Loss of p21(Waf1) expression is a strong predictor of reduced survival in primary superficial bladder cancers

P21(Waf1) is a downstream effector of p53 and belongs to the Cip1/Kip1 family of cyclin-dependent kinase inhibitors. Thus, it is a potential tumor suppressor gene and likely plays an important role in tumor development. Moreover, reduced expression of p21(Waf1) has been reported to have prognostic value in several human malignancies. In this study, we evaluated the prognostic value of p21(Waf1) in bladder cancer compared with other clinicopathological features and with p27(Kip1) and p53 expression, A total of 96 superficial (pTa-1) human bladder carcinomas were immunohistochemically stained for p21(Waf1) protein expression. Positive p21(Waf1) staining (greater than or equal to 5% positive nuclei) was observed in 68 of the 96 (71%) tumors. p21(Waf1) expression was neither associated with tumor stage (P = 0.9) nor with tumor grade (P = 0.18) but was significantly associated with both p53 protein expression (greater than or equal to 20% positive nuclei; P = 0.007) and with p53 gene mutations (P = 0.017). A significant correlation was also observed between positivity for p21(Waf1) and high (>50% positive cells) p27(Kip1) expression (P = 0.04), With regard to prognosis, patients whose tumors showed absence of p21(Waf1) staining displayed a significantly shorter overall survival (P = 0.01 by log-rank test). However, p21(Waf1) expression did not correlate with disease-free survival (P = 0.15 by log-rank test). On a multivariate analysis that also included p53 and p27(Kip1) expression, negative p21(Waf1) staining was an independent predictor of reduced overall survival (P = 0.004; relative risk, 5.32), stronger than age and tumor stage. These data indicate that expression of p21(Waf1) protein strongly correlates with survival and might represent a useful prognostic marker in primary superficial bladder carcinomas.