The Prognostic Role of CDK9 in Bladder Cancer

SIMPLE SUMMARY: In this article, we investigated the prognostic role of cyclin-dependent kinase 9 expression in urothelial carcinoma. High CDK9 expression has recently been associated with shorter patient survival time, but its role in urothelial carcinoma has not yet been explored. The expression of CDK9 was higher in cancer than in normal urothelial tissue and correlated with tumor grade, stage, and invasiveness. To our surprise, patients with high CDK9 expression lived longer than patients with low CDK9 expression. In The Cancer Genome Atlas database cohort, high CDK9 RNA concentration correlates with longer survival of patients and CDK9 status remained a statistically significant prognostic factor in multivariate analysis. It seems that CDK9 not only regulates the expression of anti-apoptotic genes, leading to longer survival of cancer cells, it also facilitates DNA repair, preventing the build-up of genomic instability, crucial in the initiation and progression of bladder cancer. The results suggest that CDK9 overexpression is not always associated with a worse prognosis, while cell maturity and disease stage may influence the efficacy of potential targeted therapy. ABSTRACT: Introduction: Most patients with urothelial carcinoma are diagnosed with non-invasive tumors, but the prognosis worsens with the progression of the disease. Overexpression of cyclin-dependent kinase 9 has been recently linked to increased cancer proliferation, faster progression, and worse prognosis. However, some cancers seem to contradict this rule. In this work, we explored the prognostic role of CDK9 expression in urothelial carcinoma. Materials and Methods: We performed immunohistochemical analysis on 72 bladder cancer samples. To assess a larger group of patients, the Cancer Genome Atlas (TCGA) database containing 406 cases and transcriptomics information through the Human Pathology Atlas were analyzed. Results: CDK9 is overexpressed in urothelial cancer tissues when compared to normal urothelial tissues (p < 0.05). High CDK9 expression was observed in low-stage, low-grade, and non-muscle-invasive tumors (p < 0.05). The patients with high CDK9 expression had a significantly higher 5-year overall survival rate than those with low CDK9 expression (77.54% vs. 53.6% in the TMA group and 57.75% vs. 35.44% in the TCGA group, respectively) (p < 0.05). The results were consistent in both cohorts. Multivariate Cox regression analysis indicated that low CDK9 status was an independent predictor for poor prognosis in the TCGA cohort (HR 1.60, CL95% 1.1–2.33, p = 0.014). Conclusions: High CDK9 expression predicts a favorable prognosis in urothelial carcinoma and is associated with clinicopathological features characteristic for early-stage disease. The decrease in CDK9 expression can be associated with the build-up of genetic instability and may indicate a key role for CDK9 in the early stages of urothelial carcinoma.