Expression and Mutation of p53 in Tumor Effusion Cells of Patients with Ovarian Carcinoma: Response to Cisplatin-Based Chemotherapy

Abstract

p53 alterations are considered as one of the most important factors responsible for drug resistance in ovarian carcinomas, although the relationship between p53 gene status and response to cisplatin-based chemotherapy in ovarian cancer patients remains unclear. The aim of the study was to evaluate the relationship between p53 protein accumulation, p53 gene mutation and response to cisplatin-based chemotherapy in patients with ovarian carcinoma considering conventional clinicopathological parameters. Tissue sections and corresponding cyst and/or ascitic fluid cells from 79 patients with epithelial ovarian cancer were analyzed immunohistochemically for p53 expression. The PCR-SSCP analysis was performed in 25 cases and the results were compared with immunohistochemical data. It was demonstrated that p53 expression reaching approximately 50% of positive cells in immunostaining was usually associated with PCR-amplified exons showing abnormal migration and suspected for mutation. p53 gene changes were not correlated with histological structure, grade of differentiation or residual tumor after cytoreductive surgery, despite being detected more frequently in III/IV than in II FIGO stages and in patients with residual disease above 2 cm. A significant correlation between p53 accumulation and p53 gene alteration and poor response to cisplatin-based chemotherapy was shown. The overall survival time of patients decreased with an increase in p53 protein expression. A strong p53 expression especially accompanied by p53 changes detectable by PCR-SSCP analysis appears to be a good indicator of the resistance to cisplatin-based chemotherapy. The association between strong p53 overexpression and shorter overall survival time was also revealed.

Associations between p53 overexpression and multiple measures of clinical outcome in high-risk, early stage or suboptimally-resected, advanced stage epithelial ovarian cancers

“…Our findings are consistent with studies showing an association between p53 overexpression and PFS (16,22) or tumor grade (12,13,15,16,17,19,22–24,26,32,33,35,37,40,42) and with studies demonstrating that p53 overexpression was not associated with PFS (10,17,30,33,35,38,41,42), OS (8,10,11,17,24,25,29,30,32–39,41,42), tumor response (16,23,25,26,30,37,39–42), or disease status (12, 27), and that p53 was not an independent prognostic factor for PFS (16,17,34,35,42) or OS (12,14,16,17,19,22,24,29,32,33,35,39,40,42) in invasive EOC. However, these results contradict studies demonstrating that p53 overexpression was associated with OS (12,13,15,16,19,20,22,23,27,28,40), and/or tumor response (18,22), and that p53 was an independent prognostic factor for PFS (22) or OS (15,20,23,27,28,31) in invasive EOC.…”

“…Among the studies that examined OS as an end-point and used the N-terminal DO-7 antibody with different cut-points in FFPE or frozen tumor, most including ours showed that p53 overexpression was not associated with OS (14,24,30,32,33,34,39,42). In contrast, Ozalp and colleagues demonstrated that p53 overexpression categorized as negative or positive was associated with OS (27).…”

“…Mutations in p53 are a common event in ovarian cancer (8–11,17,18,24,26,29,30,33,35,36,41) and have been shown to either be associated with OS (24,29,33) or response to platinum/paclitaxel based chemotherapy (26,30,33) or to not associated with OS (35,41). A strong correlation has been observed between a p53 mutation most notably a missense mutation and DO-7 expression of p53 protein (14,18,24,26,29,33).…”

p53 Gene status in relation to ex vivo chemosensitivity of non-small cell lung cancer

“…Several other studies also confirmed p53 status relevance in predicting the efficacy of NSCLC patients' treatment in vivo (Nakanishi et al 1999;Rusch et al 1995;Kawasaki et al 1997;Brattstrom et al 1998;Tanaka et al 1999). Tissues without p53 accumulation showed significantly better in vitro sensitivity, and only in those patients was a good clinical response to cisplatin-based chemo(thermo)therapy observed, in agreement with in vitro results (Higashiyama et al 2000); similar results were frequently observed in tumors of various origins (e.g., in ovarian cancer, Bar et al 2001). p53 gene status modulates the extent of chemosensitivity and the induction of apoptosis by different anticancer agents in NSCLC cells (Perdomo et al 1998;Lai et al 2000).…”

Does tumour biology determine surgical success in the treatment of epithelial ovarian cancer? A systematic literature review

“…Four publications were identified that explored the relationship of p53 and residual disease, of which two found a significant association with p53 protein overexpression and suboptimal debulking in univariate analysis ( n =82, P =0.01) (Dogan et al , 2005) ( n =83, P <0.041) (Geisler et al , 1997), one demonstrated a trend to overexpression and suboptimal debulking ( n =136, P =0.07) (Ferrandina et al , 1999) and one did not find a significant association ( n =79, P =0.36) (Bar et al , 2001). These four studies used heterogeneous histological samples, variable clinical stages and varying definitions of suboptimal and optimal debulking.…”