DNA Methylation in Early Detection of Prostate Cancer

前列腺癌（PCA）是美国男性最常见的癌症，也是癌症死亡的第二大原因。目前的筛查方式不够完善，缺乏灵敏度和特异性，以最佳检测有组织的局限性潜在可治愈的疾病。最近的报道已经确定了两种早期检测前列腺癌的候选标志物：端粒酶和甲基化状态。众所周知，致癌转化的特征包括染色体不稳定，胞嘧啶甲基化模式的广泛畸变和端粒酶系统的上调。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畸变之间存在联系。从而为这两种标志物在肿瘤检测和肿瘤进展中的应用提供了依据。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记物，这些标记物可用于提供一种高度可靠的检测前列腺癌的方法，使用从PSA升高和/或直肠指检（DRE）异常患者中获得的表达前列腺液中的细胞进行检测和预后。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序列的甲基化状态，或亚端粒DNA序列与表达前列腺分泌（EPS）中端粒酶成分水平的耦合，将是前列腺癌存在或不存在的可靠预测因素。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Gleason评分相当的预后信息。将收集所有接受TRUSP和活检以评估PCA的患者的EPS。EPS将被检测端粒酶成分的存在，以及AR、GSTP1基因、L1重复元件和亚端粒DNA序列的甲基化模式。我们将结合甲基化结果和前列腺癌患者EPS端粒酶的结果，然后将EPS谱与疾病的分期和分级进行比较。

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.