Circulating Methylated DNA as a Diagnostic Biomarker for Ovarian Cancer: A Systematic Review and Meta-Analysis

Abstract

Background: Ovarian cancer (OC) ranks top among all deadly gynaecological malignancies due to being identified at late stages resulting from the unavailability of early diagnosis methods. DNA methylation, which is greatly considered key epigenetic change, has increasingly been suggested to provide a potential marker for early OC detection. Circulating cell-free DNA (cfDNA) contains abnormal methylation patterns offering opportunities for non-invasive, stage-specific diagnostic approaches. Aim: To evaluate the diagnostic accuracy and reliability of circulating methylated DNA biomarkers for OC detection and to identify the most effective biomarkers for distinguishing between different stages of the disease. Hypothesis: Circulating methylated DNA biomarkers serve as reliable, non-invasive indicators for early OC detection and possess the potential to differentiate between various disease stages, thereby improving diagnostic accuracy and patient outcomes. Method: To conduct a comprehensive systematic review and meta-analysis, a thorough was performed across Pubmed, Embase and Web of Science databases from inception up to the end of October 2024. A total of 29 articles, encompassing 135 studies with a combined enrolment of over 10,000 participants were selected for inclusion and analysis. This research evaluated the diagnostic performance of methylated DNA biomarkers for detecting OC by analyzing diagnostic metrics including sensitivity, specificity and diagnostic odds ratio (DOR), using bivariate hierarchical random-effect models. Results: Methylated DNA panels exhibited excellent diagnostic accuracy (sensitivity 83.16%, specificity 95.63%) compared to single biomarkers (sensitivity 65.33%, specificity 99.74%). Integrating methylated DNA panels with traditional protein biomarkers, such as CA125, improved sensitivity (86.36%) while maintaining high specificity (91.34%). Biomarkers like RASSF1A and HOXA9 displayed particular promise for early-stage detection. Conclusion: This research emphasizes the potential role of circulating methylated DNA biomarkers for non-invasive and stage-specific detection of OC, especially when used in panels. These findings help establish the foundation for developing reliable diagnostic tools, facilitating earlier intervention and enhancing management strategies for OC.