TP 53 Gene Mutations in Prostate Cancer Progression

Background: We assessed the predictive value of TP53 mutations and prostate-specific antigen (PSA) for tumor progression in prostate cancer (PCa) patients. Materials and Methods: Ninety tumor tissue samples of patients with PCa from radical prostatectomy were used. Tumor progression was estimated biochemically by the PSA level (> 0.2 μg/l) or by detection of metastases. Screening for TP53 mutations was performed by temperature gradient gel electrophoresis (TGGE) in exon-specific manner. Followup data were collected from medical protocols. Statistical analysis was performed by uniand multivariate techniques. Results: In 32 out of 90 patients (35.6%), TP53 mutations were detected. Thirteen out of 32 patients (40.6%) with TP53 mutations and nine out of 58 patients (15.5%) with TP53 wild-type showed tumor progression after 25 and 45 months, respectively. Conclusion: TP53 mutations in exon 7 and exon 8 are factors of tumor progression in PCa. Their contribution to tumor recurrence is more significant than tumor stage and pretherapeutic PSA level. It has been suggested that a subset of mutant alleles acquired by a subclone of tumor cells early in tumorigenesis leads not only to a selected replication advantage, but also, later in tumorigenesis, to the ability to metastasize (1). Clinical tumor stage, Gleason score, and pretherapy serum prostate-specific antigen (PSA) in descenting order were independently associated with clinical or biochemical relapse of PCa (2). PCa is one of the malignancies with the highest frequency of genetic variations (3). Renan has calculated a probability of 12 mutated genes from epidemiological data (4). The TP53 tumor suppressor gene is one of the most frequently mutated genes in human malignancies (5). However, the mutation frequency of TP53 in PCa has a low level of about 30% (6). Furthermore, the TP53 mutation frequency in prostate tumor tissue does not show a significant rising level in correlation with rising tumor grading and staging, as for example in bladder cancer. Mutations of TP53 influence the activation of cell proliferation and suppression of DNA repair, and apoptosis (7). Therefore, an acceleration of tumor progression by TP53 mutations was claimed (8, 9). Kuczyk et al. have described a correlation between overexpression of p53 protein and tumor progression in PCa patients (10): during univariate analysis, p53 overexpression, histological grading, and tumor stage were significant prognostic factors for survival, among which only p53 overexpression remained an independent significant predictor in multivariate analysis. In an earlier study, we found a low TP53 mutation frequency of between 16.5 and 19.0% in benign prostatic hyperplasia, with a higher rate of later occurence of PCa in patients with mutations (6, 11). Recently, regulation of PSA by TP53 was suggested (12, 13). In the diagnosis the rate of PCa patients with a serum PSA less than 4.0 μg/l is very high (14). However, the PSA level is the most specific tumor marker for PCa (15, 16). After radical surgical treatment of PCa the PSA level declines to less than 0.1 μg/l. An increase of PSA of 0.2 μg/l after curative PCa treatment is assumed to be indicative of tumor progression (17, 18). A high level of pretreatment PSA was considered also as a risk factor for tumor progression (19). In this communication we present follow-up data. Examining the influence of TP53 mutation status, pretreatment PSA level, patients age, tumor grading and staging on tumor progression in PCa patients. Materials and Methods Ninety patients who were treated for clinically organ confined primary PCa between 1993 and 2000 by either radical retropubic prostatectomy (until 06/1999) or by laparoscopic radical prostatectomy (after 06/1999) were followed for 22.5 (range 3-108) months. The Gleason score was not considerd in this study. All samples were analyzed according to histopathological standard methods (20). 1579 *Both authors contributed equally to this work. Correspondence to: Dr. Thorsten H. Ecke, HELIOS Hospital, Department of Urology, Pieskower Strasse 33, D-15526 Bad Saarow, Germany. Tel: +49 3363173170, Fax: +49 3363173136, e-mail: thorsten.ecke@helios-kliniken.de