Recent studies have defined several of the multiple genetic changes underlying the genesis of common adult neoplasms such as colon, breast, and lung carcinoma. Mutations affecting two classes of genes, oncogenes and tumor suppressor genes, are considered most fundamental. Whereas oncogenes are hyperfunctional forms of endogenous genes that promote cellular proliferation, tumor suppressor genes normally function to negatively regulate cell division in response to external growth or differentiation signals. Inactivation of both suppressor alleles is necessary for an oncogenic effect; typically a recessive mutation of one allele is followed by the loss of the other wild-type allele. Two suppressor genes, Rb on chromosome 13q14 and p53 on chromosome 17p13, have been most intensely studied. Each is mutated in a substantial fraction of common epithelial neoplasms as well as unusual tumors such as retinoblastoma, bone or soft- tissue sarcomas, leukemias, and brain tumors, and exogenous copies of wild- type Rb or p53 genes are able to suppress the neoplastic phenotype of human tumor cells bearing the appropriate mutated endogenous alleles. These results strongly suggest that mutations of these genes are significant in the genesis of many types of cancer. Despite its major health impact as the most common cancer in men, prostate carcinoma is relatively poorly understood at the genetic level. It is hypothesized that, as with other neoplasms, mutations of tumor suppressor genes contribute to the genesis of prostate carcinoma, although the identities, mutational frequencies and functional roles of such genes may differ for each cancer type. This hypothesis will be tested in three Aims. First, mutations and/or allelic losses of Rb,4p53 and other potential suppressor loci will be investigated in a large series of frozen and archival prostate tumors using immunohistochemistry and molecular genetic analyses. Significant correlation of such alterations with major clinicopathological indices such as tumor stage will give insight into specific oncogenic roles for these genes. Second, cellular mechanisms of tumor suppression will be explored in a model system, including a comparison of the activities of Rb and p53 and their possible synergy in suppressing the tumorigenic phenotype. Third, chromosomal regions that are frequently affected by allelic loss in prostate cancer will be examined by complementary structural and functional approaches for direct evidence that they harbor novel suppressor loci involved in prostatic oncogenesis. These studies will provide a molecular genetic framework for understanding the development and progression of prostate cancer, and may lead to novel diagnostic or therapeutic approaches to prostate cancer management.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (SRC)
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Canji, Inc.
San Diego
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MacGrogan, D; Pegram, M; Slamon, D et al. (1997) Comparative mutational analysis of DPC4 (Smad4) in prostatic and colorectal carcinomas. Oncogene 15:1111-4
Bookstein, R; Bova, G S; MacGrogan, D et al. (1997) Tumour-suppressor genes in prostatic oncogenesis: a positional approach. Br J Urol 79 Suppl 1:28-36
Bova, G S; MacGrogan, D; Levy, A et al. (1996) Physical mapping of chromosome 8p22 markers and their homozygous deletion in a metastatic prostate cancer. Genomics 35:46-54
MacGrogan, D; Levy, A; Bova, G S et al. (1996) Structure and methylation-associated silencing of a gene within a homozygously deleted region of human chromosome band 8p22. Genomics 35:55-65
Lewis, T B; Nelson, L; Ward, K et al. (1995) A radiation hybrid map of 40 loci for the distal long arm of human chromosome 8. Genome Res 5:334-41
MacGrogan, D; Levy, A; Bostwick, D et al. (1994) Loss of chromosome arm 8p loci in prostate cancer: mapping by quantitative allelic imbalance. Genes Chromosomes Cancer 10:151-9
Bookstein, R; Levy, A; MacGrogan, D et al. (1994) Yeast artificial chromosome and radiation hybrid map of loci in chromosome band 8p22, a common region of allelic loss in multiple human cancers. Genomics 24:317-23
Cher, M L; MacGrogan, D; Bookstein, R et al. (1994) Comparative genomic hybridization, allelic imbalance, and fluorescence in situ hybridization on chromosome 8 in prostate cancer. Genes Chromosomes Cancer 11:153-62