前瞻性研究前列腺活检中 CRMP4 启动子甲基化作为淋巴结转移的预测指标。
Prospective Study of CRMP4 Promoter Methylation in Prostate Biopsies as a Predictor For Lymph Node Metastases.
机构信息
Affiliations of authors: Department of Urology (XG, LYL, JP, MKC, ZC, JGQ), Department of Pathology (DH, CKS, ZLS), and Department of Radiology (JW), The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Urology, St. Elisabeth Hospital, University of Leipzig, Leipzig, Germany (JR); Department of Urology, The First Affiliated Hospital, Nanchang University, Nanchang, China (WPL); Department of Urology, Changhai Hospital, The Second Military Medical University, Shanghai, China (SCR); Department of Urology, Cancer Center, Sun Yat-sen University, Guangzhou, China (FJZ); Department of Urology, Guangzhou First Municipal People's Hospital, Guangzhou Medical University, Guangzhou, China (KJX); Department of Urology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China (XZ); Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China (HJQ); Department of Urology, Cancer Hospital, Guangxi Medical University, Nanning, China (XZB); Department of Urology, Guangdong General Hospital, Guangzhou, China (JML); Department of Urology, Shenzhen People's Hospital, Shenzhen, China (JGY); Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China (LL).
出版信息
J Natl Cancer Inst. 2017 Jan 25;109(6). doi: 10.1093/jnci/djw282. Print 2017 Jan.
BACKGROUND
For patients with prostate cancer (PCa), the presence of pelvic lymph node metastasis (LNM) is a strong predictor of poor outcome. However, the approaches with promising sensitivity and specificity to detect LNM are still lacking. We investigated the value of collapsin response mediator protein 4 (CRMP4) promoter methylation in biopsies as a predictor for LNM.
METHODS
CRMP4 promoter methylation at two previously identified CpG sites was determined in 80 case-matched biopsy samples (the training set) using bisulfite pyrosequencing. The predictive cutoff value was independently validated using cohort I of 339 PCa patients (Southern China) and cohort II of 328 case patients (Germany, across China). Mann-Whitney U test, the receiver operating characteristic curve, McNemar's test, and logistic regression were used to assess data. All statistical tests were two-sided.
RESULTS
In the training set, CRMP4 promoter methylation (≥15.0% methylated) was statistically significantly associated with LNM (P < 001). Successful validations were achieved in both cohorts I and II (sensitivity = 92.3%, 95% confidence interval [CI] = 79.3 to 97.9, and sensitivity = 92.2%, 95% CI = 81.1 to 97.8, respectively; specificity = 92.7%, 95% CI = 80.2 to 99.1, and specificity = 91.3%, 95% CI = 87.4 to 94.4, respectively). The sensitivity of CRMP4 promoter methylation is superior to conventional MRI (cohort I: 92.3% vs 26.2%, P < 001; cohort II: 92.2% vs 33.3%, P < 001). CRMP4 promoter methylation is an independent predictor of LNM (cohort I: hazard ratio [HR] = 8.35, 95% CI = 5.64 to 12.35, P < 001; cohort II: HR = 12.46, 95% CI = 5.82 to 26.70, P < 001) in a multivariable analysis model.
CONCLUSION
CRMP4 promoter methylation in diagnostic biopsies could be a robust biomarker for LNM in PCa.
背景
对于患有前列腺癌（PCa）的患者，盆腔淋巴结转移（LNM）的存在是预后不良的强烈预测指标。然而，目前仍缺乏具有高灵敏度和特异性的检测 LNM 的方法。我们研究了在活检标本中 Collapsin 反应介质蛋白 4（CRMP4）启动子甲基化作为 LNM 预测因子的价值。
方法
使用亚硫酸氢盐焦磷酸测序法，在 80 例配对活检样本（训练集）中确定了两个先前鉴定的 CpG 位点的 CRMP4 启动子甲基化。使用来自中国南方的 339 例 PCa 患者队列 I（南方中国）和来自德国的 328 例病例患者队列 II（中国各地）独立验证预测截断值。使用 Mann-Whitney U 检验、受试者工作特征曲线、McNemar 检验和逻辑回归评估数据。所有统计检验均为双侧。
结果
在训练集中，CRMP4 启动子甲基化（≥15.0% 甲基化）与 LNM 显著相关（P<0.001）。在队列 I 和 II 中均成功验证（敏感性=92.3%，95%置信区间[CI] = 79.3 至 97.9，敏感性=92.2%，95%CI = 81.1 至 97.8；特异性=92.7%，95%CI = 80.2 至 99.1，特异性=91.3%，95%CI = 87.4 至 94.4）。CRMP4 启动子甲基化的灵敏度优于传统 MRI（队列 I：92.3% 比 26.2%，P<0.001；队列 II：92.2% 比 33.3%，P<0.001）。在多变量分析模型中，CRMP4 启动子甲基化是 LNM 的独立预测因子（队列 I：危险比[HR] = 8.35，95%CI = 5.64 至 12.35，P<0.001；队列 II：HR = 12.46，95%CI = 5.82 至 26.70，P<0.001）。
结论
在诊断性活检中，CRMP4 启动子甲基化可能是 PCa 中 LNM 的强大生物标志物。
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