The overall hypothesis of this PPA is to identify risk assessment of certain genetic markers such as miRNAs, single nucleotide mismatch repair genes or SNPs, and X-linked genes (such as TSPX) since there is evidence that they are associated with prostate cancer. The first project is to investigate the miRNAs that may serve as markers of prostate cancer by virtue of their action in suppression of oncogenic or tumor suppressor gene expression. The studies aim at delineating the underlying mechanisms that control these processes. The second project is to investigate the role of SNPs in mismatched repair (MMR) genes in prostate cancer susceptibility and progression. The third project is to investigate involvement in prostate cancer risk of the X-linked tumor suppressor gene (TSPX) which is a tumor repressor and corepressor for AR functions for its involvement in prostate cancer risk and progression. The three projects in the PPA will be supported by three Cores: 1) Administrative Core; 2) Tissue/Morphology/Molecular Core; and 3) Statistical Core. Significance: Strengths: The study of the expression of three types of molecular biomarkers of prostate cancer in a large number prostate specimens (at different stages of pathology) represents an important step towards developing a system of patient identification with respect to their potential for disease progression. This knowledge could be of much value in devising therapy approaches. This research will also contribute to the aspect of knowledge on prostate cancer pathobiology that is currently missing. Studies on the molecular mechanisms of the functions of the three types of biomarkers are also well considered and will advance the fundamental knowledge pertaining to the function of these biomarkers. A particularly noteworthy point is that investigation of molecular biomarkers along the proposed lines has not been undertaken previously making this a highly novel endeavor. The success in the proposed studies could lea

Public Health Relevance

Prostate cancer is one of the most common malignancies among our Veterans. The major problem in the management of prostate cancer is the lack of biomarkers that can identify which localized prostate tumors are likely to progress, metastasize, or become fatal, and thus require more aggressive clinical intervention. Based on the published literature, microRNAs, single nucleotide polymorphisms of mistmatch repair genes and X- linked tumor suppressor gene are associated with prostate cancer. Currently, there are no genetic biomarkers for the risk assessment of prostate cancer. Therefore, the main goal of this project is to investigate whether microRNAs, SNPs of mismatch repair genes, and X-linked genes can be utilized as a novel genetic tool for the risk assessment of prostate cancer using in vitro models. Since prostate cancer is one of the most common malignancies among our Veterans the identification of genetic biomarkers for the risk assessment of prostate cancer will have a significant impact on Veterans health and the VA mission.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (IP1)
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Oncology A (ONCA)
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Veterans Affairs Medical Center San Francisco
San Francisco
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