基于游离细胞 DNA 甲基化的血液检测在高危人群结直肠癌筛查中的疗效：一项前瞻性队列研究。

Efficacy of cell-free DNA methylation-based blood test for colorectal cancer screening in high-risk population: a prospective cohort study.

机构信息

Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

Department of Operating Rooms, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

出版信息

Mol Cancer. 2023 Sep 28;22(1):157. doi: 10.1186/s12943-023-01866-z.

DOI:10.1186/s12943-023-01866-z

PMID:37770864

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10538018/

Abstract

BACKGROUND

Although colonoscopy is the standard screening test for colorectal cancer (CRC), its use is limited by a poor compliance rate, the need for extensive bowel preparation, and the risk of complications. As an alternative, an FDA-approved stool-based DNA test, Cologuard, has demonstrated satisfactory detection performance for CRC, but its compliance rate remains suboptimal, primarily attributable to individuals' reluctance to provide stool samples.

METHODS

We developed a noninvasive blood-based CRC test, ColonSecure, based on cell-free DNA containing cancer-specific CpG island methylation patterns. We initially screened publicly available datasets for differentially methylated CpG sites in CRC with prediction potential. Subsequently, we performed two sequential bisulfite-free methylation sequencing on blood samples obtained from CRC patients and non-cancer controls. Through rigorous evaluation of each marker and machine learning-assisted feature selection, we identified 149 hypermethylated markers from over 193,000 CpG sites. These markers were then utilized to construct the ColonSecure model, enabling accurate CRC detection.

RESULTS

We validated the efficacy of our cell-free DNA methylation-based blood test for CRC screening with 3493 high-risk individuals identified from 114,136 urban residents. The ColonSecure test identified 89 out of 103 CRC patients diagnosed by the follow-up colonoscopy, outperforming CEA, CRP, and CA19-9 (with a sensitivity of 86.4% compared to 45.6%, 39.8%, and 25.2% for CEA, CRP, and CA19-9 respectively; an AUROC of 0.956 compared to an AUROC of < 0.77 for other methods).

CONCLUSION

Our observations emphasize the potential of our multiple cfDNA methylation marker-based test for CRC screening in high-risk populations.

摘要

背景

尽管结肠镜检查是结直肠癌（CRC）的标准筛查试验，但由于其依从率低、需要广泛的肠道准备以及并发症风险，其应用受到限制。作为替代方案，一种经 FDA 批准的基于粪便的 DNA 检测方法 Cologuard 已证明对 CRC 具有令人满意的检测性能，但它的依从率仍然不理想，主要是因为人们不愿意提供粪便样本。

方法

我们基于含有癌症特异性 CpG 岛甲基化模式的无细胞 DNA 开发了一种非侵入性的基于血液的 CRC 检测方法 ColonSecure。我们最初筛选了公开可用的数据集，以寻找具有预测潜力的 CRC 中差异甲基化的 CpG 位点。随后，我们对来自 CRC 患者和非癌症对照的血液样本进行了两次连续的无亚硫酸盐甲基化测序。通过对每个标记物的严格评估和机器学习辅助的特征选择，我们从超过 193000 个 CpG 位点中鉴定出 149 个高甲基化标记物。然后，我们利用这些标记物构建了 ColonSecure 模型，实现了对 CRC 的准确检测。

结果

我们使用从 114136 名城市居民中确定的 3493 名高危个体验证了我们基于细胞游离 DNA 甲基化的血液检测用于 CRC 筛查的功效。ColonSecure 检测到 103 例经后续结肠镜检查诊断的 CRC 患者中的 89 例，优于 CEA、CRP 和 CA19-9（敏感性分别为 86.4%、45.6%、39.8%和 25.2%；AUROC 为 0.956，而其他方法的 AUROC 均<0.77）。