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Genomic and Transcriptomic Profiling of High-risk Bladder Cancer Reveals Diverse Molecular and Microenvironment
Khyati Meghani1, Yanni Yu1, Noah Frydenlund1
1Department of Urology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA; Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
European Urology
|October 8, 2025
Summary
This study identifies bladder cancer subtypes to predict recurrence risk and treatment response. An inflamed subtype shows better response to bacillus Calmette-Guérin (BCG) immunotherapy, aiding personalized treatment strategies.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- High-risk bladder cancer has a significant recurrence rate (30%) and mortality (10%) within 2 years.
- Current treatments including surgery, surveillance, and bacillus Calmette-Guérin (BCG) immunotherapy are insufficient.
- A global BCG shortage necessitates novel therapeutic strategies.
Purpose of the Study:
- To identify molecular subtypes of high-risk bladder cancer.
- To develop a precision framework for predicting recurrence risk.
- To guide personalized treatment decisions for bladder cancer.
Main Methods:
- Transcriptomic profiling and targeted genomic sequencing were employed.
- Single-cell RNA sequencing and spatial transcriptomics were used for validation.
- A machine learning model integrated genomic and transcriptomic data to predict recurrence.
Main Results:
- Four distinct molecular subtypes of bladder cancer were identified.
- An inflamed subtype, characterized by high endogenous retroelement expression and increased commensal bacteria, showed superior BCG responsiveness.
- The predictive model demonstrated high accuracy (AUC=0.87) in forecasting recurrence risk.
Conclusions:
- A new conceptual framework for T1 bladder tumors is proposed.
- Subtype 2 tumors, with increased immune cells, exhibit enhanced BCG response, likely due to heightened baseline immune activity.
- These findings support a precision medicine approach for bladder cancer management.
