DNA Methylation in Early Detection of Prostate Cancer

前列腺癌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。目前的筛查模式并不完美，缺乏对有组织的限制性潜在可治愈疾病的最佳检测的敏感性和特异性。最近的报道已经确定了两个前列腺癌早期检测的候选标记物：端粒酶和甲基化状态。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以及端粒酶系统的上调。端粒酶表达和染色体稳定性之间的联系已经被认识到一段时间了，而染色体不稳定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，端粒酶的过度表达与甲基化模式中的异常之间存在联系。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度表达和局部甲基化变化的标记物，这些标记物可以使用从PSA升高和/或指诊直肠检查(DRE)异常患者的前列腺液中获得的细胞，为前列腺癌的检测和预后提供高度可靠的测试。我们的假设是，雄激素受体基因甲基化状态、pi类谷胱甘肽-S转移酶基因GSTP1、L1重复序列或端粒下DNA序列，或端粒下DNA序列与前列腺癌表达中端粒酶成分的水平耦合，将是前列腺癌存在或不存在的可靠预测因素。此外，我们认为这些不同基因和序列的甲基化状态将提供可与Gleason前列腺活检评分相媲美的预后信息。将收集所有接受TRUSP和活检的患者的EPS，以评估PCA。将对EPS进行端粒酶成分的存在以及AR、GSTP1基因、L1重复元件和亚端粒DNA序列的甲基化模式的检测。我们将结合前列腺癌患者的甲基化结果和EPS端粒酶的结果，然后将这种EPS图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.