Correlation of p53 Mutations with Resistance to Platinum-based Chemotherapy and Shortened Survival in Ovarian Cancer

• Published in: Clinical cancer research Vol. 7; no. 10; pp. 2984 - 2997
• Main Authors: RELES, Angela, WEN, Wen H, REICH, Olaf, KREIENBERG, Rolf, LICHTENEGGER, Werner, PRESS, Michael F, SCHMIDER, Annette, GEE, Conway, RUNNEBAUM, Ingo B, KILIAN, Uta, JONES, Lovell A, EL-NAGGAR, Adel, MINGUILLON, Carmen, SCHÖNBORN, Ines
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.10.2001
• Subjects: Aged; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Cisplatin - therapeutic use; Disease Progression; DNA Mutational Analysis; DNA, Neoplasm - chemistry; DNA, Neoplasm - genetics; Drug Resistance, Neoplasm; Female; Female genital diseases; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; Humans; Infant, Newborn; Medical sciences; Middle Aged; Multivariate Analysis; Mutation; Neoplasm Staging; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Polymorphism, Single-Stranded Conformational; Prognosis; Survival Analysis; Time Factors; Tumor Suppressor Protein p53 - genetics; Tumors; Antineoplastic agent; Carcinoma; Prognosis; Gene product; Tumoral tissue; Ovary; TP53 Gene; Tumor progression; Tumor suppressor gene; Platinum II Complexes; Human; Nucleotide sequence; Malignant tumor; Gene expression; In vitro; Survival; Cisplatin; Invasion; Female genital diseases; Ovarian diseases; Chemotherapy; Sensitivity resistance; Treatment; DNA; Carboplatin; Mutation; Predictive factor
• ISSN: 1078-0432; 1557-3265

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.