Association of p 21 , p 21 p 27 and p 21 p 53 Status to Histological Subtypes and Prognosis in Low-stage Epithelial Ovarian Cancer

Aim: The objective of this study was to evaluate the prognostic value of p21 alone and in combination with p53 or p27 for different histological subtypes of epithelial ovarian cancer and disease-free survival. Patients and Methods: The specimens were obtained at primary surgery from a series of 129 ovarian carcinomas in FIGO stages I-II. The technique of tissue microarray and immunohistochemistry was used for detection of positivity of the markers. Results: Positive staining for p21, p27 and p53 was detected in 36%, 58% and 25% of cases, respectively. The p21 status, p27 status and concomitant p21 p27 and p21 p53 status in four subgroups were related to histological subtypes (p=0.016, p=0.036, p=0.004 and p=0.001). Mucinous tumors mostly stained negatively for p27 and concomitantly negatively for p21 and p53. Clear cell tumors generally stained positively for p21 and p27 but negatively for p53. Serous tumors usually stained concomitantly negatively for p21 and positively for p53. In a multivariate Cox regression analysis, FIGO stage, p21 p53 and p53 status were independent prognostic factors for disease-free survival. Conclusion: A subgroup, constituting 25/129 (19%) of the patients with predominantly serous tumors with concomitant p21 negativity and p53 positivity had a poor survival. Another subgroup of 11/129 (9%) patients with non-serous tumors with concomitant p21 and p27 positivity had excellent survival. Epithelial ovarian cancer (EOC) is the most lethal malignancy of all gynecological cancers. Various clinical and pathological features of ovarian cancer are used as predictors of clinical outcome (1). The five histopathological subtypes of EOC represent five different diseases with different biological and genetic background (2, 3). Proliferation and cell cycle control are central processes in the biology of cancer (4). The cell cycle is regulated by two major families of cyclin kinase inhibitors (CKIs). One of these is the Cip/kip family including p21 and p27, which inhibit cyclin E/CDK (5). Down-regulation or inactivation of p21 and p27, which normally cause G1 arrest by binding to cyclin CDKs, result in dysregulation of normal cell cycle control and increased cell proliferation, and contribute to malignancy (6). Frequently mutated in a wide range of human cancer types, wild type p53 is a negative regulator of cell cycle control, which inhibits cell cycle progression in part by activating p21 expression, and also controls the exit of cells from the cell cycle into apoptosis (7). The p21 gene is the primary mediator of p53-induced cell cycle arrest, and cells lacking functional p53 express only low levels of p21. It was demonstrated in a study on ovarian A2780 cells that p21 not only inhibits CDK activity directly, but also increases the level of p27 as inhibitor through stabilizing the p27 protein (8). In contrast to p53 gene, mutation of the p21 and p27 genes occurs infrequently in human cancer, and epigenetic silencing seems to be another means of negative regulation of these tumor suppressors (9, 10). Findings, regarding the predictive and prognostic relevance of expression of p21 in EOC are inconsistent. Some studies have reported that immunostaining (IHC) of p21 alone was an independent prognostic factor for survival (6-7, 9) for EOC or endometrial cancer (11). The p21 p53 status was an independent prognostic factor for survival in a Cox multivariate analysis in at least three studies (6, 12, 13). Concomitant loss of p21 (negativity) and overexpression of p53 (positivity) were related to worse prognosis than the other combinations of staining (13). In two studies, the combination of low p21 and p27 expression was associated with worse overall survival (14, 15). In the present retrospective clinical study on 129 patients with EOC in FIGO stages I and II the aim was to evaluate the prognostic value of p21 separately and in combination with p53 and p27, respectively according to histological subtype and disease-free survival (DFS). 27 Correspondence to: Ingirídur Skírnisdóttir, Department of Women’s and Children’s Health, Department of Obstetrics and Gynecology, Uppsala University Hospital, Akademiska Sjukhuset, SE-751 85 Uppsala, Sweden. Tel: +46 186110000, Fax: +46 18559775, e-mail: ingiridur.skirnisdottir@kbh.uu. se