Skip to main content

Advertisement

Log in

Advances in application of circulating tumor DNA in ovarian cancer

  • Review
  • Published:
Functional & Integrative Genomics Aims and scope Submit manuscript

Abstract

Ovarian cancer is the third most common gynecologic cancer worldwide and has the highest mortality rate among gynecologic cancers. Identifying timely and effective biomarkers at different stages of the disease is the key to improve the prognosis of ovarian cancer patients. Circulating tumor DNA (ctDNA) is a fragment of free DNA produced by tumor cells in the blood. Current techniques for detecting ctDNA mainly include quantitative polymerase chain reaction (PCR), targeted next-generation sequencing (NGS), and non-targeted NGS (such as whole exon or whole genome sequencing). As a non-invasive liquid biopsy technique, ctDNA has a good application prospect in the ovarian cancer diagnosis, monitoring of treatment response and efficacy evaluation, detection of reverse mutation and related medication guidance, and prognosis evaluation. This article reviews the advances in application of ctDNA in ovarian cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Data availability

Not applicable.

References

  • Alix-Panabieres C, Pantel K (2021) Liquid Biopsy: From Discovery to Clinical Application. Cancer Discov 11(4):858–873

    CAS  PubMed  Google Scholar 

  • Arend RC et al (2018) Molecular Response to Neoadjuvant Chemotherapy in High-Grade Serous Ovarian Carcinoma. Mol Cancer Res 16(5):813–824

    CAS  PubMed  PubMed Central  Google Scholar 

  • Armstrong DK et al (2022) NCCN Guidelines(R) Insights: Ovarian Cancer, Version 3.2022. J Natl Compr Canc Netw 20(9):972–980

    PubMed  Google Scholar 

  • Arora T, Mullangi S, Lekkala MR (2023) Ovarian cancer. StatPearls, Treasure Island (FL)

    Google Scholar 

  • Asante DB et al (2020) Liquid biopsy in ovarian cancer using circulating tumor DNA and cells: Ready for prime time? Cancer Lett 468:59–71

    CAS  PubMed  Google Scholar 

  • Basuli D et al (2017) Iron addiction: a novel therapeutic target in ovarian cancer. Oncogene 36(29):4089–4099

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bettegowda C et al (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6(224):224ra24

    PubMed  PubMed Central  Google Scholar 

  • Bondurant AE et al (2011) Quantitative detection of RASSF1A DNA promoter methylation in tumors and serum of patients with serous epithelial ovarian cancer. Gynecol Oncol 123(3):581–587

    CAS  PubMed  Google Scholar 

  • Boussios S et al (2022) BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside. Cancers 14(16)

  • Cabasag CJ et al (2022) Ovarian cancer today and tomorrow: a global assessment by world region and Human Development Index using GLOBOCAN 2020. Int J Cancer 151(9):1535–1541

    CAS  PubMed  Google Scholar 

  • Calapre L et al (2023) Identification of TP53 mutations in circulating tumour DNA in high grade serous ovarian carcinoma using next generation sequencing technologies. Sci Rep 13(1):278

    CAS  PubMed  PubMed Central  Google Scholar 

  • Campos-Carrillo A et al (2020) Circulating tumor DNA as an early cancer detection tool. Pharmacol Ther 207:107458

    CAS  PubMed  Google Scholar 

  • Chao A et al (2022) Mutations in circulating tumor DNA detected in the postoperative period predict poor survival in patients with ovarian cancer. Biom J

  • Chen M, Zhao H (2019) Next-generation sequencing in liquid biopsy: cancer screening and early detection. Hum Genomics 13(1):34

    PubMed  PubMed Central  Google Scholar 

  • Cheng ML et al (2021) Circulating tumor DNA in advanced solid tumors: Clinical relevance and future directions. CA Cancer J Clin 71(2):176–190

    PubMed  Google Scholar 

  • Cheung A et al (2022) Non-Epithelial Ovarian Cancers: How Much Do We Really Know? Int J Environ Res Public Health 19(3)

  • Chin RI et al (2019) Detection of solid tumor molecular residual disease (MRD) using circulating tumor DNA (ctDNA). Mol Diagn Ther 23(3):311–331

    CAS  PubMed  PubMed Central  Google Scholar 

  • Christie EL et al (2017) Reversion of BRCA1/2 Germline mutations detected in circulating tumor DNA from patients with high-grade serous ovarian cancer. J Clin Oncol 35(12):1274–1280

    CAS  PubMed  Google Scholar 

  • Cohen PA et al (2016) Abnormal plasma DNA profiles in early ovarian cancer using a non-invasive prenatal testing platform: implications for cancer screening. BMC Med 14(1):126

    PubMed  PubMed Central  Google Scholar 

  • Crowley E et al (2013) Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol 10(8):472–484

    CAS  PubMed  Google Scholar 

  • Diehl F et al (2005) Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci USA 102(45):16368–16373

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dong R et al (2012) Frequent SLIT2 promoter methylation in the serum of patients with ovarian cancer. J Int Med Res 40(2):681–686

    CAS  PubMed  Google Scholar 

  • Dvorska D et al (2019) Aberrant methylation status of tumour suppressor genes in ovarian cancer tissue and paired plasma samples. Int J Mol Sci 20(17)

  • Elazezy M et al (2021) BRCA1 promoter hypermethylation on circulating tumor DNA correlates with improved survival of patients with ovarian cancer. Mol Oncol 15(12):3615–3625

    CAS  PubMed  PubMed Central  Google Scholar 

  • Faaborg L et al (2021) Analysis of HOXA9 methylated ctDNA in ovarian cancer using sense-antisense measurement. Clin Chim Acta 522:152–157

    CAS  PubMed  Google Scholar 

  • Forshew T et al (2012) Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med 4(136):136ra68

    PubMed  Google Scholar 

  • Gao Q et al (2022) Circulating cell-free DNA for cancer early detection. Innovation 3(4):100259

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ghose A et al (2022) Applications of proteomics in ovarian cancer: dawn of a new era. Proteomes 10(2)

  • Giannopoulou L et al (2017) RASSF1A promoter methylation in high-grade serous ovarian cancer: A direct comparison study in primary tumors, adjacent morphologically tumor cell-free tissues and paired circulating tumor DNA. Oncotarget 8(13):21429–21443

    PubMed  PubMed Central  Google Scholar 

  • Giannopoulou L et al (2018) ESR1 methylation in primary tumors and paired circulating tumor DNA of patients with high-grade serous ovarian cancer. Gynecol Oncol 150(2):355–360

    CAS  PubMed  Google Scholar 

  • Han MR et al (2020) Clinical implications of circulating tumor DNA from ascites and serial plasma in ovarian cancer. Cancer Res Treat 52(3):779–788

    CAS  PubMed  PubMed Central  Google Scholar 

  • Harris FR et al (2016) Quantification of somatic chromosomal rearrangements in circulating cell-free DNA from ovarian cancers. Sci Rep 6:29831

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heider K et al (2020) Detection of ctDNA from dried blood spots after DNA size selection. Clin Chem 66(5):697–705

    PubMed  Google Scholar 

  • Huang K et al (2023a) LncRNA SLC25A21-AS1 increases the chemosensitivity and inhibits the progression of ovarian cancer by upregulating the expression of KCNK4. Funct Integr Genomics 23(2):110

    CAS  PubMed  Google Scholar 

  • Huang Y, Zhou Y, Zhang M (2023b) Identification of seven hypoxia-related genes signature and risk score models for predicting prognosis for ovarian cancer. Funct Integr Genomics 23(1):39

    PubMed  PubMed Central  Google Scholar 

  • Jie X et al (2022) Mutation analysis of circulating tumor DNA and paired ascites and tumor tissues in ovarian cancer. Exp Ther Med 24(3):542

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim SI et al (2018) Genomic landscape of ovarian clear cell carcinoma via whole exome sequencing. Gynecol Oncol 148(2):375–382

    CAS  PubMed  Google Scholar 

  • Kim YM et al (2019) Prospective study of the efficacy and utility of TP53 mutations in circulating tumor DNA as a non-invasive biomarker of treatment response monitoring in patients with high-grade serous ovarian carcinoma. J Gynecol Oncol 30(3):e32

    CAS  PubMed  Google Scholar 

  • Kim YN et al (2023) Investigation of poly ADP-ribose polymerase inhibitor resistance based on serially collected circulating tumor DNA in patients with BRCA-mutated ovarian cancer. Clin Cancer Res

  • Lennon AM et al (2020) Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention. Science 369(6499)

  • Li C et al (2019) Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors. Proc Natl Acad Sci USA 116(2):619–624

    CAS  PubMed  Google Scholar 

  • Lin KK et al (2019) BRCA reversion mutations in circulating tumor DNA Predict Primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. Cancer Discov 9(2):210–219

    CAS  PubMed  Google Scholar 

  • Lin C et al (2021) Liquid Biopsy, ctDNA Diagnosis through NGS. Life 11(9)

  • Lu Y, Li L (2021) The prognostic value of circulating tumor DNA in ovarian cancer: a meta-analysis. Technol Cancer Res Treat 20:15330338211043784

    CAS  PubMed  PubMed Central  Google Scholar 

  • Macintyre G et al (2018) Copy number signatures and mutational processes in ovarian carcinoma. Nat Genet 50(9):1262–1270

    CAS  PubMed  PubMed Central  Google Scholar 

  • Manasa G et al (2022) Biomarkers for early diagnosis of ovarian carcinoma. ACS Biomater Sci Eng 8(7):2726–2746

    CAS  PubMed  Google Scholar 

  • Moding EJ et al (2021) Detecting liquid remnants of solid tumors: circulating tumor DNA Minimal residual disease. Cancer Discov 11(12):2968–2986

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakabayashi M et al (2018) Massively parallel sequencing of cell-free DNA in plasma for detecting gynaecological tumour-associated copy number alteration. Sci Rep 8(1):11205

    PubMed  PubMed Central  Google Scholar 

  • Nebgen DR, Lu KH, Bast RC Jr (2019) Novel Approaches to ovarian cancer screening. Curr Oncol Rep 21(8):75

    PubMed  PubMed Central  Google Scholar 

  • Noguchi T et al (2020) Comprehensive gene mutation profiling of circulating tumor dna in ovarian cancer: its pathological and prognostic impact. Cancers 12(11)

  • Oikkonen J et al (2019) Prospective longitudinal ctDNA workflow reveals clinically actionable alterations in ovarian cancer. JCO Precis. Oncol:3

  • Parkinson CA et al (2016) Exploratory analysis of TP53 mutations in circulating tumour dna as biomarkers of treatment response for patients with relapsed high-grade serous ovarian carcinoma: a retrospective study. PLoS Med 13(12):e1002198

    PubMed  PubMed Central  Google Scholar 

  • Pettitt SJ et al (2020) Clinical BRCA1/2 reversion analysis identifies hotspot mutations and predicted neoantigens associated with therapy resistance. Cancer Discov 10(10):1475–1488

    CAS  PubMed  PubMed Central  Google Scholar 

  • Postel M et al (2018) Droplet-based digital PCR and next generation sequencing for monitoring circulating tumor DNA: a cancer diagnostic perspective. Expert Rev Mol Diagn 18(1):7–17

    CAS  PubMed  Google Scholar 

  • Revythis A et al (2022) Recent insights into PARP and immuno-checkpoint inhibitors in epithelial ovarian cancer. Int J Environ Res Public Health 19(14)

  • Rusan M et al (2020) Circulating HOXA9-methylated tumour DNA: a novel biomarker of response to poly (ADP-ribose) polymerase inhibition in BRCA-mutated epithelial ovarian cancer. Eur J Cancer 125:121–129

    CAS  PubMed  Google Scholar 

  • Sabatier R et al (2022) Whole-genome/exome analysis of circulating tumor DNA and comparison to tumor genomics from patients with heavily pre-treated ovarian cancer: subset analysis of the PERMED-01 trial. Front Oncol 12:946257

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sandeep Kumar S, Swamy SN, Premalatha CS, Pallavi VR, Gawari R (2019) Aberrant promoter hypermethylation of RASSF1a and BRCA1 in circulating cell-free tumor DNA Serves as a biomarker of ovarian carcinoma. Asian Pac J Cancer Prev 20(10):3001–3005

    Google Scholar 

  • Shah S et al (2022) Epithelial Ovarian cancer: providing evidence of predisposition genes. Int J Environ Res Public Health 19(13)

  • Shen W et al (2021) Hybrid capture-based genomic profiling of circulating tumor dna from patients with advanced ovarian cancer. Pathol Oncol Res 27:581534

    PubMed  PubMed Central  Google Scholar 

  • Singh A et al (2020) Detection of aberrant methylation of HOXA9 and HIC1 through multiplex MethyLight assay in serum DNA for the early detection of epithelial ovarian cancer. Int J Cancer 147(6):1740–1752

    CAS  PubMed  Google Scholar 

  • Siegmund B (2023) Distal Fecal wash: intestinal liquid biopsy? Cell Mol Gastroenterol Hepatol

  • Soletormos G et al (2016) Clinical Use of cancer biomarkers in epithelial ovarian cancer: updated guidelines from the European Group on Tumor Markers. Int J Gynecol Cancer 26(1):43–51

    PubMed  Google Scholar 

  • Stadler JC et al (2022) Current and future clinical applications of ctDNA in immuno-oncology. Cancer Res 82(3):349–358

    CAS  PubMed  Google Scholar 

  • Tao J et al (2022) Next-generation sequencing identifies potential novel therapeutic targets in Chinese HGSOC patients. Pathol Res Pract 238:154074

    CAS  PubMed  Google Scholar 

  • Terp SK et al (2023) Early diagnosis of ovarian cancer based on methylation profiles in peripheral blood cell-free DNA: a systematic review. Clin Epigenetics 15(1):24

    CAS  PubMed  PubMed Central  Google Scholar 

  • Thomsen CB et al (2019) Delta tocotrienol in recurrent ovarian cancer. A phase II trial. Pharmacol Res 141:392–396

    CAS  PubMed  Google Scholar 

  • Thusgaard CF et al (2021) Epithelial ovarian cancer and the use of circulating tumor DNA: A systematic review. Gynecol Oncol 161(3):884–895

    CAS  PubMed  Google Scholar 

  • Tobalina L et al (2021) A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance. Ann Oncol 32(1):103–112

    CAS  PubMed  Google Scholar 

  • Torre LA et al (2018) Ovarian cancer statistics, 2018. CA Cancer J Clin 68(4):284–296

    PubMed  PubMed Central  Google Scholar 

  • Vanderstichele A et al (2017) Chromosomal instability in cell-free DNA as a highly specific biomarker for detection of ovarian cancer in women with adnexal masses. Clin Cancer Res 23(9):2223–2231

    CAS  PubMed  Google Scholar 

  • Wang B et al (2017) Detection of OPCML methylation, a possible epigenetic marker, from free serum circulating DNA to improve the diagnosis of early-stage ovarian epithelial cancer. Oncol Lett 14(1):217–223

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y et al (2018) Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers. Sci Transl Med 10(433)

  • Weigelt B et al (2017) Diverse BRCA1 and BRCA2 Reversion mutations in circulating cell-free DNA of therapy-resistant breast or ovarian cancer. Clin Cancer Res 23(21):6708–6720

    CAS  PubMed  PubMed Central  Google Scholar 

  • Widschwendter M et al (2017) The potential of circulating tumor DNA methylation analysis for the early detection and management of ovarian cancer. Genome Med 9(1):116

    PubMed  PubMed Central  Google Scholar 

  • Wu Y et al (2014) Aberrant methylation of RASSF2A in tumors and plasma of patients with epithelial ovarian cancer. Asian Pac J Cancer Prev 15(3):1171–1176

    PubMed  Google Scholar 

  • Yang F et al (2021) Circulating tumor DNA: a noninvasive biomarker for tracking ovarian cancer. Reprod Biol Endocrinol 19(1):178

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang J et al (2022) Liquid biopsy for ovarian cancer using circulating tumor cells: Recent advances on the path to precision medicine. Biochim Biophys Acta Rev Cancer 1877(1):188660

    CAS  PubMed  Google Scholar 

  • Zhang Q et al (2013) A multiplex methylation-specific PCR assay for the detection of early-stage ovarian cancer using cell-free serum DNA. Gynecol Oncol 130(1):132–139

    CAS  PubMed  Google Scholar 

  • Zhu JW, Charkhchi P, Akbari MR (2022) Potential clinical utility of liquid biopsies in ovarian cancer. Mol Cancer 21(1):114

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by grants from Medical and Health research Project of Zhejiang Province (No. 2023KY572).

Author information

Authors and Affiliations

Authors

Contributions

TX wrote this manuscript. CF searched the literature. YC wrote and edited this manuscript. All authors approved the final version.

Corresponding author

Correspondence to Yaqing Chen.

Ethics declarations

Ethics approval

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xia, T., Fang, C. & Chen, Y. Advances in application of circulating tumor DNA in ovarian cancer. Funct Integr Genomics 23, 250 (2023). https://doi.org/10.1007/s10142-023-01181-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10142-023-01181-2

Keywords

Navigation