Elisa Redl

The cervico‐vaginal DNA methylation WID ‐ qEC test: An epigenetic marker associated with ovarian cancer in the absence of endometrial and cervical cancer

Abstract The DNA methylation‐based WID‐qEC test, applied to cervico‐vaginal samples, has been validated for the accurate detection of endometrial and cervical cancers. However, a small proportion of women test positive despite the absence of these cancers. The aim of this study was to explore the biological and clinical characteristics associated with such WID‐qEC‐positive cases to inform potential follow‐up strategies. We analyzed 1269 cervico‐vaginal samples from women without endometrial or cervical cancer, including healthy controls ( n  = 624), women with benign gynecological conditions ( n  = 324), and ovarian cancer cases ( n  = 321). Of the 80 WID‐qEC‐positive results, 43 (54%) were from women with ovarian cancer. WID‐qEC positivity was associated with the presence of ovarian cancer (adjusted odds ratio [OR] 2.93; 95% CI 1.75–4.95) and with a higher number of lifetime ovulatory cycles (adjusted OR 2.67; 95% CI 1.06–7.50), a known ovarian cancer risk factor. Both associations were independent of age, menopausal status, hormone replacement therapy usage, or family history of breast or ovarian cancer. Our findings suggest that in the absence of endometrial or cervical cancer, WID‐qEC positivity may indicate an elevated risk or presence of ovarian cancer. While the standalone positive predictive value (PPV) for ovarian cancer detection remains low in the general population, we outline how WID‐qEC could be used in a two‐step triage approach. In women presenting with abnormal bleeding, combining WID‐qEC positivity with a highly specific plasma‐based cell‐free DNA methylation test (e.g., with 60%–80% sensitivity and ~98.4% specificity) could theoretically yield a PPV of around 30%–40%. This hypothetical modeling is intended solely to illustrate how WID‐qEC positivity might inform future triage research, rather than to propose a clinical diagnostic algorithm.

Performance of the WID‐qEC test to detect uterine cancers in black women with abnormal uterine bleeding: A prospective observational cohort study in Ghana

AbstractThe burden of uterine cancer is growing and, in the US and UK, mortality rates are poorest among black women. Early detection of these cancers is critical and poor performance of ultrasound in black women may contribute to adverse outcomes. Limited data on this topic are available from Africa. We assessed whether a simple DNA methylation test, the WID‐qEC, enables detection of all epithelial uterine (endometrial and cervical) cancers in women presenting with abnormal uterine bleeding (AUB) in Ghana. Among 118 women ≥40 years presenting with AUB, 106 consented to the study and a cervicovaginal sample was obtained for WID‐qEC testing. Subsequent to ultrasound assessment 102 women had a cervical or endometrial biopsy. Histopathology, ultrasound and WID‐qEC testing were analyzed and compared. Among the 102 volunteers, 8 and 15 were diagnosed with endometrial and cervical cancer (EC and CC), respectively. The receiver operating characteristic (ROC) area under the curve (AUC) was 0.56 (95% confidence interval [CI] 0.25–0.86) for sonographic endometrial thickness (ET) and 0.98 (95% CI 0.94–1.00) for the WID‐qEC test. Sensitivity and specificity of the prespecified ET ≥5 mm were 66.7% (95% CI 24.1–94.0) and 22.7 (95% CI 12.0–38.2) and for the prespecified WID‐qEC SUM‐PMR ≥ 0.3 were 100% (95% CI 56.1–100.0) and 76.1 (96%CI 60.9–86.9), respectively. In addition, 15 CCs were detected by the WID‐qEC test [sensitivity 100% (95% CI 74.7–100.0)]. The WID‐qEC test accurately detects both EC and CC in black women presenting with AUB.

High performance of the DNA methylation‐based WID‐qEC test for detecting uterine cancers independent of sampling modalities

AbstractEndometrial cancer (EC) is the most prevalent gynaecological cancer in high‐income countries and its incidence is continuing to rise sharply. Simple and objective tools to reliably detect women with EC are urgently needed. We recently developed and validated the DNA methylation (DNAme)‐based women's cancer risk identification—quantitative polymerase chain reaction test for endometrial cancer (WID‐qEC) test that could address this need. Here, we demonstrate that the stability of the WID‐qEC test remains consistent regardless of: (i) the cervicovaginal collection device and sample media used (Cervex brush and PreservCyt or FLOQSwab and eNAT), (ii) the collector of the specimen (gynaecologist‐ or patient‐based), and (iii) the precise sampling site (cervical, cervicovaginal and vaginal). Furthermore, we demonstrate sample stability in eNAT medium for 7 days at room temperature, greatly facilitating the implementation of the test into diagnostic laboratory workflows. When applying FLOQSwabs (Copan) in combination with the eNAT (Copan) sample collection media, the sensitivity and specificity of the WID‐qEC test to detect uterine (i.e., endometrial and cervical) cancers in gynaecologist‐taken samples was 92.9% (95% confidence interval [CI] = 75.0%–98.8%) and 98.6% (95% CI = 91.7%–99.9%), respectively, whilst the sensitivity and specificity in patient collected self‐samples was 75.0% (95% CI = 47.4%–91.7%) and 100.0% (95% CI = 93.9%–100.0%), respectively. Taken together these data confirm the robustness and clinical potential of the WID‐qEC test.

Cervical cancer screening using DNA methylation triage in a real-world population

AbstractCervical cancer (CC) screening in women comprises human papillomavirus (HPV) testing followed by cytology triage of positive cases. Drawbacks, including cytology’s low reproducibility and requirement for short screening intervals, raise the need for alternative triage methods. Here we used an innovative triage technique, the WID-qCIN test, to assess the DNA methylation of human genes DPP6, RALYL and GSX1 in a real-life cohort of 28,017 women aged ≥30 years who attended CC screening in Stockholm between January and March 2017. In the analysis of all 2,377 HPV-positive samples, a combination of WID-qCIN (with a predefined threshold) and HPV16 and/or HPV18 (HPV16/18) detected 93.4% of cervical intraepithelial neoplasia grade 3 and 100% of invasive CCs. The WID-qCIN/HPV16/18 combination predicted 69.4% of incident cervical intraepithelial neoplasia grade 2 or worse compared with 18.2% predicted by cytology. Cytology or WID-qCIN/HPV16/18 triage would require 4.1 and 2.4 colposcopy referrals to detect one cervical intraepithelial neoplasia grade 2 or worse, respectively, during the 6 year period. These findings support the use of WID-qCIN/HPV16/18 as an improved triage strategy for HPV-positive women.