Prospective Study of CRMP4 Promoter Methylation in Prostate Biopsies as a Predictor For Lymph Node Metastases
Prospective Study of CRMP4 Promoter Methylation in Prostate Biopsies as a Predictor For Lymph Node Metastases
复制标题
前列腺活检中 CRMP4 启动子甲基化作为淋巴结转移预测因子的前瞻性研究
DOI：
10.1093/jnci/djw282
复制
发表时间：
2017-06-01
影响因子：
10.3
通讯作者：
Ling, Li
中科院分区：
文献类型：
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作者：
Gao, Xin;Li, Liao-Yuan;Ling, Li
背景
对于前列腺癌(PCA)患者，盆腔淋巴结转移(LNM)是预后不良的有力预测因素。然而，目前尚缺乏灵敏度和特异度较高的方法来检测淋巴结转移。我们调查了活检组织中崩解素反应介体蛋白4(CRMP4)启动子甲基化作为预测淋巴结转移的价值。
方法
使用亚硫酸氢盐焦磷酸测序法，在80例匹配的活检样本(训练组)中检测了CRMP4启动子在先前发现的两个CpG位点的甲基化。使用队列I对339例PCa患者(南部中国)和328例患者队列II(德国，包括中国)进行独立验证。采用Mann-Whitney U检验、受试者操作特征曲线、McNemar‘s检验和Logistic回归对数据进行评估。所有的统计检验都是双面的。
结果
在训练组中，CRMP4启动子甲基化(≥15.0%甲基化)与淋巴结转移显著相关(P <； 001)。队列I和II均获得成功验证(敏感度=92.3%，95%可信区间[CI]=79.3~97.9；敏感度=92.2%，95%CI = 81.1~97.8；特异度=92.7%，95%CI = 80.2~99.1；特异度=91.3%，95%CI = 87.4~94.4)。CRMP4启动子甲基化检测的敏感性明显高于常规磁共振检查(队列I：92.3%vs 26.2%，P <； 001；队列II：92.2%vs 33.3%，P <； 001)。在多变量分析模型中，CRMP4启动子甲基化是一个独立的预测因素(队列I：危险比[HR]=8.35，95%CI = 5.64~12.35，P <； 001；队列II：HR = 12.46，95%CI = 5.82~26.70，P <； 001)。
结论
诊断活检中CRMP4启动子甲基化可能是PCa中LNM的一个强有力的生物标志物。
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.