bladder cancer (MIBC) is a malignant carcinoma with high mortality. There is an urgent need to develop new drugs with low toxicity and high efficiency for MIBC because existing medication has defects, such as high toxicity, poor efficacy, and side effects. Jorunnamycin A (JorA), a natural marine compound, has been found to have a high efficiency anticancer effect, but its anticancer function and mechanism on bladder cancer have not been studied.MethodsTo examine the anticancer effect of JorA on MIBC, Cell Counting Kit 8, EdU staining, and colony formation analyses were performed. Moreover, a xenograft mouse model was used to verify the anticancer effect in vivo. To investigate the pharmacological mechanism of JorA, high-throughput quantitative proteomics, transcriptomics, RT-qPCR, western blotting, immunofluorescence staining, flow cytometry, pulldown assays, and molecular docking were performed.ResultsJorA inhibited the proliferation of MIBC cells, and the IC50 of T24 and UM-UC-3 was 0.054 and 0.084 μM, respectively. JorA-induced significantly changed proteins were enriched in "cancer-related pathways" and "EGFR-related signaling pathways", which mainly manifested by inhibiting cell proliferation and promoting cell apoptosis. Specifically, JorA dampened the DNA synthesis rate, induced phosphatidylserine eversion, and inhibited cell migration. Furthermore, it was discovered that fatty acid synthase (FASN) and topoisomerase 1 (TOP1) are the JorA interaction proteins. Using DockThor software, the 3D docking structures of JorA binding to FASN and TOP1 were obtained (the binding affinities were - 8.153 and - 7.264 kcal/mol, respectively).ConclusionsThe marine compound JorA was discovered to have a specific inhibitory effect on MIBC, and its potential pharmacological mechanism was revealed for the first time. This discovery makes an important contribution to the development of new high efficiency and low toxicity drugs for bladder cancer therapy.

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

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

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