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Updated: Oct 11, 2025
Culture of Bladder Cancer Organoids as Precision Medicine Tools
Published on: December 28, 2021
5mC regulator-mediated molecular subtypes depict the hallmarks of the tumor microenvironment and guide precision
Jiao Hu1, Belaydi Othmane1, Anze Yu1,2
1Department of Urology, Xiangya Hospital, Central South University, Changsha, 410008, China.
Background:
Depicting the heterogeneity and functional characteristics of the tumor microenvironment (TME) is necessary to achieve precision medicine for bladder cancer (BLCA). Although classical molecular subtypes effectively reflect TME heterogeneity and characteristics, their clinical application is limited by several issues.
Methods:
In this study, we integrated the Xiangya cohort and multiple external BLCA cohorts to develop a novel 5-methylcytosine (5mC) regulator-mediated molecular subtype system and a corresponding quantitative indicator, the 5mC score. Unsupervised clustering was performed to identify novel 5mC regulator-mediated molecular subtypes. The principal component analysis was applied to calculate the 5mC score. Then, we correlated the 5mC clusters (5mC score) with classical molecular subtypes, immunophenotypes, clinical outcomes, and therapeutic opportunities in BLCA. Finally, we performed pancancer analyses on the 5mC score.
Results:
Two 5mC clusters, including 5mC cluster 1 and cluster 2, were identified. These novel 5mC clusters (5mC score) could accurately predict classical molecular subtypes, immunophenotypes, prognosis, and therapeutic opportunities of BLCA. 5mC cluster 1 (high 5mC score) indicated a luminal subtype and noninflamed phenotype, characterized by lower anticancer immunity but better prognosis. Moreover, 5mC cluster 1 (high 5mC score) predicted low sensitivity to cancer immunotherapy, neoadjuvant chemotherapy, and radiotherapy, but high sensitivity to antiangiogenic therapy and targeted therapies, such as blocking the β-catenin, FGFR3, and PPAR-γ pathways.
Conclusions:
The novel 5mC regulator-based subtype system reflects many aspects of BLCA biology and provides new insights into precision medicine in BLCA. Furthermore, the 5mC score may be a generalizable predictor of immunotherapy response and prognosis in pancancers.
Insights
A new 5-methylcytosine (5mC) regulator-based system and 5mC score for bladder cancer (BLCA) accurately predict subtypes, prognosis, and treatment response. This offers new insights for precision medicine in BLCA and potentially other cancers.
Area of Science:
- Oncology
- Epigenetics
- Bioinformatics
Background:
- Understanding tumor microenvironment (TME) heterogeneity is crucial for bladder cancer (BLCA) precision medicine.
- Classical molecular subtypes offer insights but have clinical limitations.
Purpose of the Study:
- To develop a novel 5-methylcytosine (5mC) regulator-mediated molecular subtype system for BLCA.
- To create a quantitative 5mC score for predicting clinical outcomes and therapeutic strategies.
Main Methods:
- Integrated multiple BLCA cohorts for analysis.
- Employed unsupervised clustering to identify 5mC subtypes.
- Utilized principal component analysis to derive the 5mC score.
- Correlated 5mC clusters/score with molecular subtypes, immunophenotypes, prognosis, and treatment response.
- Conducted pancancer analyses of the 5mC score.
Main Results:
- Identified two distinct 5mC clusters (cluster 1 and cluster 2).
- The 5mC score accurately predicted BLCA molecular subtypes, immunophenotypes, and prognosis.
- 5mC cluster 1 (high 5mC score) associated with luminal subtype, noninflamed phenotype, better prognosis, and specific treatment sensitivities (antiangiogenic, targeted therapies) while predicting lower response to immunotherapy and neoadjuvant chemotherapy/radiotherapy.
Conclusions:
- The novel 5mC regulator-based subtype system provides valuable insights into BLCA biology and precision medicine.
- The 5mC score shows potential as a generalizable predictor of immunotherapy response and prognosis across pancancer types.
