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Diagnostic Performance of the ASCL1/ZNF582 Methylation Test for Detection of High-Grade Vulvar Intraepithelial
Dominique C de Vries1,2, Flavia Runello1,2, Sylvia Duin1,2
1Department of Pathology, Amsterdam UMC, Vrije Universiteit, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
Introduction:
High-grade vulvar intraepithelial neoplasia (VIN), the precursor lesion to vulvar cancer, comprises human papillomavirus (HPV)-associated high-grade squamous intraepithelial lesion (HSIL) and HPV-independent VIN (HPVi-VIN), differing in pathogenesis and cancer risk. HSIL typically develops from low-grade squamous intraepithelial lesion (LSIL), and HPVi-VIN from lichen sclerosus (LS). The PreCursor-M AnoGYN Methylation test, targeting ASCL1/ZNF582, may improve diagnostic accuracy and risk stratification in high-grade VIN patients. This study assessed its diagnostic performance to detect high-grade VIN and cancer.
Methods:
ASCL1/ZNF582 methylation was analyzed in 170 vulvar formalin-fixed paraffin-embedded (FFPE) tissue samples from healthy controls, LS, LSIL, HSIL, HPVi-VIN and vulvar cancer patients by quantitative methylation-specific polymerase chain reaction (qMSP). Logistic regression analysis was used to evaluate its diagnostic performance and compare it to the previously established ZNF582/SST/miR124-2 marker panel.
Results:
Methylation levels increased with disease severity, from low in controls, LS and LSIL to high in HSIL, HPVi-VIN and vulvar cancer. The ASCL1/ZNF582 marker panel detected 92% and 84% of HSIL at 70% and 80% specificity, respectively, and 96% of HPVi-VIN and 100% of vulvar cancer at both specificities. Both marker panels (ASCL1/ZNF582 and ZNF582/SST/miR124-2) showed comparable excellent diagnostic performance for high-grade VIN detection, with an area under the curve (AUC) of 0.93 (95% confidence interval [CI] 0.88-0.98) and AUC 0.91 (95% CI 0.86-0.97), respectively.
Conclusions:
In conclusion, the ASCL1/ZNF582 methylation assay accurately detects high-grade VIN and vulvar cancer, while minimizing the detection of benign and low-grade lesions, indicating its clinical value.
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