Prostate cancer (PCA) is the most commonly diagnosed cancer in American males and the second leading cause of cancer deaths. Current screening modalities lack the sensitivity and specificity necessary for the optimal detection of organ confined and potentially curable disease. It is well established that the hallmarks of oncogenic transformation include general chromosome instability, widespread aberrations in cytosine methylation patterning and upregulation of the telomerase system. This has led to recent reports which have identified telomerase and DNA methylation status as candidate markers for the early detection of prostate cancer. Our experiments suggest that there may also be a direct link between ectopic telomerase expression and aberrations in methylation patterning. Taken together, these findings provide the basis for the use of these markers in the detection of tumor and tumor progression. Our long term goal is to exploit expressed prostatic secretion (EPS) as a non-invasive specimen in the diagnosis of prostate cancer. To this end, we propose to validate a model of prostate cancer diagnosis based on the synchronous use of multiple markers of risk classification. Based on our preliminary findings with a series of 28 patients, we expect that age, prostate specific antigen levels (PSA), digital rectal exam (DRE), and EPS markers of telomerase over-expression and local methylation change will provide a highly reliable test for the detection of prostate cancer. Our hypothesis is that methylation status at the pi-class glutathione-S transferase gene GSTP1 in DNA obtained from EPS specimens will be a reliable predictor of the presence of PCA when coupled with telomerase component levels determined on these same EPS specimens and augmented with patient age, PSA levels and DRE information. We hypothesize that this combination will have higher assay sensitivity, specificity, positive and negative predictive values than any single assay alone, including PSA. Using methodology that has now been benchmarked in EPS specimens and a cohesive team of clinicians and scientists, EPS will be collected and analyzed from 300 patients, who, as part of a local or multi-institutional trial, undergo TRUSP (transrectal ultrasound of the prostate) and biopsy. ? ? ?
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