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）是美国男性中最常见的癌症，也是癌症死亡的第二大原因。目前的筛查方式并不完美，缺乏灵敏度和特异性，无法最佳检测有组织的局限性潜在可治愈的疾病。最近的报告已经确定了两个候选标记物的前列腺癌的早期检测：端粒酶和甲基化状态。众所周知，致癌转化的标志包括一般的染色体不稳定性、胞嘧啶甲基化模式的广泛畸变和端粒酶系统的上调。端粒酶表达和染色体稳定性之间的联系已经被认识了一段时间，染色体不稳定性和胞嘧啶甲基化之间的联系最近已经被牢固地建立起来。我们最近的肿瘤生物学研究表明端粒酶过度表达和甲基化模式的畸变之间存在联系。从而为利用这两种标志物检测肿瘤及肿瘤进展提供依据。我们的长期目标是验证一组端粒酶过表达和局部甲基化变化的标志物，其可用于提供高度可靠的检测和预后前列腺癌的测试，使用从PSA升高和/或直肠指检（DRE）异常的患者获得的表达的前列腺液中存在的细胞。我们的假设是，在雄激素受体基因甲基化状态，π类谷胱甘肽-S转移酶基因GSTP 1，L1重复，或亚端粒DNA序列，或亚端粒DNA序列与端粒酶组分在前列腺分泌物（EPS）的水平将是可靠的预测前列腺癌的存在或不存在。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Gleason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，以评价PCA。将检测EPS中端粒酶组分的存在以及AR、GSTP 1基因、L1重复元件和亚端粒DNA序列的甲基化模式。我们将结合甲基化结果与前列腺癌患者的EPS端粒酶结果，然后将此EPS谱与疾病的分期和分级进行比较。