Department of Molecular Diagnostics, Aalborg University Hospital, 9000, Aalborg, Denmark.
Department of Clinical Medicine, Aalborg University, 9000, Aalborg, Denmark.
Clin Epigenetics. 2023 Feb 14;15(1):24. doi: 10.1186/s13148-023-01440-w.
Patients diagnosed with epithelial ovarian cancer (OC) have a 5-year survival rate of 49%. For early-stage disease, the 5-year survival rate is above 90%. However, advanced-stage disease accounts for most cases as patients with early stages often are asymptomatic or present with unspecific symptoms, highlighting the need for diagnostic tools for early diagnosis. Liquid biopsy is a minimal invasive blood-based approach that utilizes circulating tumor DNA (ctDNA) shed from tumor cells for real-time detection of tumor genetics and epigenetics. Increased DNA methylation of promoter regions is an early event during tumorigenesis, and the methylation can be detected in ctDNA, accentuating the promise of methylated ctDNA as a biomarker for OC diagnosis. Many studies have investigated multiple methylation biomarkers in ctDNA from plasma or serum for discriminating OC patients from patients with benign diseases of the ovaries and/or healthy females. This systematic review summarizes and evaluates the performance of the currently investigated DNA methylation biomarkers in blood-derived ctDNA for early diagnosis of OC. PubMed's MEDLINE and Elsevier's Embase were systematically searched, and essential results such as methylation frequency of OC cases and controls, performance measures, as well as preanalytical factors were extracted. Overall, 29 studies met the inclusion criteria for this systematic review. The most common method used for methylation analysis was methylation-specific PCR, with half of the studies using plasma and the other half using serum. RASSF1A, BRCA1, and OPCML were the most investigated gene-specific methylation biomarkers, with OPCML having the best performance measures. Generally, methylation panels performed better than single gene-specific methylation biomarkers, with one methylation panel of 103,456 distinct regions and 1,116,720 CpGs having better performance in both training and validation cohorts. However, the evidence is still limited, and the promising methylation panels, as well as gene-specific methylation biomarkers highlighted in this review, need validation in large, prospective cohorts with early-stage asymptomatic OC patients to assess the true diagnostic value in a clinical setting.
被诊断患有上皮性卵巢癌（OC）的患者的 5 年生存率为 49%。对于早期疾病，5 年生存率超过 90%。然而，晚期疾病占大多数病例，因为早期患者通常无症状或出现非特异性症状，这凸显了对早期诊断的诊断工具的需求。液体活检是一种微创的基于血液的方法，利用来自肿瘤细胞的循环肿瘤 DNA（ctDNA）进行实时肿瘤遗传学和表观遗传学检测。启动子区域的 DNA 甲基化增加是肿瘤发生过程中的早期事件，并且可以在 ctDNA 中检测到甲基化，这凸显了甲基化 ctDNA 作为 OC 诊断生物标志物的潜力。许多研究已经在来自血浆或血清的 ctDNA 中研究了多种甲基化生物标志物，以区分 OC 患者与卵巢良性疾病和/或健康女性患者。本系统综述总结并评估了目前在血液衍生的 ctDNA 中研究的 DNA 甲基化生物标志物在 OC 早期诊断中的性能。对 PubMed 的 MEDLINE 和 Elsevier 的 Embase 进行了系统搜索，并提取了重要结果，如 OC 病例和对照的甲基化频率、性能指标以及分析前因素。总的来说，有 29 项研究符合本系统综述的纳入标准。最常用的甲基化分析方法是甲基化特异性 PCR，其中一半的研究使用血浆，另一半使用血清。RASSF1A、BRCA1 和 OPCML 是研究最多的基因特异性甲基化生物标志物，其中 OPCML 的性能指标最好。一般来说，甲基化谱比单个基因特异性甲基化生物标志物表现更好，一个包含 103456 个不同区域和 1116720 个 CpG 的甲基化谱在训练和验证队列中都表现出更好的性能。然而，证据仍然有限，本综述中强调的有前途的甲基化谱和基因特异性甲基化生物标志物需要在有早期无症状 OC 患者的大型前瞻性队列中进行验证，以评估其在临床环境中的真正诊断价值。
