Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Department of Gynecology, Xiangya Hospital, Central South University, Changsha, China.
EBioMedicine. 2022 Sep;83:104222. doi: 10.1016/j.ebiom.2022.104222. Epub 2022 Aug 13.
Plasma cell-free DNA (cfDNA) methylation has shown the potential in the detection and prognostic testing in multiple cancers. Herein, we thoroughly investigate the performance of cfDNA methylation in the detection and prognosis of ovarian cancer (OC).
The OC-specific differentially methylated regions (DMRs) were identified by sequencing ovarian tissue samples from OC (n = 61), benign ovarian disease (BOD, n = 49) and healthy controls (HC, n = 37). Based on 1,272 DMRs, a cfDNA OC detection model (OC-D model) was trained and validated in plasma samples from patients of OC (n = 104), BOD (n = 56) and HC (n = 56) and a prognostic testing model (OC-P model) was developed in plasma samples in patients with high-grade serous OC (HG-SOC) in the training cohort and then tested the rationality of this model with International Cancer Genome Consortium (ICGC) tissue methylation data. Mechanisms were investigated in the TCGA-OC cohort.
In the validation cohort, the cfDNA OC-D model consisting of 18 DMRs achieved a sensitivity of 94.7% (95% CI: 85.4%‒98.9%) at a specificity of 88.7% (95% CI: 78.7%‒94.9%), which outperformed CA 125 (AUC: 0.967 vs 0.905, P = 0.03). Then the cfDNA OC-P model consisting of 15 DMRs was constructed and associated with a better prognosis of HG-SOC in multivariable Cox regression analysis (HR: 0.29, 95% CI, 0.11‒0.78, P = 0.01) in the training cohort, which was also observed in the ICGC cohort using tissue methylation (HR: 0.56, 95% CI, 0.32‒0.98, P = 0.04). Investigation into mechanisms revealed that the low-risk group had higher homologous recombination deficiency and immune cell infiltration (P < 0.05).
Our study demonstrated the potential utility of cfDNA methylation in the detection and prognostic testing in OC. Future studies with a larger population are warranted.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sector.
血浆无细胞游离 DNA（cfDNA）甲基化在多种癌症的检测和预后检测中显示出了潜力。在此，我们深入研究了 cfDNA 甲基化在卵巢癌（OC）检测和预后中的性能。
通过对来自 OC（n=61）、良性卵巢疾病（BOD，n=49）和健康对照（HC，n=37）的卵巢组织样本进行测序，确定 OC 特异性差异甲基化区域（DMRs）。基于 1,272 个 DMR，在 OC 患者的血浆样本中（n=104）、BOD（n=56）和 HC（n=56）中训练和验证了 cfDNA OC 检测模型（OC-D 模型），并在高级别浆液性 OC（HG-SOC）患者的血浆样本中建立了预后检测模型（OC-P 模型），然后使用国际癌症基因组联盟（ICGC）组织甲基化数据检验该模型的合理性。在 TCGA-OC 队列中研究了机制。
在验证队列中，由 18 个 DMR 组成的 cfDNA OC-D 模型在特异性为 88.7%（95%CI：78.7%‒94.9%）时，其灵敏度达到 94.7%（95%CI：85.4%‒98.9%），优于 CA125（AUC：0.967 比 0.905，P=0.03）。然后构建了由 15 个 DMR 组成的 cfDNA OC-P 模型，在多变量 Cox 回归分析中，该模型与 HG-SOC 的预后更好相关（HR：0.29，95%CI，0.11‒0.78，P=0.01），在训练队列中也观察到了 ICGC 队列中的组织甲基化情况（HR：0.56，95%CI，0.32‒0.98，P=0.04）。对机制的研究表明，低风险组具有更高的同源重组缺陷和免疫细胞浸润（P<0.05）。
我们的研究表明 cfDNA 甲基化在 OC 的检测和预后检测中有应用潜力。需要更大规模的人群研究来验证。
本研究无任何特定的公共、商业或非营利性机构的资金支持。
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