147 - Bladder-Specific 15-Gene Transcriptomic Signature Predicts (Chemo)radiation Therapy Response in Muscle-Invasive Bladder Cancer

04:55pm - 05:05pm PT

Room 24

Presenter(s)

Xiaohui Li, MD - Peking University First Hospital, Beijing, Beijing

X. Li¹, F. Wang², Q. Huang³, X. Ding¹, X. Gao², S. Wu¹, and C. Liu²; ¹Department of Medical Oncology, Peking University First Hospital, Beijing, China, ²Department of Radiation Oncology, Peking University First Hospital, Beijing, China, ³Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China

Purpose/Objective(s): Organ-sparing (chemo)radiation therapy is a promising strategy for muscle-invasive bladder cancer (MIBC). However, current radiosensitivity indices lack bladder-specific predictive capacity. This study aimed to develop a transcriptomics-driven prognostic model to stratify MIBC patients for optimized bladder preservation therapy.

Materials/Methods: Single-cell RNA sequencing (13,353 cells) and bulk RNA sequencing data (401 MIBC samples) were analyzed. Prognostic gene selection combined differential expression analysis, Kaplan-Meier survival stratification, and multivariate Cox regression. Predictive models were constructed using elastic net regression algorithm and the area under receiver operating characteristic curve (AUC). Biological characterization employed Gene Ontology, Gene Set Enrichment Analysis, and single-cell spatial validation.

Results: MIBC cohort treated with (chemo)radiation therapy exhibited distinct transcriptomic profiles, identifying 18 progression-free survival (PFS)-associated radiation-responsive genes. To overcome the limited MIBC-specific predictive utility of the conventional radiosensitivity index (RSI), we constructed a novel 15-gene prognostic signature through systematic screening and integration the novel radiation-responsive genes with RSI-related biomarkers using deep learning algorithms. The prognostic model demonstrated significantly enhanced discriminative performance compared to RSI, achieving superior AUC values (0.81 vs 0.58, P < 0.001). Single-cell data revealed predominant expression of signature genes in malignant epithelial cells. Furthermore, stratification by the 15-gene prognostic signature revealed divergent pathway patterns: the high-risk group demonstrated significant enrichment in epidermal cell differentiation and developmental pathways, whereas the low-risk group exhibited predominant enrichment of humoral immune response and mononuclear cell migration pathways. Notably, patients in the low-risk category achieved significantly better PFS (HR = 3.82; P < 0.001), indicative of enhanced therapeutic responsiveness to chemoradiation regimen.

Conclusion: This bladder-specific 15-gene transcriptomic signature effectively predicts (chemo)radiation therapy outcomes in MIBC, providing a molecular framework for selecting optimal candidates for bladder preservation.