Li Jiawei, Luo Wanjun, Nie Daohong, Lin Zidan, Zhou Chenfei
Department of Gynecology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People's Republic of China.
School of Medical South China University of Technology, Guangzhou, People's Republic of China.
Epigenetics. 2025 Dec;20(1):2527145. doi: 10.1080/15592294.2025.2527145. Epub 2025 Jul 3.
Epithelial ovarian cancer (EOC) is a heterogeneous malignancy with distinct histological subtypes, and DNA methylation has emerged as a promising biomarker for early detection. However, the role of methylation patterns in EOC heterogeneity and prognosis remains unclear. In this study, genome-wide association studies (GWAS) data from the Ovarian Cancer Association Consortium (OCAC) and Methylation quantitative trait loci (mQTL) data from the Genetics of DNA Methylation Consortium (GoDMC) were analysed using two-sample Mendelian randomization (MR). We investigated the genetic effects of CpG methylation on the risk and prognosis of five major EOC histotypes. To further explore the mechanisms by which DNA methylation affects EOC outcomes, we performed mediation analysis to evaluate the role of immunophenotypes. Our analysis identified 94 CpG sites associated with high-grade serous ovarian cancer (HGSOC), 9 of which were linked to prognosis. Additional significant associations were found for clear cell, low-grade serous, endometrioid, and mucinous subtypes. Hypomethylation at specific CpG sites was linked to increased EOC risk and shorter survival. Mediation analysis revealed significant interactions between CpG methylation and immunophenotypes, suggesting that immune modulation mediates the effects of DNA methylation on EOC outcomes. These results provide novel insights into the importance of epigenetic and immune-related factors in EOC pathogenesis.
上皮性卵巢癌（EOC）是一种具有不同组织学亚型的异质性恶性肿瘤，DNA甲基化已成为一种有前景的早期检测生物标志物。然而，甲基化模式在EOC异质性和预后中的作用仍不清楚。在本研究中，我们使用两样本孟德尔随机化（MR）分析了来自卵巢癌协会联盟（OCAC）的全基因组关联研究（GWAS）数据和来自DNA甲基化遗传学联盟（GoDMC）的甲基化定量性状位点（mQTL）数据。我们研究了CpG甲基化对五种主要EOC组织学类型的风险和预后的遗传效应。为了进一步探索DNA甲基化影响EOC结局的机制，我们进行了中介分析以评估免疫表型的作用。我们的分析确定了94个与高级别浆液性卵巢癌（HGSOC）相关的CpG位点，其中9个与预后相关。在透明细胞、低级别浆液性、子宫内膜样和黏液性亚型中也发现了其他显著关联。特定CpG位点的低甲基化与EOC风险增加和生存期缩短有关。中介分析揭示了CpG甲基化与免疫表型之间的显著相互作用，表明免疫调节介导了DNA甲基化对EOC结局的影响。这些结果为表观遗传和免疫相关因素在EOC发病机制中的重要性提供了新的见解。
