EPS Markers in the Early Detection of Prostate Cancer

EPS 标记物在前列腺癌早期检测中的应用

• 批准号: 6781147
• 负责人: STEVEN Sidney SMITH
• 金额: $ 26.73万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6781147
• 关键词: DNA methylation; age difference; biomarker; biopsy; cancer risk; clinical research; diagnosis design /evaluation; early diagnosis; enzyme activity; enzyme mechanism; genetic mapping; glutathione transferase; human subject; male; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplastic growth; neoplastic transformation; patient oriented research; polymerase chain reaction; prostate neoplasms; prostate specific antigen; secretion; telomerase

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.

描述（由申请人提供）：前列腺癌（PCA）是美国男性中最常诊断出的癌症，也是癌症死亡的第二大原因。目前的筛查方式缺乏最佳检测器官局限性和潜在可治愈疾病所需的敏感性和特异性。众所周知，致癌转化的标志包括普遍的染色体不稳定、胞嘧啶甲基化模式的广泛畸变和端粒酶系统的上调。这导致最近的报告将端粒酶和 DNA 甲基化状态确定为前列腺癌早期检测的候选标记。我们的实验表明，异位端粒酶表达与甲基化模式异常之间也可能存在直接联系。总而言之，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。我们的长期目标是利用表达的前列腺分泌物（EPS）作为诊断前列腺癌的非侵入性标本。为此，我们建议验证一种基于同步使用多种风险分类标志物的前列腺癌诊断模型。根据我们对 28 名患者进行的一系列初步研究结果，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 标记物将提供高度可靠的测试用于检测前列腺癌。我们的假设是，从 EPS 样本中获得的 DNA 中 pi 类谷胱甘肽-S 转移酶基因 GSTP1 的甲基化状态，与在这些相同 EPS 样本上测定的端粒酶成分水平相结合，并随着患者年龄的增加而增加，将成为 PCA 存在的可靠预测因子。 、PSA 水平和 DRE 信息。我们假设这种组合比任何单独的检测（包括 PSA）具有更高的检测灵敏度、特异性、阳性和阴性预测值。使用现已在 EPS 样本中进行基准测试的方法以及由临床医生和科学家组成的团结团队，将从 300 名患者中收集和分析 EPS，作为本地或多机构试验的一部分，这些患者接受了 TRUSP（经直肠前列腺超声检查） ）和活检。