Clinical relevance of dominant-negative p73 isoforms for responsiveness to chemotherapy and survival in ovarian cancer: evidence for a crucial p53-p73 cross-talk in vivo.
OBJECTIVE
We aimed to determine the clinical role of the p53 family members p53 and p73 in the responsiveness to platinum-based chemotherapy and survival in ovarian cancer, considering their cross-talk and the p53 polymorphism at codon 72.


METHODS
A detailed analysis of p53 and p73 in a series of 122 ovarian cancers was done. We used a functional yeast-based assay to determine the p53 mutational status. Red yeast colonies, indicating mutant p53, were subsequently sequenced to determine the specific p53 alteration. p53 mutations were divided into two groups according to their previous characterization in the literature: those that efficiently inhibit transcriptionally active TAp73 function and those that do not. A p53 polymorphism at codon 72 was determined in corresponding normal tissue or blood of ovarian cancer patients. Isoform-specific p73 expression analysis using real-time reverse transcription-PCR has previously been done in the majority of ovarian cancers included in this study. In a retrospective chart review, responsiveness to chemotherapy was assessed, and survival data with long follow-up times were collected.


RESULTS
Eighty of 122 (65.6%) of ovarian cancers harbored p53 mutations. p53 mutational status was an important determinant of responsiveness to platinum-based chemotherapy in all patients with a residual tumor of <2 cm in diameter after initial surgery (wild-type versus mutant, P = 0.029). In addition, p53 mutational status was a strong prognosticator for recurrence-free and overall survival (P < 0.0001 and P = 0.003, respectively) in univariate analyses. High expression levels of dominant-negative p73 isoforms (DeltaNp73 and DeltaN'p73) significantly correlated with chemotherapeutic failure (P = 0.048) and with worse recurrence-free and overall survival in patients with p53 mutant cancers (P = 0.048 and P = 0.005, respectively). Eight p53 mutations, present in 19 cases, were found that efficiently inhibit TAp73 (i.e., 175H, 220C, 245S, 245D, 248W, 248Q, 266E, and 273H). Patients with p53 mutations that efficiently inhibit TAp73 function had a significantly shorter overall survival than patients with p53 mutations of unknown effect on TAp73 (P = 0.044). The p53 polymorphism at codon 72 had no influence on responsiveness to chemotherapy or survival.


CONCLUSIONS
We provide the first clinical evidence that dominant-negative p73 isoforms contribute to drug resistance in vivo, underscoring the importance of a p53-p73 cross-talk. NH2-terminally truncated p73 isoforms were of significant clinical effect by providing an additional unfavorable factor for response to platinum-based chemotherapy and survival in p53 mutant ovarian cancers.
Concin
Nicole
N
Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria. nicole.concin@uibk.ac.at
Hofstetter
Gerda
G
Berger
Astrid
A
Gehmacher
Adriana
A
Reimer
Daniel
D
Watrowski
Rafal
R
Tong
Dan
D
Schuster
Eva
E
Hefler
Lukas
L
Heim
Kurt
K
Mueller-Holzner
Elisabeth
E
Marth
Christian
C
Moll
Ute M
UM
Zeimet
Alain G
AG
Zeillinger
Robert
R
D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018269:Carcinoma, Endometrioid / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D016147:Genes, Tumor Suppressor; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D020033:Protein Isoforms; D012189:Retrospective Studies; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development; D015996:Survival Rate; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human