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Department of Pathology [A. R., W. H. W.], Department of Preventive Medicine [C. G.], and The Norris Comprehensive Cancer Center [M. F. P.], University of Southern California School of Medicine, Los Angeles, California 90033; Department of Obstetrics and Gynecology, Charité, Campus Virchow-Klinikum, Humboldt-University, Berlin, Germany [A. R., A. S., U. K., C. M., I. S., W. L.]; Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany [I. B. R., R. K.]; and Departments of Gynecologic Oncology [L. A. J.] and Pathology [A. E-N.], M. D. Anderson Cancer Center, University of Texas, Houston, Texas 77030; Department of Obstetrics and Gynecology, University of Graz, Graz, Austria, 112 [O. R.]
Purpose: The p53 tumor suppressor gene plays a central role in cell cycle regulation and induction of apoptosis. We analyzed p53 alterations and their impact on response to chemotherapy and clinical outcome in ovarian cancer patients.
Experimental Design: One hundred seventy-eight ovarian carcinomas, snap frozen and stored at -80°C, were analyzed for mutations of the p53 gene (exons 2–11) by single-strand conformation polymorphism and DNA sequencing and for p53 overexpression by immunohistochemistry (monoclonal antibody DO7).
Results: p53 mutations were found in 56% (99 of 178) of the tumors, and 62% of these were located in evolutionary highly conserved domains of the gene. Time to progression and overall survival were significantly shortened in patients with p53 mutations compared with wild-type p53 (P = 0.029 and P = 0.014) and patients with mutations in highly conserved domains as opposed to nonconserved domains or wild-type p53 (P = 0.010 and P = 0.007). p53 protein overexpression (>10% positively stained nuclei) was found in 62% (110 of 178). Time to progression and overall survival were shorter in cases with p53 overexpression (cutpoint, 10%: P = 0.071 and P = 0.056) but only marginally significant. Resistance to adjuvant cisplatin or carboplatin chemotherapy was significantly more frequent in patients with p53 overexpression (P = 0.001) or p53 missense mutations (P = 0.008) than patients with normal p53.
Conclusions: p53 alterations correlate significantly with resistance to platinum-based chemotherapy, early relapse, and shortened overall survival in ovarian cancer patients in univariate analysis. In multivariable analysis though, p53 was not an independent prognostic factor.
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