EPS Markers in the Early Detection of Prostate Cancer

描述(申请人提供)：前列腺癌(PCa)是美国男性最常见的癌症，也是导致癌症死亡的第二大原因。目前的筛查模式缺乏最佳检测器官受限和潜在可治愈疾病所需的敏感性和特异性。众所周知，致癌转化的特征包括普遍的染色体不稳定，胞嘧啶甲基化模式中广泛存在的异常和端粒酶系统的上调。这导致了最近的报道，认为端粒酶和DNA甲基化状态是前列腺癌早期检测的候选标记物。我们的实验表明，异位端粒酶表达和甲基化模式中的异常之间也可能存在直接联系。综上所述，这些发现为使用这些标记物检测肿瘤和肿瘤进展提供了基础。我们的长期目标是将前列腺液(EPS)作为一种非侵入性标本用于前列腺癌的诊断。为此，我们建议验证基于多个风险分类标记物同步使用的前列腺癌诊断模型。根据我们对一系列28例患者的初步发现，我们预计年龄、前列腺特异性抗原水平(PSA)、直肠指检(DRE)以及端粒酶过度表达和局部甲基化变化的EPS标志物将为前列腺癌的检测提供高度可靠的检测方法。我们的假设是，从前列腺癌标本中获得的DNA中pi类谷胱甘肽-S转移酶基因GSTP1的甲基化状态将是Pca存在的可靠预测因子，当结合在这些相同的EPS标本上测定的端粒酶成分水平时，并随着患者年龄、PSA水平和DRE信息的增加而增强。我们推测，与包括PSA在内的任何单一检测方法相比，这种联合检测方法将具有更高的检测灵敏度、特异性、阳性预测值和阴性预测值。使用目前已在EPS样本中确定基准的方法以及一个由临床医生和科学家组成的有凝聚力的团队，EPS将从300名患者中收集和分析，作为本地或多机构试验的一部分，这些患者接受TRUSP(经直肠前列腺超声)和活检。

DESCRIPTION (provided by applicant): 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.