Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer

Purpose: The p53 tumor suppressor gene plays a central role in cell cycle r egulation 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 fro zen and stored at -80 degreesC, were analyzed for mutations of the p53 gene (exons 2-11) by single-strand conformation polymorphism and DNA sequencing and for p53 overexpression by immumohistochemistry (monoclonal antibody DO 7). 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 ge ne. Time to progression and overall survival were significantly shortened i n 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 pr otein overexpression (> 10% positively stained nuclei) was found in 62% (11 0 of 178). Time to progression and overall survival were shorter in cases w ith p53 overexpression (cutpoint, 10%: P = 0.071 and P = 0.056) but only ma rginally significant. Resistance to adjuvant cisplatin or carboplatin chemo therapy was significantly more frequent in patients with p53 overexpression (P = 0.001) or p53 missense mutations (P = 0.008) than patients with norma l p53. Conclusions: p53 alterations correlate significantly with resistance to pla tinum-based chemotherapy, early relapse, and shortened overall survival in ovarian cancer patients in univariate analysis. In multivariable analysis t hough, p53 was not an independent prognostic factor.