We hypothesize that multiple genes are involved in risk of prostate cancer and tumor aggressiveness and that many of these genetic risk factors will be represented by low penetrance gene mutations, each accounting for a small effect on risk. We propose to build upon two promising areas of our research program concerned with the influence of genes on prostate cancer risk and tumor aggressiveness. We have localized prostate tumor aggressiveness genes to 7q32-q33 and 19q13.1 through whole genome linkage analysis of sib pairs and loss of heterozygosity studies. We have identified a strong candidate, podocalyxin (PODXL), on 7q32-q33 in which in-frame deletions and SNPs independently are associated with markers of tumor aggressiveness. We will also build upon our studies investigating the impact of single nucleotide polymorphisms (SNPs) in candidate genes involved in metabolic pathways involved in prostate growth on prostate cancer risk and tumor aggressiveness. Thus our Specific Aims are:
Specific Aim 1 : To further characterize candidate prostate tumor aggressiveness loci identified through whole genome linkage analysis. We will determine whether PODXL functions as a prostate tumor aggressiveness gene by developing stable transfectants expressing wild-type or variant-containing PODXL and assessing their effect on in vitro and in vivo growth of prostate cancer cells. We will also determine PODXL expression in prostate tumors by in situ hybridization and immunohistochemical staining using tissue microarrays. We will further pursue the identification of the 19q13.1 aggressiveness gene using complementary approaches, including positional cloning methods and use of the public Human Genome Project (HGP) and Celera databases. The relationship between the 19q13.1 candidate gene(s) and prostate tumor aggressiveness will be evaluated by mutation analyses followed by association studies. Candidates will be further evaluated by in situ hybridization and immunohistochemical staining.
Specific Aim 2 : To determine the impact of single nucleotide polymorphisms (SNPs) in candidate genes on prostate cancer risk and tumor aggressiveness. We will study SNPs in candidate genes involved in 1) vitamin D metabolism (vitamin D receptor, 1-alpha-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24)), 2) insulin-like growth factor signaling (IGFBP-3), 3) folate metabolism (5,10- Methylene-tetrahydrofolate reductase (MTHFR) and Methionine Synthase (MTR)), and 4) steroid hormone metabolism (CYP3A7). For SNP association studies, we will employ a fully recruited population consisting of 943 men in 431 families with at least one brother affected with prostate cancer. Epidemiologic and clinical data have been collected, as well as biospecimens and banked DNA. The relationship between these genetic factors and prostate cancer risk and aggressiveness will be statistically evaluated.
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