title: Minichromosome maintenance proteins 2 and 5 in non-benign epithelial ovarian tumours: relationship with cell cycle regulators and prognostic implications.
abstract: 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.
authors.affiliation: First Department of Pathology, Athens University, School of Medicine, GR-11527 Athens, Greece.
authors.forename: H
authors.initials: H
authors.lastname: Gakiopoulou
authors.forename: P
authors.initials: P
authors.lastname: Korkolopoulou
authors.forename: G
authors.initials: G
authors.lastname: Levidou
authors.forename: I
authors.initials: I
authors.lastname: Thymara
authors.forename: A
authors.initials: A
authors.lastname: Saetta
authors.forename: C
authors.initials: C
authors.lastname: Piperi
authors.forename: N
authors.initials: N
authors.lastname: Givalos
authors.forename: I
authors.initials: I
authors.lastname: Vassilopoulos
authors.forename: K
authors.initials: K
authors.lastname: Ventouri
authors.forename: A
authors.initials: A
authors.lastname: Tsenga
authors.forename: A
authors.initials: A
authors.lastname: Bamias
authors.forename: M-A
authors.initials: MA
authors.lastname: Dimopoulos
authors.forename: E
authors.initials: E
authors.lastname: Agapitos
authors.forename: E
authors.initials: E
authors.lastname: Patsouris
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D018797:Cell Cycle Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D064111:Minichromosome Maintenance Complex Component 2; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C489423:MCM5 protein, human; D009687:Nuclear Proteins; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2