CINBIO, Universidade de Vigo, Spain.
Department of Biochemistry, Genetics and Immunology, Universidade de Vigo, Spain.
Mol Oncol. 2024 Nov;18(11):2696-2713. doi: 10.1002/1878-0261.13573. Epub 2024 Jan 10.
The clinical relevance of the colorectal cancer serrated pathway is evident, but the screening of serrated lesions remains challenging. We aimed to characterize the serum methylome of the serrated pathway and to evaluate circulating cell-free DNA (cfDNA) methylomes as a potential source of biomarkers for the non-invasive detection of serrated lesions. We collected serum samples from individuals with serrated adenocarcinoma (SAC), traditional serrated adenomas, sessile serrated lesions, hyperplastic polyps and individuals with no colorectal findings. First, we quantified cfDNA methylation with the MethylationEPIC array. Then, we compared the methylation profiles with tissue and serum datasets. Finally, we evaluated the utility of serum cfDNA methylation biomarkers. We identified a differential methylation profile able to distinguish high-risk serrated lesions from no serrated neoplasia, showing concordance with tissue methylation from SAC and sessile serrated lesions. Serum methylation profiles are pathway-specific, clearly separating serrated lesions from conventional adenomas. The combination of ninjurin 2 (NINJ2) and glutamate-rich 1 (ERICH1) methylation discriminated high-risk serrated lesions and SAC with 91.4% sensitivity (64.4% specificity), while zinc finger protein 718 (ZNF718) methylation reported 100% sensitivity for the detection of SAC (96% specificity). This is the first study exploring the serum methylome of serrated lesions. Differential methylation of cfDNA can be used for the non-invasive detection of colorectal serrated lesions.
结直肠癌锯齿状途径的临床相关性是明显的，但锯齿状病变的筛查仍然具有挑战性。我们旨在描述锯齿状通路的血清甲基组，并评估循环无细胞 DNA（cfDNA）甲基组作为非侵入性检测锯齿状病变的潜在生物标志物来源。我们收集了锯齿状腺癌（SAC）、传统锯齿状腺瘤、无蒂锯齿状病变、增生性息肉以及无结直肠发现的个体的血清样本。首先，我们使用 MethylationEPIC 阵列定量 cfDNA 甲基化。然后，我们将甲基化谱与组织和血清数据集进行比较。最后，我们评估了血清 cfDNA 甲基化生物标志物的效用。我们确定了一个能够区分高危锯齿状病变和无锯齿状肿瘤的差异甲基化谱，与 SAC 和无蒂锯齿状病变的组织甲基化具有一致性。血清甲基化谱是通路特异性的，能够清楚地区分锯齿状病变和传统腺瘤。NINJ2 和 ERICH1 甲基化的组合能够以 91.4%的灵敏度（64.4%的特异性）区分高危锯齿状病变和 SAC，而锌指蛋白 718（ZNF718）甲基化对 SAC 的检测具有 100%的灵敏度（96%的特异性）。这是第一项探索锯齿状病变血清甲基组的研究。cfDNA 的差异甲基化可用于非侵入性检测结直肠锯齿状病变。
