Plasma cell‐free DNA methylation analysis for ovarian cancer detection: Analysis of samples from a case‐control study and an ovarian cancer screening trial

Author:

Herzog Chiara12ORCID,Jones Allison3,Evans Iona3,Reisel Daniel3,Olaitan Adeola3,Doufekas Konstantinos3,MacDonald Nicola3,Rådestad Angelique Flöter4,Gemzell‐Danielsson Kristina4,Zikan Michal5,Cibula David6,Dostálek Lukáš6,Paprotka Tobias7,Leimbach Andreas8,Schmitt Markus8,Ryan Andy9,Gentry‐Maharaj Aleksandra39,Apostolidou Sophia9,Rosenthal Adam N3,Menon Usha9ORCID,Widschwendter Martin1234ORCID

Affiliation:

1. European Translational Oncology Prevention and Screening (EUTOPS) Institute Hall in Tirol Austria

2. Research Institute for Biomedical Aging Research Universität Innsbruck Innsbruck Austria

3. Department of Women's Cancer, UCL EGA Institute for Women's Health University College London London UK

4. Department of Women's and Children's Health, Division of Obstetrics and Gynecology Karolinska Institutet and Karolinska University Hospital Stockholm Sweden

5. Department of Gynecology and Obstetrics, Charles University in Prague First Faculty of Medicine and Hospital Na Bulovce Czech Republic

6. Department of Gynaecology, Obstetrics and Neonatology, First Faculty of Medicine, Charles University, Prague and General University Hospital Prague Czech Republic

7. GENEWIZ Germany GmbH Bahnhofstraße Germany

8. Eurofins Genomics Europe Sequencing GmbH Konstanz Germany

9. MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology University College London London UK

Abstract

AbstractAnalysis of cell‐free DNA methylation (cfDNAme), alone or combined with CA125, could help to detect ovarian cancers earlier and may reduce mortality. We assessed cfDNAme in regions of ZNF154, C2CD4D and WNT6 via targeted bisulfite sequencing in diagnostic and early detection (preceding diagnosis) settings. Diagnostic samples were obtained via prospective blood collection in cell‐free DNA tubes in a convenience series of patients with a pelvic mass. Early detection samples were matched case‐control samples derived from the UK Familial Ovarian Cancer Screening Study (UKFOCSS). In the diagnostic set (ncases = 27, ncontrols = 41), the specificity of cfDNAme was 97.6% (95% CI: 87.1%‐99.9%). High‐risk cancers were detected with a sensitivity of 80% (56.3%‐94.3%). Combination of cfDNAme and CA125 resulted in a sensitivity of 94.4% (72.7%‐99.9%) for high‐risk cancers. Despite technical issues in the early detection set (ncases = 29, ncontrols = 29), the specificity of cfDNAme was 100% (88.1%‐100.0%). We detected 27.3% (6.0%‐61.0%) of high‐risk cases with relatively lower genomic DNA (gDNA) contamination. The sensitivity rose to 33.3% (7.5%‐70.1%) in samples taken <1 year before diagnosis. We detected ovarian cancer in several patients up to 1 year before diagnosis despite technical limitations associated with archival samples (UKFOCSS). Combined cfDNAme and CA125 assessment may improve ovarian cancer screening in high‐risk populations, but future large‐scale prospective studies will be required to validate current findings.

Publisher

Wiley

Subject

Cancer Research,Oncology

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