P53 PROTEIN ACCUMULATION AND GENE MUTATION IN THE PROGRESSION OF HUMAN PROSTATE CARCINOMA

Background: Nuclear accumulation of p53 protein has been shown to be s trongly associated with missense p53 mutations. Studies of nuclear acc umulation of p53 protein in prostate carcinoma cells have to date been confined to material from primary tumors. Purpose: We studied the acc umulation of p53 protein in specimens obtained from primary and metast atic sites of prostate carcinoma. By examining the accumulation of thi s protein as a function of stage, histologic grade, and androgen respo nsiveness of the tumor, we hoped to determine the role of p53 mutation in the progression of prostate carcinoma. Methods: The accumulation o f the p53 protein in the cell nuclei was determined by immunohistochem ical methods using polyclonal antibody to human p53 CM-1. The material studied consisted of formalin-fixed, paraffin-embedded tissue obtaine d from primary tumors and metastases of 92 patients with prostate carc inoma. Twelve samples from 11 patients were analyzed for the presence of mutations within exons 5-8 of the p53 gene (also known as TP53) by polymerase chain reaction-single-stranded conformation polymorphism (P CR-SSCP) analysis. Sequence analysis was subsequently performed on DNA obtained by polymerase chain reaction amplification of PCR-SSCP react ions produced from six different specimens. The chi-square test, Fishe r's exact test, and the Freeman Halton test were used for statistical analyses of the results. Results: All tumors with p53 accumulation wer e metastatic (stage D), poorly differentiated, and androgen independen t. Nuclear accumulation of p53 protein was strongly associated with st age (D2 versus D1 versus A-C, P<.0001), grade (Gleason score 8-10 vers us 5-7, P<.003), and androgen sensitivity (androgen independent versus dependent, P<.0001). Logistic regression analysis demonstrated that a ndrogen sensitivity predicted p53 outcome better than did stage (P<.00 01) or grade alone (P<.006). There was a perfect concordance between t he results obtained by PCR-SSCP analysis and the p53 protein accumulat ion determined by immunohistochemistry in the 12 samples studied. Muta tion of the p53 gene was confirmed by sequencing DNA obtained from six specimens positive in the PCR-SSCP assay. Conclusions: p53 gene mutat ion is a late event in the progression of prostate cancer and is assoc iated with advanced (metastatic) stage, loss of differentiation, and t he transition from androgen-dependent to androgen-independent growth. Implication: Testing of prostate cancer biopsy specimens from metastat ic sites for p53 protein accumulation and gene mutation may provide us eful prognostic information and could influence the recommended course of treatment.