113 Molecular analysis for ovarian cancer detection in patient-friendly samples MATERIAL AND METHODS Study population This study prospectively included patients with a highly suspicious ovarian mass according to current triage methods (>40% risk of malignancy using the IOTA adnex model) (23, 24). Paired samples (i.e. urine, cervicovaginal self-samples, and cliniciantaken cervical scrapes) were consecutively collected within the SOLUTION1 study, between July 2018 and September 2022, at the Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands. Samples were collected from patients who underwent pelvic surgery with post-operatively confirmed ovarian cancer of any stage and histological subtype, and patients with a benign ovarian mass who were referred to a highly specialized tertiary oncology unit for further assessment. Patients scheduled for pelvic surgery, involving exploratory laparotomy to determine the origin of their ovarian mass or cytoreductive surgery, were asked to collect samples prior to surgery. Patients without residual tumor/ovarian mass at time of inclusion or no possibility to collect cytological or urine samples prior to surgery were excluded from participation. Patients diagnosed with a borderline tumor were also excluded to focus on the most distinct tumor types in this feasibility stage (i.e. benign and malignant ovarian masses). Patients of which not all three paired sample types (i.e. cervical scrape, cervicovaginal self-sample, and urine) were available were not excluded. Control urine samples were obtained from the URIC biobank, including healthy women without any prior cancer diagnosis within the last five years. Control cervicovaginal self-samples and cervical scrapes were collected from high-risk human papillomavirus (hrHPV)-negative women. Both were retrieved from leftover material of the Dutch national cervical cancer screening program coordinated by the Dutch National Institute for Public Health and the Environment (RIVM). To verify the discriminatory power of the methylation assays and concordance of copy number profiles, formalin-fixed paraffin-embedded (FFPE) and fresh frozen high-grade serous ovarian cancer (HGSOC) tissue samples were retrieved from the Pathology archives of Amsterdam UMC, locations AMC and VUmc, Amsterdam, The Netherlands. FFPE normal fallopian tube tissues were collected from patients undergoing a hysterectomy for the treatment of benign endometrial conditions. Sample collection, processing, DNA extraction, and bisulfite modification The sample collection, processing, DNA extraction, and bisulfite modification procedures were carried out as described previously for cervical (8, 25) and endometrial cancer (10, 19). A detailed description is provided in the Supplemental Methods. Briefly, urine and 5
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