Mechanisms of inactivation of multiple tumor suppressor genes in human prostate cancer

Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in US males. With an increasingly aging population, the incidence and mortality are rising at an alarming rate. However, the exact molecular mechanisms of prostate cancer formation are still elusive. We hypothesized that multiple tumor suppressor genes are involved in the formation of human prostate cancer and tumor suppressor genes are inactivated by multiple mechanisms. To test this hypothesis, we investigated the involvement of the tumor suppressor genes (e.g., DCC, RB, APC/MCC, p53, BRCA1, WAF1/CIP1 genes) in prostatic tumorigenesis and elucidated inactivational mechanisms of tumor suppressor genes. Fifty-seven (57) pairs of matched normal and tumor tissue specimens from patients with prostate cancer and a number of human and animal tumor cell lines were included in this study.;We identified a unique profile of tumor suppressor gene involvement in human prostate cancer. Tumor suppressor genes (e.g., the p53, DCC, APC, MCC, BRCA1, WAF1/CIP1 genes, and unknown genes on chromosome 6p12-24 and 17q21) were found to be inactivated at various frequencies via a number of mechanisms, including loss of heterozygosity (LOH), loss of mRNA expression (LOE), mutation, and inactivation by cellular binding protein. Several novel observations have been made. The potential tumor suppressor loci on chromosome 17q21 have been localized to a ;In conclusion, the results obtained in the present study support the initial hypothesis that multiple tumor suppressor genes (e.g., p53, DCC, APC, MCC, BRCA1, and WAF1/CIP1) are inactivated at different frequencies via various mechanisms (e.g., LOH, LOE, mutation, and inactivation by cellular binding protein) in human prostate cancer. In individual patients, however, it is likely that single or very limited number of tumor suppressor genes is(are) involved. This study offers a better understanding of the tumor suppressor gene involvement in human prostate cancer and pinpoints at a relatively narrow subchromosomal region for positional cloning of novel tumor suppressor gene(s) on chromosome 17q.