p53 mutations in prostatic intraepithelial neoplasia and concurrent carcinoma: Analysis of laser capture microdissected specimens from non-transitionand transition zones

Prostatic intraepithelial neoplasia (PIN) is characterized by intraluminal proliferation of epithelial cells and is divided into high-grade (HGPIN) an d low-grade (LGPIN) lesions. HGPIN is regarded as the most likely precursor of prostatic cancer (PCA). Microdissected DNA selectively extracted from p araffin-embedded sections of 27 cases with PCA were analyzed for p53 mutati on in exons 5-8 by single-strand conformation polymorphism of polymerase ch ain reaction-amplified DNA fragments (PCR-SSCP) followed by direct sequenci ng. These patients received total prostatectomy (27 cases). After a review of histologic sections, DNA was extracted from 193 locations; 111 lesions f rom 27 cases with HGPIN (75 lesions from non-transition zone and 36 from tr ansition zone), 55 lesions from 27 cases with PCA (30 lesions from non-tran sition zone and 25 from transition zone), and 27 from 27 benign glands. Ana lysis revealed 27 mutations of the p53 gene in 24 lesions from 12 cases. Be nign glands adjoining PIN and/or PCA had no mutations. All mutations were p oint mutations: 17 missense, 7 silent, and 2 nonsense. Mutations were detec ted in 6 cases (22.2%) or 13 of 111 lesions (11.7%) with HGPIN and 8 cases (29.6%) or 11 of 55 lesions (20.0%) with PCA, In a given case, HGPIN and PC A lesions had different p53 mutations from each other, suggesting multiclon al development of prostatic precancerous lesions. The frequency of p53 muta tion of PCA was significantly higher in the non-transition zone (33.3%) tha n in the transition zone (4%), and higher in the stage T3 cases (30.3%) tha n in the stage T2 cases (4.5%, 1 of 22 lesions) (both P<0.05), Frequency of p53 mutation of PIN in the non-transition zone (14.7%) was higher than tha t in the transition zone (5.6%), although the difference was not significan t. The frequency rate of p53 mutation in HGPIN close to PCA (less than or e qual to 2 mm) was significantly higher (24%) than that in HGPIN lesions >2 mm from PCA (3%), All these findings indicate that the p53 gene mutations a re involved in prostatic carcinogenesis and explain why the non-transition zone is the predominant site of PCA.