Predictive value of progression-related gene classifier in primary non-muscle invasive bladder cancer

Abstract

Background: While several molecular markers of bladder cancer prognosis have been identified, the limited value of current prognostic markers has created the need for new molecular indicators of bladder cancer outcomes. The aim of this study was to identify genetic signatures associated with disease prognosis in bladder cancer.

Results: We used 272 primary bladder cancer specimens for microarray analysis and real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Microarray gene expression analysis of randomly selected 165 primary bladder cancer specimens as an original cohort was carried out. Risk scores were applied to stratify prognosis-related gene classifiers. Prognosis-related gene classifiers were individually analyzed with tumor invasiveness (non-muscle invasive bladder cancer [NMIBC] and muscle invasive bladder cancer [MIBC]) and prognosis. We validated selected gene classifiers using RT-PCR in the original (165) and independent (107) cohorts. Ninety-seven genes related to disease progression among NMIBC patients were identified by microarray data analysis. Eight genes, a progression-related gene classifier in NMIBC, were selected for RT-PCR. The progression-related gene classifier in patients with NMIBC was closely correlated with progression in both original and independent cohorts. Furthermore, no patient with NMIBC in the good-prognosis signature group experienced cancer progression.

Conclusions: We identified progression-related gene classifier that has strong predictive value for determining disease outcome in NMIBC. This gene classifier could assist in selecting NMIBC patients who might benefit from more aggressive therapeutic intervention or surveillance.

Figure 1

Study design and validation strategies.

Figure 2

Hierarchical cluster analysis of 165 primary bladder cancers (103 NMIBC and 62 MIBC). Genes with expression values that had a standard deviation of at least .7 were selected (4,532 genes). The red and green colors reflect high and low expression levels, respectively.

Figure 3

Kaplan-Meier estimations in primary bladder cancer with gene signatures based on microarray analysis of the original training cohort. Kaplan-Meier curves of (A) recurrence (B) and progression in NMIBC. Kaplan-Meier curves of (C) progression, (D) cancer-specific survival and (E) overall survival in MIBC.

Figure 4

Kaplan-Meier estimations in primary bladder cancer with gene signatures based on RT-PCR analysis of the original validation cohort. Kaplan-Meier curves of (A) recurrence and (B) progression in NMIBC, and (C) progression in MIBC.

Figure 5

Kaplan-Meier estimations in primary bladder cancer with gene signatures based on RT-PCR analysis of the independent validation cohort. Kaplan-Meier curves of (A) recurrence and (B) progression in NMIBC, and (C) progression in MIBC.