GENETIC LOCI ASSOCIATED WITH PROSTATE CANCER DEVELOPMENT

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Loss of heterozygosity for a number of chromosomal regions and the RB and P53 suppressor genes has been observed in human prostate tumors. However, these alterations are not yet sufficiently well defined to associate specific chromosomal loci with prostate malignancy. Our goal is to identify chromosomal loci associated with the malignant phenotype which provide a genetic basis for understanding the occurrence and clinical manifestations of this disease. We will focus on chromosomal regions previously identified as candidates for involvement in prostate cancer (8p, 10q, 10p, 16q, Y). This will be accomplished using DNA probes available for these chromosomal regions and FIGE gel, southern and PCR analysis of DNA from human prostate tumors and normal prostate or WBC DNA. These studies will include analysis of the RB-1 and P53 genes at the DNA, RNA and protein level. Efforts will be made to demonstrate the presence of defined chromosomal deletions associated with prostate cancers and to characterize defects in the RB-1 and P53 suppressor genes and their products. We will expand our previous studies on the altered expression of Y-encoded genes in prostate tumors by examining the expression of two important regulatory genes, ZFY and SRY, in tumor and normal tissues. This will include correlating gene expression with clinical parameters and gene methylation patterns. Finally, molecular data from these studies will be correlated with information on the race and age of individuals and the clinical behavior of the tumor. This effort is directed toward identifying specific genetic loci which can be used as markers for, and provide a genetic basis toward, understanding the ethnic and age bias observed in this disease, and that can distinguish localized from metastatic disease. These studies are a first step in defining the chromosomal regions associated with prostate cancer and toward identifying specific genetic loci which participate in the development of the disease.