Expression Signature Defined byFOXM1–CCNB1Activation 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. Clin Cancer Res; 20(12); 3233–43. ©2014 AACR.

CDK4/6 Inhibitor as a Novel Therapeutic Approach for Advanced Bladder Cancer Independently of RB1 Status

“…Our data revealed that the increased activity and expression of FOXM1 in NMIBC identifies primary tumors at high risk of recurrence, and the possibility that these tumors display invasive characteristics in the recurrences. These data support the previous FOXM1dependent gene signature related to recurrence in bladder cancer (54). Moreover, integrative global genomic analyses of advanced bladder cancer supported its relevance (10,11).…”

Long Non-Coding RNA Expression Profiles for the Characterization of Different Bladder Cancer Grade

“…In our study, IL8 is the second highest enriched connectivity nodes. Surprising, further investigation indicates that IL-8-stimulated cell proliferation correlates with alteration of cell cycle distribution by increasing levels of cell cycle-regulated Cyclin D1 and Cyclin B1 proteins as well as activation of PI3K/Akt and Raf/MEK/ERK [34]. Therefore, IL8 and CCNB1 may have potential function in the progress of bladder cancer.…”

microRNA‐216b inhibits cell proliferation and migration in human melanoma by targeting FOXM1 in vitro and in vivo

“…As a member of an evolutionarily conserved family of transcription factors characterized by a DNA-binding domain called the Forkhead Box (Kalin et al, 2011), FOXM1 is also known as a representative proliferationassociated transcription factor, such as prostate cancer (Lokody, 2014), hepatocellular carcinoma (Yamashita et al, 2014), glioblastoma (Gong et al, 2015), and bladder cancer (Kim et al, 2014). The overexpression of FOXM1 observed that FOXM1 is associated with an aggressive phenotype and poor prognosis in patients with breast cancer (Rajamanickam et al, 2016).…”