Frequency and characterization of p53 mutations in clinically localized prostate cancer

Abstract

Objectives To determine the frequency of abnormal p53 expression and to characterize confirmed p53 mutations in tumors from patients with clinically localized adenocarcinoma of the prostate. Methods p53 protein nuclear accumulation was determined immunohistochemically in the initial diagnostic tumor specimens from 37 patients with clinically localized prostate carcinoma. Two primary antibodies were used on all specimens. Structural analysis of the p53 gene was performed using the methods of polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) and DNA sequencing. Results In 1 of the 37 (2.7%) tumor specimens, intense p53 nuclear staining was demonstrated using either antibody PAb 1801 or CM-1. The staining in this case was heterogeneous, with approximately 40% of tumor nuclei staining for p53. This tumor specimen was microdissected and DNA was extracted. Following PCR amplification, abnormally migrating bands were noted on SSCP analysis of exon 8. DNA sequencing confirmed the mutation as a C → A transversion in codon 281 (asp → glu). PCR/SSCP analysis of exons 5 through 8 was also performed for seven additional tumors that were negative for p53 nuclear accumulation by immunohistochemical (IHC) methods. All of these specimens demonstrated wild-type p53. Conclusions The results of this study confirm and extend our previous findings that p53 mutations are rare in clinically localized adenocarcinoma of the prostate. In detecting clonal p53 mutations, standard immunohistochemical technique correlates reliably with structural p53 gene analysis of the evolutionary conserved domains encompassing exons 5–8. Importantly, most reports have demonstrated that p53 mutations detected by IHC are a late step in the progression of prostate cancer and are associated with advanced disease, dedifferentiation, and the acquisition of androgen independence.