Circulating tumor DNA methylation profiles enable early diagnosis, prognosis prediction, and screening for colorectal cancer (Publication with Expression of Concern)
Circulating tumor DNA methylation profiles enable early diagnosis, prognosis prediction, and screening for colorectal cancer (Publication with Expression of Concern)
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循环肿瘤 DNA 甲基化谱可实现结直肠癌的早期诊断、预后预测和筛查
DOI：
10.1126/scitranslmed.aax7533
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发表时间：
2020-01-01
影响因子：
17.1
通讯作者：
Xu, Rui-hua
中科院分区：
文献类型：
--
作者：
Luo, Huiyan;Zhao, Qi;Xu, Rui-hua
循环肿瘤DNA（ctDNA）已成为许多癌症的诊断和预后生物标志物。在这里，我们进行了一项研究，探讨ctDNA甲基化标记物在结直肠癌（CRC）诊断和鉴别中的潜在用途，并使用前瞻性队列来验证其在筛查CRC高危患者中的有效性。我们首先通过将CRC组织与正常血液白细胞进行比较来鉴定CRC特异性甲基化特征。然后，我们应用机器学习算法，使用来自801名CRC患者和1021名正常对照队列的无细胞DNA（cfDNA）样本开发预测诊断和预后模型。所获得的诊断预测模型以高准确度（曲线下面积= 0.96）将CRC患者与正常对照区分开。预后预测模型也能有效预测结直肠癌患者的预后和生存（P < 0.001）。此外，我们使用无监督聚类方法生成了基于ctDNA的CRC分子分类，并获得了两个具有显著不同总生存期的CRC患者亚组（验证队列中P = 0.011）。最后，我们发现，在一项前瞻性队列研究中，单个ctDNA甲基化标志物cg10673833可以在1493名参与者的高危人群中产生高灵敏度（89.7%）和特异性（86.8%）检测CRC和癌前病变。总之，我们的研究结果显示了ctDNA甲基化标志物在CRC的诊断、监测和预后中的价值。
Circulating tumor DNA (ctDNA) has emerged as a useful diagnostic and prognostic biomarker in many cancers. Here, we conducted a study to investigate the potential use of ctDNA methylation markers for the diagnosis and prognostication of colorectal cancer (CRC) and used a prospective cohort to validate their effectiveness in screening patients at high risk of CRC. We first identified CRC-specific methylation signatures by comparing CRC tissues to normal blood leukocytes. Then, we applied a machine learning algorithm to develop a predictive diagnostic and a prognostic model using cell-free DNA (cfDNA) samples from a cohort of 801 patients with CRC and 1021 normal controls. The obtained diagnostic prediction model discriminated patients with CRC from normal controls with high accuracy (area under curve = 0.96). The prognostic prediction model also effectively predicted the prognosis and survival of patients with CRC (P < 0.001). In addition, we generated a ctDNA-based molecular classification of CRC using an unsupervised clustering method and obtained two subgroups of patients with CRC with significantly different overall survival (P = 0.011 in validation cohort). Last, we found that a single ctDNA methylation marker, cg10673833, could yield high sensitivity (89.7%) and specificity (86.8%) for detection of CRC and precancerous lesions in a high-risk population of 1493 participants in a prospective cohort study. Together, our findings showed the value of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of CRC.