Significance of Cell Cycle Regulatory Proteins as Malignant and Prognostic Biomarkers in Ovarian Epithelial Tumors

The principal objective of this study was to comprehensively assess the clinicopathologic and prognostic impacts of the expression of various cell cycle regulatory proteins in patients with ovarian epithelial tumors. The tissue microarrays were constructed from formalin-fixed, paraffin-embedded tissues of 205 ovarian epithelial tumors. We investigated 55 benign (20 serous cystadenomas, 17 mucinous cystadenomas, and 18 endometriotic cysts), 72 borderline (26 serous borderline tumors and 46 mucinous borderline tumors), and 78 malignant tumors (45 serous carcinomas, 10 mucinous adenocarcinomas, 15 endometrioid adenocarcinomas, and 8 clear cell carcinomas). Immunohistochemical staining was performed using antibodies to p16^Ink4a, p53, p21^Waf1/Cip1, p27^Kip1, Cyclin D1, Cyclin E, Cyclin A, Cyclin B1, and Cyclin-dependent Kinase2. We noted significantly different levels of p53 and Cyclin B1 expressions between malignant and borderline tumors and between borderline and benign tumors excepting the mucinous type. The p21^Waf1/Cip1 and Cyclin A were significantly overexpressed in malignant tumors compared with borderline tumors. Cyclin A, Cyclin E, and p16^Ink4a were more pronounced proteins, showing differential expression patterns among the histologic types of ovarian carcinomas. We determined that the overexpression of p16^Ink4a (P=0.031), Cyclin E (P=0.009), and Cyclin-dependent Kinase2 (P=0.004) were significantly associated with higher tumor grades. Overexpression of p16^Ink4a was correlated with both lymph node metastasis (P=0.030) and distant metastasis (P=0.034). Overexpression of Cyclin E was associated with advanced stage (P=0.004). Higher tumor grade (P=0.008), advanced stage (P=0.001), mucinous histologic type (P=0.012), low expression levels of p16^Ink4a (P=0.032), and overexpression of p53 (P=0.032) were associated with poor overall survival on multivariate analysis in patients with ovarian cancer. In serous carcinomas, old age (P=0.005), distant metastasis (P=0.020), low expression of p16^Ink4a (P=0.047), and overexpression of cytoplasmic p27^Kip1 (P=0.007) and Cyclin A (P=0.031) were all independent predictors of worse overall survival. Our data indicate that the overexpression of p16^Ink4a and Cyclin E are valuable factors predicting disease progression and metastatic potential. Low p16^Ink4a expression, overexpression of p53, cytoplasmic p27^Kip1, and Cyclin A are predictive markers for shorter overall survival in ovarian carcinomas.