title: Cyclin D1 predicts the prognosis of advanced serous ovarian cancer.
abstract: We previously reported that cyclin E (CCNE1) amplification is strongly associated with resistance to treatment in serous ovarian cancer by high-resolution oligonucleotide copy number analysis. Dysregulation of cell cycle control has been implicated as the key event in human oncogenesis, and aberrant expression of G1-S phase-related genes in particular has been reported in epithelial ovarian cancer (EOC). Nevertheless, there are conflicting results concerning the prognostic values of these abnormalities in EOC. This study focused on advanced serous EOC cases and investigated the association between the expression of G1-S phase-regulatory proteins and clinicopathological parameters. The utility of these proteins as prognostic factors was assessed, and whether these targets reflect chemoresistance of advanced serous EOC was investigated. A total of 66 patients treated by primary surgery were evaluated in this study. Immunohistochemical analysis for cyclin D1, pRb, p16, p53, p27(Kip1), p21(Waf1/Cip1) and cyclin E was performed on formalin-fixed tissue sections collected from primary surgical specimens. The correlations between the expression of these proteins and the clinicopathological parameters, including progression-free survival (PFS), overall survival (OS) and chemosensitivity, were examined. Upon univariate analysis, overexpression of cyclin D1 was positively correlated with reduced PFS (p=0.00062) and OS (p=0.00037). Reduced expression of p27(Kip1) was associated with shorter OS (p=0.064). Upon multivariate analysis, overexpression of cyclin D1 (p=0.0019), reduced expression of p27(Kip1) (p=0.042) and residual tumor volume (p=0.0092) were identified as independent predictors of OS. Overexpression of cyclin D1 (p=0.011) as well as residual tumor volume (p=0.006) were significantly associated with first-line chemosensitivity. In advanced serous EOC, overexpression of cyclin D1 contributed largely to poor prognosis, and this may have been in part mediated by chemoresistance. Cyclin D1 is a possible target for overcoming the refractory nature of advanced serous EOC.
authors.affiliation: Department of Obstetrics and Gynecology, The Jikei University School of Medicine;
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Nozomu
authors.initials: N
authors.lastname: Yanaihara
authors.forename: Aikou
authors.initials: A
authors.lastname: Okamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Nikaido
authors.forename: Misato
authors.initials: M
authors.lastname: Saito
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takakura
authors.forename: Makoto
authors.initials: M
authors.lastname: Yasuda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sasaki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ochiai
authors.forename: Tadao
authors.initials: T
authors.lastname: Tanaka