Prognostic value of p27Kip1 and p21WAF/Cip protein expression in muscle invasive bladder cancer.

Abstract

Two genes, namely p27Kip1 and p21WAF/Cip1 that reveal distinct structural homology, have been identified as inductors of cell cycle arrest at the G1-checkpoint to prevent entry of somatic cells into the S phase of the cell cycle when substantial DNA damage has occurred. It was demonstrated that the p21WAF/Cip1 gene is induced by pathways dependent and independent from a functionally intact p53 tumour suppressor protein. It has been suggested that decreased expression both of the p21WAF/Cip1 and p27Kip1 protein may contribute to the development of human malignancies due to loss of critical antiproliferative mechanisms. So far, the role of altered p21WAF/Cip1 and mainly of a decreased p27Kip1 protein expression in patients with muscle invasive bladder cancer has not been investigated. In the present study, 50 tumour specimens from 50 patients undergoing radical cystectomy (T2-T4) were investigated for different biological and clinical characteristics as possible prognostic factors: age, depth of tumour infiltration (T-stage), histological grading (G), lymph node status as well as immunohistochemical staining for the p21WAF/Cip1 and p27Kip1 proteins. The median recurrence-free survival for patients with and without retained p21WAF/Cip1 protein expression was 54 months (3-86 months) and 13 months (1-40 months), respectively (p=0.07). During univariate analysis, loss of p21WAF/Cip1 protein expression (p=0.02), T-stage (p=0.02) and histological grading (p=0.03) were significant prognostic factors for survival, among which a negative reaction for the p21WAF/Cip1 protein (p=0.02) as well as T-stage (p=0.005) remained independent significant predictors during multivariate analysis. Loss of p27Kip1 protein expression was not correlated with the recurrence-free or the overall survival of the patients. Prospective studies are needed to confirm the independent prognostic potential of cell-cycle associated proteins such as p21WAF/Cip1 in patients with muscle invasive bladder cancer. The availability of more refined prognostic factors should assist decision making regarding the value of more aggressive treatment options, such as adjuvant or neoadjuvant chemotherapy, for defined subgroups of patients.