Methylated ZNF582 gene as a marker for triage of women with Pap smear reporting low-grade squamous intraepithelial lesions — A Taiwanese Gynecologic Oncology Group (TGOG) study

Objective Our previous work revealed that host genes ZNF582 , PTPRR , PAX1 , and SOX1 are highly methylated in cervical intraepithelial neoplasias grade 3 or worse (CIN3 + ). In this study, we used a standardized testing assay to evaluate the clinical efficacy of these biomarkers in the triage of cytological diagnoses of low-grade squamous intraepithelial lesions (LSILs), and compared the performance with human papillomavirus (HPV) testing. Methods This 2-year multicenter prospective study examined a population of 230 women from 12 medical centers who were diagnosed with LSILs on cervical cytology. Cervical scrapings were obtained prior to a colposcopy-directed biopsy for quantitative methylation analysis of ZNF582 , PTPRR , PAX1 , and SOX1 , and HPV testing. Using logistic regression and receiver operating characteristic curve analyses, the abilities of methylated genes and HPV to predict CIN3 + were assessed. Results Fifteen (6.5%) of the 230 women with a cytological diagnosis of LSIL were confirmed to have CIN3 + after a colposcopy-directed biopsy. Among the 4 methylated genes, ZNF582 was found to be the best biomarker for detecting CIN3 + . The sensitivities for methylated ZNF582 and HPV testing were 73% and 80%, and the specificities were 71% and 28%, respectively. The odds ratio for predicting CIN3 + using methylated ZNF582 was 6.8 (95% confidence interval (CI) 2.1–22.1), which was much better than HPV testing (OR=1.6, 95% CI 0.4–5.8). Conclusion This is the first study to show that ZNF582 methylation analysis of cervical swabs may be a promising choice in the positive triage of cytological diagnoses of LSILs.