DNA Methylation in Early Detection of Prostate Cancer

DNA 甲基化在前列腺癌早期检测中的作用

• 批准号: 6334628
• 负责人: STEVEN Sidney SMITH
• 金额: $ 7.5万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6334628
• 关键词: DNA methylation; androgen receptor; biopsy; clinical research; diagnosis design /evaluation; early diagnosis; glutathione transferase; human subject; male; neoplasm /cancer classification /staging; neoplasm /cancer diagnosis; neoplasm /cancer genetics; nucleic acid repetitive sequence; prognosis; prostate neoplasms; secretion; telomerase

Prostate cancer (PCA) is the most commonly diagnosed cancer in American males and the second leading cause of cancer deaths. Current screening modalities are less than perfect, lacking the sensitivity and specificity for the optimal detection of organized confined potentially curable disease. Recent reports have identified two candidate markers for the early detection of prostate cancer: telomerase and methylation status. It is well established that the hallmarks of oncogenic transformation include general chromosome instability, widespread aberrations in cytosine methylation patterning and up-regulation of the telomerase system. A link between telomerase expression and chromosome stability has been recognized for some time, and links between chromosome instability and cytosine methylation have recently been firmly established. Our recent tumor biology studies suggest a link between telomerase over-expression and aberrations in methylation patterning. Thus, providing the basis for the use of these two markers in the detection of tumor and tumor progression. Our long term goal is to validate a set of markers of telomerase over- expression and local methylation change that can be used in providing a highly reliable test for detection and prognosis of prostate cancer using cells present in expressed prostatic fluid obtained from patients with elevated PSA and/or abnormal digital rectal exam (DRE). Our hypothesis is that methylation status at the androgen receptor gene, pi-class glutathione-S transferase gene GSTP1, L1 repetitive, or subtelomeric DNA sequences, or subtelomeric DNA sequences coupled with telomerase component levels in expressed prostatic secretion (EPS) will be reliable predictors of the presence or absence of prostate cancer. In addition, we believe that the methylation status of these various genes and sequences will provide prognostic information comparable to the Gleason's score on the prostate biopsy. EPS will be collected on all patients undergoing a TRUSP and biopsy for the evaluation of PCA. The EPS will be tested for the presence of the telomerase components and for the methylation patterns of the AR, GSTP1 gene, L1 repetitive elements and subtelomeric DNA sequences. We will combined the methylation results with the results of the EPS telomerase in patients with prostatic cancer and then compare this EPS profile to the stage and grade of the disease.

前列腺癌（PCA）是美国男性最常诊断出的癌症，也是癌症死亡的第二大原因。目前的筛查方式并不完美，缺乏对有组织的局限性潜在可治愈疾病进行最佳检测的敏感性和特异性。最近的报告确定了用于早期检测前列腺癌的两种候选标记：端粒酶和甲基化状态。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。一段时间以来，端粒酶表达与染色体稳定性之间的联系已被认识，并且染色体不稳定与胞嘧啶甲基化之间的联系最近已被牢固确立。我们最近的肿瘤生物学研究表明端粒酶过度表达与甲基化模式异常之间存在联系。从而为这两种标志物在肿瘤及肿瘤进展检测中的应用提供了基础。我们的长期目标是验证一组端粒酶过度表达和局部甲基化变化的标记物，这些标记物可用于使用从 PSA 升高的患者获得的表达前列腺液中存在的细胞，为前列腺癌的检测和预后提供高度可靠的测试。和/或直肠指检 (DRE) 异常。我们的假设是，雄激素受体基因、pi 类谷胱甘肽-S 转移酶基因 GSTP1、L1 重复或亚端粒 DNA 序列或亚端粒 DNA 序列与表达的前列腺分泌物 (EPS) 中端粒酶成分水平相结合的甲基化状态将是可靠的预测因子是否存在前列腺癌。此外，我们相信这些不同基因和序列的甲基化状态将提供与前列腺活检的格里森评分相当的预后信息。将收集所有接受 TRUSP 和活检的患者的 EPS，以评估 PCA。 EPS 将测试端粒酶成分的存在以及 AR、GSTP1 基因、L1 重复元件和亚端粒 DNA 序列的甲基化模式。我们将把前列腺癌患者的甲基化结果与 EPS 端粒酶的结果相结合，然后将该 EPS 图谱与疾病的分期和分级进行比较。