Innovative insights into extrachromosomal circular DNAs in gynecologic tumors and reproduction

Abstract

Originating but free from chromosomal DNA, extrachromosomal circular DNAs (eccDNAs) are organized in circular form and have long been found in unicellular and multicellular eukaryotes. Their biogenesis and function are poorly understood as they are characterized by sequence homology with linear DNA, for which few detection methods are available. Recent advances in high-throughput sequencing technologies have revealed that eccDNAs play crucial roles in tumor formation, evolution, and drug resistance as well as aging, genomic diversity, and other biological processes, bringing it back to the research hotspot. Several mechanisms of eccDNA formation have been proposed, including the breakage-fusion-bridge (BFB) and translocation-deletion-amplification models. Gynecologic tumors and disorders of embryonic and fetal development are major threats to human reproductive health. The roles of eccDNAs in these pathological processes have been partially elucidated since the first discovery of eccDNA in pig sperm and the double minutes in ovarian cancer ascites. The present review summarized the research history, biogenesis, and currently available detection and analytical methods for eccDNAs and clarified their functions in gynecologic tumors and reproduction. We also proposed the application of eccDNAs as drug targets and liquid biopsy markers for prenatal diagnosis and the early detection, prognosis, and treatment of gynecologic tumors. This review lays theoretical foundations for future investigations into the complex regulatory networks of eccDNAs in vital physiological and pathological processes.

Characterization, biogenesis model, and current bioinformatics of human extrachromosomal circular DNA

“…It is hypothesized that eccDNAs in circulation may complement miRNA and linear DNA, potentially serving as a means for disease diagnosis and intercellular communication ( Kumar et al, 2017 ). Unfortunately, Circle_finder cannot discriminate between eccDNA and chromosomal segmental tandem repeats ( Zhao et al, 2023 ; Wu et al, 2024 ). iii) Circle-Map.…”

“…Furthermore, results such as eccDNA containing oncogenes ( Kalavska et al, 2018 ; Gu et al, 2020 ; Li et al, 2022 ; Li et al, 2022 ) and being associated with drug resistance ( Alt et al, 1978 ; Kaufman et al, 1979 ; Haber and Schimke, 1981 ; Kaufman et al, 1981 ; Shoshani et al, 2021 ) have highlighted the possible use of eccDNA in tumor therapy and monitoring. Freshly, several studies have suggested the use of eccDNA for the diagnosis, treatment, and monitoring of gliomas ( Li et al, 2023 ), gynecologic tumors ( Wu et al, 2024 ), and genitourinary disorders ( Lv et al, 2022 ).…”

“…Yang et al meticulously summarized the regulatory mechanisms, and physiological functions of eccDNAs, as well as their roles and potential applications in cancers ( Yang et al, 2022 ). Complementarily, the role of eccDNAs in gynecologic tumors and reproduction has been addressed from a specialized perspective, with the proposal of using eccDNAs as drug targets and biomarkers for non-invasive prenatal testing as well as the early detection, prognosis, and treatment of gynecological tumors ( Wu et al, 2024 ). However, despite the objective contribution of computational methods and tools in advancing eccDNA research, we discovered that there are very few reports that provide a comprehensive summary of this aspect, limiting researchers with a strong interest in eccDNA from understanding the strengths and weaknesses of these tools and making rational choices in their studies.…”