The prognostic significance of p53 tumor suppressor gene alterations in ovarian carcinoma

BACKGROUND. The prognostic significance and nature of p53 dysfunction in ov arian carcinoma is unclear. The relation between p53 overexpression, p53 mu tations, and their effects on overall survival in primary ovarian carcinoma is explored. METHODS. Tumor specimens from 171 consecutive epithelial ovarian carcinomas were examined for overexpression of p53 protein with DO7 antibody. P53 mut ations were determined by direct sequencing. The influences of conventional histopathologic prognostic factors and various p53 molecular alterations o n overall survival were assessed. RESULTS. Overall, 48.5% and 57.3% of the samples showed p53 overexpression and p53 mutation, respectively. Although neither p53 overexpression nor the mere presence of a p53 mutation impacted overall survival, the combination did prognosticate survival both in univariate and multivariate models. The authors' results suggest 4 mechanisms that may affect p53 dysfunction in n early 100% of advanced stage ovarian carcinomas. These include null mutatio n, nonresponsive p53 wildtype [wt] p53 sequence, DO7 negative), sequestrati on (wt p53 sequence, DO7 positive], and missense mutation. Median survival for these groups that constitute sequentially 21.3%, 20.5%, 12.3%, and 45.9 % of the 122 Stage III or IV (International Federation of Gynecology and Ob stetrics) cancers was 1.49, 1.31, 3.09, and 3.6 years, respectively. The no nresponsive p53 and null sequence tumors grouped together as Functionally n ull convey the worst prognosis relative to missense mutations in a univaria te model (P = 0.006). Functionally null p53 (P = 0.002), stage (P = 0.008), and optimal cytoreduction (P = 0.008) were independent prognostic factors by multivariate analysis. CONCLUSIONS. Sequestration of wt p53 is unique to advanced stage ovarian ca rcinoma Functionally null p53 represents an independent molecular predictor of compromised survival. (C) 2000 American Cancer Society.