Minichromosome maintenance proteins 2 and 5 in non-benign epithelial ovarian tumours: relationship with cell cycle regulators and prognostic implications.

Minichromosome maintenance proteins (MCM) have recently emerged as novel proliferation markers with prognostic implications in several tumour types. This is the first study investigating MCM-2 and MCM-5 immunohistochemical expression in a series of ovarian adenocarcinomas and low malignant potential (LMP) tumours aiming to determine possible associations with clinicopathological parameters, the conventional proliferation index Ki-67, cell cycle regulators (p53, p27(Kip1), p21(WAF1) and pRb) and patients' outcome. Immunohistochemistry was applied in a series of 43 cases of ovarian LMP tumours and 85 cases of adenocarcinomas. Survival analysis was restricted to adenocarcinomas. The median MCM-2 and MCM-5 labelling indices (LIs) were significantly higher in adenocarcinomas compared to LMP tumours (P<0.0001 for both associations). In adenocarcinomas, the levels of MCM-2 and MCM-5 increased significantly with advancing tumour stage (P=0.0052 and P=0.0180, respectively), whereas both MCM-2 and MCM-5 increased significantly with increasing tumour grade (P=0.0002 and P=0.0006, respectively) and the presence of bulky residual disease (P<0.0001 in both relationships). A strong positive correlation was established between MCM-2 or MCM-5 expression level and Ki-67 LI (P<0.0001) as well as p53 protein (P=0.0038 and P=0.0500, respectively). Moreover, MCM-2 LI was inversely correlated with p27(Kip-1) LI (P=0.0068). Finally, both MCM-2 and MCM-5 were associated significantly with adverse patients' outcome in both univariate (> or =20 vs >20%, P=0.0011 and > or =25 vs <25%, P=0.0100, respectively) and multivariate (P=0.0001 and 0.0090, respectively) analysis. An adequately powered independent group of 45 patients was used in order to validate our results in univariate survival analysis. In this group, MCM-2 and MCM-5 expression retained their prognostic significance (P<0.0001 in both relationships). In conclusion, MCM-2 and MCM-5 proteins appear to be promising as prognostic markers in patients with ovarian adenocarcinomas.

Evaluation of the cyclin-dependent kinase inhibitor p21Cip1 in epithelial ovarian tumors of low malignant potential and adenocarcinomas.

OBJECTIVE: In view of the controversial information on the significance of the cyclin-dependent kinase inhibitor p21Cip1 in ovarian cancer, we conducted a retrospective investigation to clarify the relationships of this protein to proliferation rate, clinicopathological variables and prognosis of epithelial ovarian tumors. METHODS: Paraffin-embedded tissue from 43 ovarian tumors of low malignant potential (LMP) and 82 primary ovarian adenocarcinomas were stained immunohistochemically for p21Cip1, p53 protein and Ki-67 antigen (a marker of cell proliferation). RESULTS: p21Cip1 levels were significantly higher in LMP tumors (p<0.001) as well as in early stage adenocarcinomas (p=0.021) and those associated with minimal residual disease (p=0.008). However, no relationship existed between p21Cip1 expression and the proliferation rate of adenocarcinomas or LMP tumors. In the vast majority of LMP tumors p21Cip1 expression was not accompanied by p53 accumulation. This p21Cip1-positive/p53-negative phenotype prevailed in the early stage (p=0.026), lower grade (p=0.018) adenocarcinomas as well as in those left with minimal residual disease (p=0.059). In patients with lower grade adenocarcinomas, decreased p21Cip1 expression was adversely related to poor overall survival on its own (p=0.0500) and when combined with p53 protein overexpression (p=0.0323). In multivariate analysis, only the stage remained as the independent predictor of survival. CONCLUSIONS: Decreased p21Cip1 expression is related to several indicators of aggressiveness in ovarian adenocarcinomas and seems to be differentially regulated in LMP tumors and adenocarcinomas. On the contrary, deregulation of p21Cip1 expression does not seem to participate in the pathogenesis of LMP tumors. Furthermore, although p21Cip1 alone or combined with p53 is of prognostic significance in lower grade adenocarcinomas, it does not appear to add to the information gained from traditional prognosticators.