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Distant Metastases in Ovarian Cancer: Association with p53 Mutations¹

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology [A. K. S., J. I. S., M. D., B. A., R. E. B.] and Department of Pharmacology [R. E. B.], University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242

Distant metastases are unusual occurrences at presentation and during the progression of epithelial ovarian cancer. There are no good clinical predictors of this phenomenon. Because p53 dysfunction is common in ovarian cancer, we chose to investigate whether specific types of mutations predicted a predisposition to distant metastasis. We hypothesized that the complete absence of intact p53 protein as seen with p53 null mutations may be associated with an enhanced tendency to develop distant metastatic disease. The complete coding sequence of 130 tumor DNA samples was screened for p53 mutations by single-strand conformational polymorphism analysis. Abnormal single-strand conformational polymorphism findings were correlated with the specific DNA sequence abnormalities and outcome. Ninety-four (72%) tumors carried p53 mutations. Sixty-two were missense mutations, and 32 were null mutations (6 nonsense mutations, 23 frameshift mutations, and 3 splice-site mutations). Twenty-eight patients were found to have distant metastases (pericardium, brain, parenchymal liver, spleen, or lung) either at presentation or during the course of their treatment. Distant metastases were nearly 8-fold more common in patients whose tumors carried a null mutation (66%) than in those with either missense mutations (8%) or wild-type p53 (8%; P < 0.001). When a null mutation was present, 25% of the tumors were associated with distant metastases at initial diagnosis. No individual with wild-type p53 or a missense mutation in the tumor presented with distant metastasis. Tumors with null mutations were more likely to be associated with lymph node metastasis (P = 0.003), advanced stage (stage III/IV; P < 0.001) and high grade (grade II/III; P < 0.001), at presentation. These tumors progressed with distant metastases more swiftly than did tumors with either missense mutations (mean, 1.18 versus 2.71 years; P = 0.04) or wild-type p53 (3.57 years; P = 0.015). In contrast to the popular dogma, distant metastases in ovarian cancer do not necessarily result from prolonged treatment of disease. They may be predicted to occur early in the disease course due to a specific molecular genetic abnormality: null mutation of the p53 tumor suppressor gene. These findings need to be carefully considered when choosing between regional versus systemic treatment modalities.

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