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Objectives: EphA2 tyrosine kinase receptor is highly expressed in ovarian cancer and predictive of poor clinical outcome. Based on the suggested role of p53 in regulating EphA2, we examined possible associations between them in the present study. Methods: After IRB approval, 78 invasive ovarian cancers and 5 ovarian cell lines were analyzed for p53 and EphA2 expression by immunohistochemistry (IHC). p53 exons 2-11 were analyzed using single-strand confirmation polymorphism (SSCP) and sequence analysis. Results: The EG, SKOV3 (both with p53 null mutations) and Hey A8 (missense p53 mutation) demonstrated EphA2 overexpres sion. However, A2780-PAR (wild type p53) and the non-transformed HIO-180 cell line did not express EphA2. Next, we analyzed ovarian cancers from 78 patients (median age 60.3 years, range 49-81). p53 mutations were found in 49 (63%) of 78 tumors and 36 (73%) of these 49 stained positive by IHC. Specifically, null mutations (nonsense, deletion, insertion, or splice site) were found in 21 (27%) tumors. Remarkably, 67% of the tumors with p53 null mutations stained negative for p53 protein. Loss of heterozygosity at the p53 locus was demonstrated in 68% of tumors. EphA2 was overexpressed in 61 (78%) of samples. No statistical association existed between EphA2 overexpression and any p53 mutation or missense mutation. However, 95% of tumors with p53 null mutations had EphA2 overexpression (p<0.03). There was no difference in incidence of EphA2 overexpression between critical vs. non-critical site missense p53 mutations or based on the location of mutations on specific p53 exons. Conclusions: The presence of p53 null mutations is highly associated with EphA2 overexpression. Implications for therapeutic approaches in ovarian cancer may be based on these molecular findings.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]