Expression signature defined by FOXM1-CCNB1 activation predicts disease recurrence in non-muscle-invasive bladder cancer

Abstract

Purpose: Although standard treatment with transurethral resection and intravesical therapy (IVT) is known to be effective to address the clinical behavior of non-muscle-invasive bladder cancer (NMIBC), many patients fail to respond to the treatment and frequently experience disease recurrence. Here, we aim to identify a prognostic molecular signature that predicts the NMIBC heterogeneity and response to IVT. Experimental Design: We analyzed the genomic profiles of 102 patients with NMIBC to identify a signature associated with disease recurrence. The validity of the signature was verified in three independent patient cohorts (n = 658). Various statistical methods, including a leave-one-out cross-validation and multivariate Cox regression analyses, were applied to identify a signature. We confirmed an association between the signature and tumor aggressiveness with experimental assays using bladder cancer cell lines. Results: Gene expression profiling in 102 patients with NMIBC identified a CCNB1 signature associated with disease recurrence, which was validated in another three independent cohorts of 658 patients. The CCNB1 signature was shown to be an independent risk factor by a multivariate analysis and subset stratification according to stage and grade [HR, 2.93; 95% confidence intervals (CI), 1.302-6.594; P = 0.009]. The subset analysis also revealed that the signature could identify patients who would benefit from IVT. Finally, gene network analyses and experimental assays indicated that NMIBC recurrence could be mediated by FOXM1-CCNB1-Fanconi anemia pathways. Conclusions: The CCNB1 signature represents a promising diagnostic tool to identify patients with NMIBC who have a high risk of recurrence and to predict response to IVT.