INTRATUMOR CELLULAR HETEROGENEITY AND ALTERATIONS IN RAS ONCOGENE ANDP53 TUMOR-SUPPRESSOR GENE IN HUMAN PROSTATE CARCINOMA

To assess the potential role of ras oncogene activation and p53 tumor suppressor gene mutations in the development of human prostate carcino ma, nine cases of histologically heterogeneous prostate tumors obtaine d from total prostatectomies were probed for these specific events. Ea ch tumor vas divided into 5 to 10 areas according to different growth or histological patterns. Targeted DNA sequences coding for ras and p5 3 were amplified by the polymerase chain reaction, analyzed by single- strand conformational polymorphisms, and confirmed by direct DNA seque ncing. Point mutations of the ras gene were found in three of the nine tumors. Two contained K-ras codon 13 and H-ras codon 61 mutations, fo und in only one and three areas of each lesion, respectively. The thir d tumor contained two different point mutations in K-ras codons 13 and 61 in different foci of the sample. Loss of heterozygosity at the pol ymorphic codon 72 in the p53 gene was detected in two of four informat ive cases (50%) showing fragment cleavage by restriction fragment leng th poly,morphism analysis. Mutations in p53, missense transversions, s ingle base insertions, and two base deletions, were also detected ill three tumors. The present results reveal mutated ras and p53 occasiona lly occurring in small foci of the tumor and that genetic mutations in p53, as opposed to those in ras, are more closely associated with inv asive growth of heterogeneous prostate carcinoma.