p21 Expression Predicts Outcome in p53-null Ovarian Carcinoma

Purpose: p21 is a direct p53 response gene. Although several studies have correlated p21 and p53 expression, only one has evaluated p21 expression as a function of sequenced p53 gene mutation. We hypothesize that such an analysis may be useful in prognosticating outcome for individuals diagnosed with epithelial ovarian cancer. Experimental Design: DNA from the primary ovarian cancers of 267 patients was studied. p53 mutations were directly sequenced. Two percent or greater nuclear staining with WAF1/CIP1 monoclonal antibody was determined by a hazard ratio analysis to constitute positive p21 expression. Results: Positive p21 nuclear staining occurred more frequently in p53 wild-type ovarian tumors than tumors found to have a p53 mutation ( P = 0.001). Positive p21 staining conferred an overall survival advantage ( P = 0.02). p21 expression in cancers with p53 missense mutations was not prognostic but did show a strong trend toward significance in the wild-type p53 subset ( P = 0.056). Surprisingly, positive p21 staining reflected compromised survival for individuals with p53-null ovarian cancers ( P = 0.005). The mean expression level for p21-positive stains in the wild-type group was greater than in null p53 cancers (23 versus 11%; P = 0.001). A Cox multivariable analysis revealed p21 to be a strong independent prognostic factor in p53-null ovarian cancer ( P = 0.02). Conclusion: p21 expression is closely related to sequenced p53 mutations. This is the first study of positive p21 staining as an independent poor prognostic factor in p53-null ovarian cancer. A dual role for p21 activity, dependent on levels of expression, appears to explain these paradoxical results and is consistent with a complex model for regulation of p21.