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 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.