Division of Urologic Surgery and Duke Prostate Center, and Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
J Urol. 2010 Jul;184(1):149-56. doi: 10.1016/j.juro.2010.03.012. Epub 2010 May 15.
Radical prostatectomy is potentially curative in patients with clinically localized prostate cancer. However, biochemical recurrence affects 15% to 30% of men who undergo radical prostatectomy. We previously reported the prognostic potential of PITX2 gene promoter methylation using conventional assays. In the current study we validated PITX2 methylation status as a biochemical recurrence predictor after radical prostatectomy using a novel microarray based platform in a multi-institutional setting.
PITX2 methylation status was assessed in formalin fixed, paraffin embedded prostatectomy tumor tissue samples from 476 patients from a total of 4 institutions on customized EpiChip PITX2 microarrays. Associations between PITX2 methylation and biochemical recurrence were assessed using the log rank test and Cox regression controlling for prostate cancer features.
On multivariate analysis men with high methylation status were at significantly higher risk for biochemical recurrence than those with low methylation status (HR 3.0, 95% CI 2.0-4.5, p <10(-5)). The biochemical recurrence-free survival rate 5 years after surgery was 85% and 61% in the low and high methylation groups, respectively. In men with pathological Gleason 7 tumors the relative risk of biochemical recurrence was twice as high for high than for low PITX2 methylation (HR 2.0, 95% CI 1.2-3.3, p = 0.005).
PITX2 methylation status assessed by EpiChip PITX2 identifies patients with prostate cancer who are most likely to have biochemical recurrence. This test independently adds to the prognostic information provided by standard clinicopathological analysis, improving prostatectomy case stratification into those at high and low risk for biochemical recurrence. This new clinical tool would be of particular benefit to assess intermediate risk cases (Gleason 7) in which risk stratification remains a challenge.
根治性前列腺切除术有可能治愈临床局限性前列腺癌患者。然而，15%至 30%接受根治性前列腺切除术的患者会出现生化复发。我们之前曾报道过使用传统检测方法检测 PITX2 基因启动子甲基化的预后潜力。在当前研究中，我们使用基于微阵列的新型平台在多机构环境中验证了 PITX2 甲基化状态作为根治性前列腺切除术后生化复发的预测因子。
评估了来自 4 个机构的 476 名患者的福尔马林固定、石蜡包埋的前列腺切除术肿瘤组织样本中的 PITX2 甲基化状态，这些样本使用定制的 EpiChip PITX2 微阵列进行检测。使用对数秩检验和 Cox 回归分析控制前列腺癌特征，评估 PITX2 甲基化与生化复发之间的关联。
多变量分析显示，高甲基化状态的男性发生生化复发的风险明显高于低甲基化状态的男性（HR 3.0，95%CI 2.0-4.5，p<10(-5)）。手术后 5 年生化无复发生存率分别为低甲基化组和高甲基化组的 85%和 61%。在病理 Gleason 7 肿瘤患者中，高甲基化 PITX2 与低甲基化 PITX2 相比，生化复发的相对风险高两倍（HR 2.0，95%CI 1.2-3.3，p=0.005）。
通过 EpiChip PITX2 评估的 PITX2 甲基化状态可识别出最有可能发生生化复发的前列腺癌患者。该检测方法独立于标准临床病理分析提供的预后信息，可改善前列腺切除术病例分层，将生化复发风险高和低的患者区分开来。这种新的临床工具对于评估中间风险病例（Gleason 7）特别有益，因为在这些病例中，风险分层仍然是一个挑战。
