Yun Peng, Kulaixijiang Kamila, Pan Jiang, Yang Luping, Wang Nengzhuang, Xu Zheng, Zhang Yaodong, Cai Haifang, Zhao Zi-Ye, Zhu Min, Yan Hongli
Reproductive Medicine Center, The First Affiliated Hospital of Naval Medical University, Shanghai, China.
Department of Pathology, Karamay Central Hospital of Xinjiang, Karamay, China.
United European Gastroenterol J. 2025 Apr;13(3):402-415. doi: 10.1002/ueg2.12696. Epub 2024 Nov 2.
Methylated stool DNA (sDNA) is a reliable noninvasive biomarker for early colorectal cancer (CRC) diagnosis. However, there are barely any diagnostic panels that can achieve both a sensitivity and specificity exceeding 90% simultaneously.
We aimed to identify a novel methylated sDNA panel and model for the early diagnosis of CRC.
We conducted methyl-CpG binding domain isolated genome sequencing (MiGS) on CpG island methylation phenotype (CIMP)-positive (n = 3) and CIMP-negative CRC tissues (n = 3) and their corresponding normal adjacent tissues. Subsequently, by utilizing both the aforementioned data and public datasets, we identified a set of promising methylated sDNA markers for CRC. Next, we validated 5 of these genes using pyrosequencing in CRC patients (n = 31). Then, we developed a combined diagnostic model (CDM) for CRC based on the methylation status of PRDM12, FOXE1, and SDC2 by a Training cohort (n = 231). Finally, the performance of CDM was evaluated in an independent multicenter Validation cohort (n = 800).
A total of 1062 participants were included in this study. The area under the curve (AUC) of the CDM was 0.979 (95% CI: 0.960-0.997), and the optimal sensitivity and specificity were 97.35% and 99.05%, respectively, in the training cohort (n = 231). In the independent validation cohort (n = 800), the AUC was 0.950 (95% CI: 0.927-0.973), along with the optimal sensitivity of 92.75% and specificity of 97.21%. When CRC and advanced adenoma (AAD) were used as diagnostic targets, the model AUC was 0.945 (95% CI: 0.922-0.969), with an optimal sensitivity of 91.89% and a specificity of 95.21%. The model sensitivity for nonadvanced adenoma patients was 68.66%.
The sDNA diagnostic model CDM, developed from both CIMP-P and CIMP-N, exhibited exceptional performance in CRC and could serve as a potential alternative strategy for CRC screening.
甲基化粪便DNA（sDNA）是早期结直肠癌（CRC）诊断的可靠非侵入性生物标志物。然而，几乎没有任何诊断面板能够同时实现灵敏度和特异性超过90%。
我们旨在鉴定一种用于CRC早期诊断的新型甲基化sDNA面板和模型。
我们对CpG岛甲基化表型（CIMP）阳性（n = 3）和CIMP阴性CRC组织（n = 3）及其相应的正常相邻组织进行了甲基化CpG结合域分离基因组测序（MiGS）。随后，利用上述数据和公共数据集，我们鉴定了一组有前景的CRC甲基化sDNA标志物。接下来，我们在CRC患者（n = 31）中使用焦磷酸测序验证了其中5个基因。然后，我们通过一个训练队列（n = 231）基于PRDM12、FOXE1和SDC2的甲基化状态开发了一种CRC联合诊断模型（CDM）。最后，在一个独立的多中心验证队列（n = 800）中评估了CDM的性能。
本研究共纳入1062名参与者。在训练队列（n = 231）中，CDM的曲线下面积（AUC）为0.979（95%CI：0.960 - 0.997），最佳灵敏度和特异性分别为97.35%和99.05%。在独立验证队列（n = 800）中，AUC为0.950（95%CI：0.927 - 0.973），最佳灵敏度为92.75%，特异性为97.21%。当将CRC和高级别腺瘤（AAD）作为诊断靶点时，模型AUC为0.945（95%CI：0.922 - 0.969），最佳灵敏度为91.89%，特异性为95.21%。该模型对非高级别腺瘤患者的灵敏度为68.66%。
从CIMP-P和CIMP-N开发的sDNA诊断模型CDM在CRC中表现出卓越的性能，可作为CRC筛查的潜在替代策略。
