Novel Gene expression-based Risk Stratification tool predicts recurrence in Non-muscle invasive Bladder cancer
Background Bladder cancer represents a heterogeneous disease with distinct clinical challenges. Non-muscle invasive bladder cancer (NMIBC) typically presents as indolent and slow-growing, yet a critical clinical challenge remains: identifying which patients will progress to muscle-invasive disease requiring radical interventions. Early detection of progression propensity is essential, as once muscle invasion occurs, the risk of distant metastasis increases substantially, and treatment shifts from conservative TURBT (Transurethral Resection of Bladder Tumor) to aggressive surgical interventions with significant morbidity. Current risk stratification methods fail to adequately predict this transition in approximately 30% of cases, highlighting the urgent need for more accurate prognostic tools. Objective This retrospective study aimed to develop and validate a transcriptomics-based mRNA score for predicting early NMIBC recurrence, comparing its performance against traditional risk stratification methods. Methods We analyzed mRNA expression profiles from primary retrospective NMIBC tumor specimens (n=25) collected between [2018-2022]. Traditional risk stratification tools, including EORTC scoring, were applied alongside our novel mRNA-based risk score to evaluate predictive accuracy for recurrence. Results The transcriptomics-based mRNA score demonstrated a median prediction accuracy of 90% across 10,000 resampling iterations for predicting early NMIBC recurrence, significantly outperforming traditional EORTC risk scores. Our comprehensive gene set identified 435 differentially expressed genes associated with recurrence. Kaplan-Meier analysis showed significantly different recurrence-free survival between high and low mRNA risk score groups (Bonferroni corrected p-value<0.0001). Conclusions This retrospective analysis confirms that mRNA expression-based risk stratification provides superior predictive accuracy compared to conventional clinicopathologic risk tools. Implementation of this gene signature could potentially reduce over-investigation and improve surveillance cost-effectiveness after TURBT in patients with primary high-risk NMIBC. These findings may transform the clinical management paradigm by enabling more personalized follow-up protocols based on molecular risk assessment. Overall design: RNA was extracted from FFPE blocks of NMIBC tumors and subjected to RNA sequencing analysis