Prostate adenocarcinoma accounts for nearly one-third of all invasive cancers not involving the skin in American men. Prostate cancer has a marked degree of clinical variability compared to other cancers and even with accurate stage determination and appropriate therapy, a finite number of men will suffer tumor progression. Thus, one of the highest priorities in prostate cancer research is to identify new laboratory tests, especially genetic markers, which can more accurately predict the rate of progression for a given prostate tumor and how it might respond to appropriate therapy. Comparative genomic hybridization (CGH) studies have shown that 8q24 is commonly overrepresented and/or amplified in prostate cancer. Using fluorescence in situ hybridization (FISH) we have recently shown that 8q24 overrepresentation is a marker of clinical progression in stage pT2N0M0, pT3N0M0, and pT2-3N1-3M0 prostate cancer. It should be noted that we define overrepresentation as a significant increase in 8q24 copy number relative to centromere 8 copy number; thus, overrepresentation includes overt amplification. 8q24 contains c-myc. Thus, c-myc could be the target of the overrepresentation. However, it is becoming clear that the actual (or only) target of many overrepresented regions is not necessarily the first gene identified in that region. Very few studies of 8q24 overrepresentation mapping have been reported.
In Specific Aim 1, we propose to map the extent of the minimally overrepresented region at 8q24 using FISH, CGH, and genomic CGH (gCGH) technology.
In Specific Aim 2, we will isolate the genes from the minimal region(s) of overrepresentation using various approaches including database searches and cDNA selection. The expression level of these genes will be evaluated in tumors with overrepresentation to determine which genes are candidates for mutational and functional studies.
In Specific Aim 3, we will extend and validate the clinical-translational relevance of 8q24 overrepresentation. This project will identify the actual target of overrepresentation at 8q24. It may be that we will identify c-myc as the common target of the 8q24 overrepresentation event. If so, then we will have identified a known target for gene therapy and will have validated a means to stratify patients for this therapy. Importantly, it is possible that other genes are common targets in 8q24, or at least that they are commonly co-overrepresented with c-myc. Such genes will define new targets for gene and/or immunotherapy in prostate cancer and will potentially provide new prognostic and predictive markers.
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