The Prognostic Value of Cell Cycle Gene Expression Signatures in Muscle Invasive, High-Grade Bladder Cancer

BACKGROUND: Approximately half of patients with muscle invasive bladder cancer succumb to their disease. Previous work identified cell cycle related genes as a prognostic class of gene expression biomarkers in bladder cancer and found a specific 31-gene cell cycle proliferation (CCP) signature predicted outcome across multiple bladder cancer cohorts. However, the prognostic value of the CCP signature specifically in muscle invasive tumors was not evaluated. OBJECTIVE: To determine the prognostic value of cycle related genes in patients with muscle invasive bladder cancers. METHOD: We collected all publicly available gene expression data for patients with high-grade, muscle invasive bladder cancer (8 cohorts, N = 458). We evaluated the CCP signature and two larger cell cycle gene sets: 1826 genes with a Gene Ontology (GO) annotation of “cell cycle” (GO-CCS) and 124 genes belonging to the “cell cycle” pathway in the KEGG pathway database (KEGG-CCS). An independently derived a sex identification gene signature (SIS) was developed as a positive control. RESULTS: While SIS distinguished males from females in all cohorts with information about patient sex, the CCP signature was not prognostic in any of the cohorts we analyzed, and the GO-CCS and KEGG-CCS were never prognostic in more than 2 independent cohorts. Furthermore, neither the CCP, GO-CCS, nor KEGG-CCS signatures were consistently enriched in prognostic genes while SIS was enriched with genes associated with sex in all cohorts. CONCLUSIONS: Our findings suggest that cell cycle related genes have limited prognostic value in patients with high-grade, muscle invasive tumors. Their usefulness in predicting progression of noninvasive disease and patient response to chemotherapy remains to be determined.