van den Berg Caroline B, Nieuwenhuyzen-de Boer Gatske M, Boere Ingrid A, Boers Ruben G, Boers Joachim B, van-IJcken Wilfred F J, Jansen Maurice P H M, Kirmizitas Tugce S, Gribnau Joost H, van Beekhuizen Heleen J
Department of Gynaecological Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Netherlands.
Department of Gynaecological Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Netherlands; Department of Obstetrics and Gynaecology, Albert Schweitzer Hospital, Dordrecht, Netherlands.
Cancer Treat Res Commun. 2025;43:100903. doi: 10.1016/j.ctarc.2025.100903. Epub 2025 Mar 22.
The aim of this study was to identify differentially methylated regions in cell-free DNA (cfDNA) between healthy persons and patients with advanced stage ovarian cancer (ASOC) and to identify differences in cfDNA methylation before and after cytoreductive surgery. Plasma-derived cfDNA was analyzed by a high-throughput genome wide DNA methylation sequencing technique: MeD-seq. A training set of therapy naïve cfDNA samples of patients with ASOC (≥FIGO stage IIIB, n=10) was compared with cfDNA of healthy controls (n=10) to define a ASOC specific cfDNA methylation signature. A cumulative hypermethylation score was constructed and a validation set of pre- and postoperative samples of 39 patients were compared using this score. MeD-seq results of tumor tissue samples were correlated with cfDNA results. Patients with ASOC showed a clear distinct cfDNA methylation signature from healthy controls (p<0.0001). This cfDNA-methylation signature resulted in preoperative hypermethylation scores (135; interquartile range 110-163) that were significantly higher than postoperative hypermethylation scores (91; interquartile range 76-101) (p<0.001). The cfDNA methylation signature at baseline differed from tumor tissue and was more closely related to DNA methylation of immune-related cells (T-lymphocytes, neutrophil granulocytes, monocytes, and B-lymphocytes) than to ASOC tissue. MeD-seq provides a promising method for genome wide methylation profiling of cfDNA. Patients with ASOC could clearly be distinguished from healthy controls and differed pre- and postoperatively.
本研究的目的是确定健康人与晚期卵巢癌（ASOC）患者游离DNA（cfDNA）中的差异甲基化区域，并确定细胞减灭术前和术后cfDNA甲基化的差异。采用高通量全基因组DNA甲基化测序技术：MeD-seq分析血浆来源的cfDNA。将一组未经治疗的ASOC患者（≥FIGO IIIB期，n=10）的cfDNA样本与健康对照者的cfDNA（n=10）进行比较，以确定ASOC特异性cfDNA甲基化特征。构建累积高甲基化评分，并使用该评分比较39例患者术前和术后样本的验证集。将肿瘤组织样本的MeD-seq结果与cfDNA结果进行关联。ASOC患者显示出与健康对照者明显不同的cfDNA甲基化特征（p<0.0001）。这种cfDNA甲基化特征导致术前高甲基化评分（135；四分位间距110-163）显著高于术后高甲基化评分（91；四分位间距76-101）（p<0.001）。基线时的cfDNA甲基化特征与肿瘤组织不同，与免疫相关细胞（T淋巴细胞、中性粒细胞、单核细胞和B淋巴细胞）的DNA甲基化更密切相关，而不是与ASOC组织相关。MeD-seq为cfDNA的全基因组甲基化分析提供了一种有前景的方法。ASOC患者可以明显与健康对照者区分开来，并且术前和术后存在差异。
