Huang Jinyong, Soupir Alex C, Schlick Brian D, Teng Mingxiang, Sahin Ibrahim H, Permuth Jennifer B, Siegel Erin M, Manley Brandon J, Pellini Bruna, Wang Liang
Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
Cancers (Basel). 2021 Nov 9;13(22):5611. doi: 10.3390/cancers13225611.
Cell-free DNA (cfDNA) methylation has emerged as a promising biomarker for early cancer detection, tumor type classification, and treatment response monitoring. Enrichment-based cfDNA methylation profiling methods such as cfMeDIP-seq have shown high accuracy in the classification of multiple cancer types. We have previously optimized another enrichment-based approach for ultra-low input cfDNA methylome profiling, termed cfMBD-seq. We reported that cfMBD-seq outperforms cfMeDIP-seq in the enrichment of high-CpG-density regions, such as CpG islands. However, the clinical feasibility of cfMBD-seq is unknown. In this study, we applied cfMBD-seq to profiling the cfDNA methylome using plasma samples from cancer patients and non-cancer controls. We identified 1759, 1783, and 1548 differentially hypermethylated CpG islands (DMCGIs) in lung, colorectal, and pancreatic cancer patients, respectively. Interestingly, the vast majority of DMCGIs were overlapped with aberrant methylation changes in corresponding tumor tissues, indicating that DMCGIs detected by cfMBD-seq were mainly driven by tumor-specific DNA methylation patterns. From the overlapping DMCGIs, we carried out machine learning analyses and identified a set of discriminating methylation signatures that had robust performance in cancer detection and classification. Overall, our study demonstrates that cfMBD-seq is a powerful tool for sensitive detection of tumor-derived epigenomic signals in cfDNA.
游离DNA（cfDNA）甲基化已成为一种有前景的生物标志物，可用于早期癌症检测、肿瘤类型分类和治疗反应监测。基于富集的cfDNA甲基化分析方法，如cfMeDIP-seq，在多种癌症类型的分类中已显示出高准确性。我们之前优化了另一种基于富集的超低输入cfDNA甲基化组分析方法，称为cfMBD-seq。我们报告称，cfMBD-seq在高CpG密度区域（如CpG岛）的富集方面优于cfMeDIP-seq。然而，cfMBD-seq的临床可行性尚不清楚。在本研究中，我们应用cfMBD-seq对癌症患者和非癌症对照的血浆样本进行cfDNA甲基化组分析。我们分别在肺癌、结直肠癌和胰腺癌患者中鉴定出1759个、1783个和1548个差异高甲基化CpG岛（DMCGI）。有趣的是，绝大多数DMCGI与相应肿瘤组织中的异常甲基化变化重叠，这表明cfMBD-seq检测到的DMCGI主要由肿瘤特异性DNA甲基化模式驱动。从重叠的DMCGI中，我们进行了机器学习分析，并鉴定出一组在癌症检测和分类中具有强大性能的鉴别甲基化特征。总体而言，我们的研究表明cfMBD-seq是一种用于灵敏检测cfDNA中肿瘤衍生表观基因组信号的强大工具。
