A panel of DNA methylation markers reveals extensive methylation in histologically benign prostate biopsy cores from cancer patients
A panel of DNA methylation markers reveals extensive methylation in histologically benign prostate biopsy cores from cancer patients
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DOI：
10.1186/s40364-014-0025-9
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发表时间：
2014-01-01
影响因子：
11.1
通讯作者：
Freije, Diha
中科院分区：
文献类型：
--
作者：
Brikun, Igor;Nusskern, Deborah;Freije, Diha
背景：第一次前列腺活检呈阴性的男性，如果仍高度怀疑患有前列腺癌，将接受一次或多次额外的活检。迄今为止，还没有任何诊断测试能够识别有阳性诊断风险的患者，并具有消除不必要的重复活检所需的预测能力。使用从首次活检中回收的核心的表观遗传特征来开发临床测试的努力仅限于少数标记物，并且缺乏广泛临床采用所需的敏感性和特异性。方法：我们针对前列腺癌中优先甲基化的一组 24 种标记物开发了甲基化特异性定量聚合酶链反应测定。我们修改了亚硫酸氢盐转化条件，以允许整合来自多个标记的甲基化信息。我们确定了来自 104 名患者、37 名前列腺癌患者和 67 名对照者的 213 个前列腺活检核心中 24 种标记物的甲基化状态。我们对标记物组合以及整个 24 个标记物组进行逻辑回归，以确定诊断测试的最佳候选者。结果：标记物组以 100% 的敏感性和 97% 的特异性区分非癌症患者的癌症核心和良性核心。此外，该小组在前列腺癌患者的良性核心中检测到显着的甲基化，而对照组中不存在这种甲基化。通过使用 24 例中的 5 例甲基化来定义癌症病例，对单个良性活检核心的分析确定了 62% 接受重复活检的前列腺癌患者。 ROC 曲线分析表明，癌症患者良性核心中普遍甲基化的标记物是诊断测试的最佳候选者。结果表明，需要 5 到 10 个标记才能达到最佳预测能力。结论：这项研究表明，癌症患者和对照者之间的表观遗传场效应存在显着差异。它们在良性活检核心中的检测可以构成诊断测试的基础，以识别需要重复活检的患者，从而将持续 PCA 筛查的成本降低高达 40%。它们还可用于识别患有低度疾病的前列腺癌患者，这些患者可能是主动监测或局部治疗的候选者。
Background: Men with a negative first prostate biopsy will undergo one or more additional biopsies if they remain at high suspicion of prostate cancer. To date, there are no diagnostic tests capable of identifying patients at risk for a positive diagnosis with the predictive power needed to eliminate unnecessary repeat biopsies. Efforts to develop clinical tests using the epigenetic signature of cores recovered from first biopsies have been limited to a few markers and lack the sensitivity and specificity needed for widespread clinical adoption.Methods: We developed methylation-specific quantitative polymerase chain reaction assays for a panel of 24 markers that are preferentially methylated in prostate cancer. We modified the bisulfite conversion conditions to allow the integration of the methylation information from multiple markers. We determined the methylation status of the 24 markers in 213 prostate biopsy cores from 104 patients, 37 prostate cancer patients and 67 controls. We performed logistic regression on combinations of markers as well as the entire panel of 24 markers to identify the best candidates for a diagnostic test.Results: The marker panel differentiated between cancer cores and benign cores from non-cancer patients with 100% sensitivity and 97% specificity. Furthermore, the panel detected significant methylation in benign cores from prostate cancer patients that was not present in controls. Using methylation of 5 out of 24 to define a cancer case, the analysis of a single benign biopsy core identified 62% of prostate cancer patients undergoing repeat biopsies. ROC curve analysis showed that markers commonly methylated in benign cores from cancer patients are the best candidates for a diagnostic test. The results suggest that 5 to 10 markers will be needed to achieve optimal predictive power.Conclusions: This study shows that epigenetic field effects differ significantly between cancer patients and controls. Their detection in benign biopsy cores can form the basis of diagnostic tests to identify patients in need of repeat biopsies, reducing the cost of continued PCA screening by up to 40%. They could also be used to identify prostate cancer patients with low grade disease who are likely candidates for active surveillance or focal therapy.