Methylation Biomarker Panel Performance in EsophaCap Cytology Samples for Diagnosing Barrett's Esophagus: A Prospective Validation Study
Methylation Biomarker Panel Performance in EsophaCap Cytology Samples for Diagnosing Barrett's Esophagus: A Prospective Validation Study
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DOI：
10.1158/1078-0432.ccr-18-3696
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发表时间：
2019-04-01
影响因子：
11.5
通讯作者：
Meltzer, Stephen J.
中科院分区：
文献类型：
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作者：
Wang, Zhixiong;Kambhampati, Swetha;Meltzer, Stephen J.
目的：巴雷特食管是唯一已知的食管腺癌 (EAC) 前兆。尽管内窥镜检查和活检是巴雷特食管诊断的标准方法，但其高昂的成本和风险限制了它们作为筛查方式的使用。在这里，我们试图开发一种巴雷特食管检测方法，该方法基于 EsophaCap 捕获的细胞学样本中的甲基化状态，使用简化的敏感技术，珠子甲基化 (MOB)。 实验设计：我们对 80 名患者进行了一项前瞻性队列研究（训练集中 52 名；测试集中 28 名）。我们使用 MOB 提取 DNA 并进行亚硫酸氢盐转化，然后进行定量甲基化特异性 PCR 来评估先前选择的 8 个候选标记的甲基化水平。应用Lasso回归在训练集中建立预测模型，然后在独立测试集上进行测试。结果：在训练集中，巴雷特食管患者的8个候选甲基化生物标志物中的5个（p16、HPP1、NELL1、TAC1和AKAP12）显着高于对照组。我们为巴雷特食管诊断建立了四种生物标志物加年龄套索回归模型。训练集中的 AUC 为 0.894，敏感性为 94.4% [95% 置信区间 (CI)，71%-99%]，特异性为 62.2%（95% CI，44.6%-77.3%）。该模型在独立测试集中对 Barrett 食管的诊断也具有很高的准确性：AUC = 0.929（P < 0.001；95% CI，0.810%-1%），敏感性 = 78.6%（95% CI，48.8%-94.3%），特异性 = 92.8%（95% CI， 64.1%-99.6%)。结论：EsophaCap 与表观遗传生物标志物组和 MOB 方法相结合，是一种有前途、耐受性良好、低成本的食管取样策略，用于 Barrett 食管诊断。这种方法值得在更大的人群中进行进一步的前瞻性研究。
Purpose: Barrett's esophagus is the only known precursor of esophageal adenocarcinoma (EAC). Although endoscopy and biopsy are standard methods for Barrett's esophagus diagnosis, their high cost and risk limit their use as a screening modality. Here, we sought to develop a Barrett's esophagus detection method based on methylation status in cytology samples captured by EsophaCap using a streamlined sensitive technique, methylation on beads (MOB).Experimental Design: We conducted a prospective cohort study on 80 patients (52 in the training set; 28 in the test set). We used MOB to extract and bisulfite-convert DNA, followed by quantitative methylation-specific PCR to assess methylation levels of 8 previously selected candidate markers. Lasso regression was applied to establish a prediction model in the training set, which was then tested on the independent test set.Results: In the training set, five of eight candidate methylation biomarkers (p16, HPP1, NELL1, TAC1, and AKAP12) were significantly higher in Barrett's esophagus patients than in controls. We built a four-biomarker-plus-age lasso regression model for Barrett's esophagus diagnosis. The AUC was 0.894, with sensitivity 94.4% [95% confidence interval (CI), 71%-99%] and specificity 62.2% (95% CI, 44.6%-77.3%) in the training set. This model also performed with high accuracy for Barrett's esophagus diagnosis in an independent test set: AUC = 0.929 (P < 0.001; 95% CI, 0.810%-1%), with sensitivity = 78.6% (95% CI, 48.8%-94.3%) and specificity = 92.8% (95% CI, 64.1%-99.6%).Conclusions: EsophaCap, in combination with an epigenetic biomarker panel and the MOB method, is a promising, well-tolerated, low-cost esophageal sampling strategy for Barrett's esophagus diagnosis. This approach merits further prospective studies in larger populations.