ALTERATION OF THE P53 TUMOR-SUPPRESSOR GENE IN PROSTATE-CANCER - ANALYTICAL APPROACHES AND CLINICAL IMPLICATIONS

Adenocarcinoma of the prostate is one of the most frequently diagnosed malignancies in Western countries. While some patients die within 1-2 years after diagnosis, other patients with 'latent' tumors will never suffer from any symptoms during their lifetime. These observations in dicate the highly variable biological potential of prostate cancer and demonstrate the need for improved prognostic factors to determine the clinical prognosis of the individual patient and to guide currently a vailable treatment options to a more aggressive (radical prostatectomy ) or conservative (surveillance) therapeutical approach. Additionally recent investigations aim at the identification of patients at high ri sk for early tumor relapse following radical prostectomy, who should b e considered as candidates for an intensified follow-up or an adjuvant therapy (hormonal ablation/radiotherapy). Alteration of the p53 tumor suppressor gene is currently the most common genetic alteration assoc iated with human malignancies, and for a variety of tumor types such a s superficial bladder cancer, p53 inactivation could be clearly identi fied as an independent prognostic variable to predict the biological a ggressiveness of the individual rumor. With an average frequency of 25 -30% former investigations have reported alterations of the p53 tumor suppressor gene as a genetic event rarely occurring in prostate cancer . However, although several questions regarding the determination of p 53 alterations in prostate cancer, for example the poor correlation be tween immunohistochemistry and moleculargenetic analysis; remain to be clarified, recent studies strongly indicate that the determination of p53 inactivation allows the identification of a highly aggressive sub group of prostatic tumors with decreased recurrence-free and long-term survival following radical prostatectomy. Recently suggested statisti cal models recognizing biological and genetic markers such as p53 in a ddition to classical parameters (Gleason score: preoperative PSA level , extracapsular growth) have been developed to better predict the clin ical course of the individual patient. Opposite to the identification of p53 alteration as a single biological variable, the combination wit h other prognostically relevant parameters allows to include a larger cohort of patients into ana lysis. The introduction of new biomarkers e. g. p53, bcl-2 and the Retinoblastoma gene, into multiparametric pro gnostic models promises to reveal better prognostic information, possi bly sufficient enough to adjust the therapeutic strategy to the biolog ical aggressiveness of the individual tumor. However, future investiga tions will have to determine the reliability of genetic findings in ra ndom biopsies in comparison with moleculargenetic analysis of radical prostetectomy specimens in order to gain more experience in the validi ty of this technical approach to determine the individual prognosis Dr ier to prostatectomy.