Cyclin D1, p53, and p21Waf1/Cip1 Expression Is Predictive of Poor Clinical Outcome in Serous Epithelial Ovarian Cancer

Abstract

Purpose: Dysregulation of cell cycle control, in particular G₁-S-phase transition, is implicated in the pathogenesis of most human cancers, including epithelial ovarian cancer (EOC). However, the prognostic significance of aberrant cell cycle gene expression in EOC remains unclear. Experimental Design: The expression of selected genes from the pRb pathway that regulates G₁-S-phase progression, including cyclin D1, p16^Ink4a, cyclin E, p27^Kip1, p21^Waf1/Cip1, and p53, was examined in a consecutive series of 134 serous EOC using immunohistochemistry and the results correlated to disease outcome. Results: Molecular markers predictive of reduced overall survival in univariate analysis were overexpression of cyclin D1 (P = 0.03) and p53 (P = 0.03) and reduced expression of p27^Kip1 (P = 0.05) and p21^Waf1/Cip1 (P = 0.02), with the latter three also being prognostic for a shorter progression-free interval. In addition, patients displaying overexpression of p53 with concurrent loss of p21^Waf1/Cip1 had a significantly shorter overall (P = 0.0008) and progression-free survival (P = 0.0001). On multivariate analysis, overexpression of cyclin D1 and combined loss of p21^Waf1/Cip1 in the presence of p53 overexpression were independent predictors of overall survival. Similarly, the combination of p21^Waf1/Cip1 loss and p53 overexpression was independently predictive of a shorter progression-free interval. Overexpression of p53 and cyclin E and reduced expression of p27^Kip1 and p21^Waf1/Cip1 were significantly associated with increasing tumor grade. Conclusions: This study confirms that dysregulation of cell cycle genes is common in EOC, and that aberrant expression of critical cell cycle regulatory proteins can predict patient outcome in serous EOC.