Circulating Cell-Free DNA Methylation Profiles in the Early Detection of Ovarian Cancer: A Scoping Review of the Literature

Abstract

Epithelial ovarian cancer is the most lethal gynecologic malignancy and has few reliable non-invasive tests for early detection or diagnosis. Recent advances in genomic techniques have bolstered the utility of cell-free DNA (cfDNA) evaluation from peripheral blood as a viable cancer biomarker. For multiple reasons, comparing alterations in DNA methylation is particularly advantageous over other molecular assays. We performed a literature review for studies exploring cfDNA methylation in serum and plasma for the early diagnosis of ovarian cancer. The data suggest that serum/plasma cfDNA methylation tests have strong diagnostic accuracies for ovarian cancer (median 85%, range 40–91%). Moreover, there is improved diagnostic performance if multiple genes are used and if the assays are designed to compare detection of ovarian cancer with benign pelvic masses. We further highlight the vast array of possible gene targets and techniques, and a need to include more earlier-stage ovarian cancer samples in test development. Overall, we show the promise of cfDNA methylation analysis in the development of a viable diagnostic biomarker for ovarian cancer.

New Trends in the Detection of Gynecological Precancerous Lesions and Early-Stage Cancers

“…However, these data suggest that serum/plasma cfDNA methylation assays can achieve a robust diagnostic accuracy in EOC (with a median of 85% and a range of 40–91%), especially when multiple genes are used, and ovarian tumors are compared to benign pelvic masses. However, even here it is necessary to optimize the range of possible gene targets and techniques, and to include more early-stage EOC samples [ 166 ].…”

The Molecular Landscape Influencing Prognoses of Epithelial Ovarian Cancer

“…Recent studies showed steady improvements in diagnostic accuracies using circulating cell-free (cf)DNA resulting from genetic mutations, copy number alerations, allelic imbalance, and promoter methylation in tumors [65]. Using subgroup analyses and metaregression analyses of systematic reviews suggested that epigenetic markers (i.e., epigenetic DNA modifications, methylation, and alterations) are particularly more effective over other quantitative detection methods of cell-free (cf)DNA and RNA concentrations or chromosomal instability [65,66]. Many susceptibility genes in hereditary ovarian carcinomas are known to alter homologous recombination (HR)/DNA repair pathways [67,68], and recent genomic/epigenomic studies indicated that EOC represents a genetically heterogeneous and complex group of diseases [67][68][69].…”

“…Approximately 15~20% of EOCs occur in a familial context with a high penetrant autosomal dominant genetic predisposition. To increase EOC patient survival, application of biomarkers for early diagnosis/detection and risk factor prediction, including genomic/epigenomic variants, copy number aberrations (CNAs), and DNA methylation in EOC surveillance are promising [66,70]. Moreover, due to rapid developments in DNA sequencing technology, various novel germline mutations have also been identified in familial EOC cases and in patients with early-onset EOC.…”

Precision gynecologic oncology: circulating cell free DNA epigenomic analysis, artificial intelligence and the accurate detection of ovarian cancer

“…DNA methylation changes are known to occur in multiple locations throughout the genome and thus have lower detection limits compared to mutation or protein marker assays. Indeed, relevant methylation changes that occur in cancer tend to be rare in normal cells 10 . Quantitation of circulating cfTDNA has been evaluated as a diagnostic approach for OC, however systematic reviews suggest the superiority of epigenetic markers over circulating cfTDNA quantitation 11 .…”

“…A limitation of current DNA methylation analysis of cfTDNA in ovarian cancer is the focus on single or a small number of target genes previously identified to be involved in cancer pathogenesis 10 which limits diagnostic precision. In this preliminary study, we performed genome wide methylation analysis of cfDNA for the minimally invasive detection of OC.…”