PAX1 and ZNF582 methylation as a triage strategy in cytological and hrHPV-positive scrapings in both Chinese and Dutch cohorts

BACKGROUND: The methylation of PAX1 and ZNF582 has been proven to have good diagnostic efficacy to detect cervical precancerous lesions in Asian populations, but their performance in Dutch populations is still unclear. We assessed PAX1 and ZNF582 methylation in both Dutch and Chinese cohorts. METHODS: Cervical scrapings were evaluated from 2 independent groups. The Dutch cohort(population-based screening) provided 190 abnormal cytology scrapings, 138 cases tested positive for hrHPV. The hospital-based Chinese cohort included 246 specimens(205 abnormal cytology, 227 hrHPV-positive). Quantitative methylation-specific PCR (QMSP) was employed to analyze methylation. RESULTS: PAX1 and ZNF582 methylation showed high specificity of 91-97% with moderate sensitivity of 43-61% for cervical intraepithelial neoplasia 2 or worse (CIN2+) in abnormal cytology and hrHPV-positive samples in both cohorts. Sensitivity for CIN3+ increased to 55-86%, but with lower specificity (85-93%). For detecting CIN2+, PAX1/ZNF582 methylation performed similarly in Dutch and Chinese cohorts. However, for CIN3+, the Chinese cohort showed significantly higher sensitivity, with comparable specificity. We also evaluated combining these genes with our established markers (C13ORF18, JAM3, ZSCAN1). The best diagnostic performance was achieved by combining PAX1 or ZNF582 with JAM3 in the Dutch cohort. CONCLUSIONS: In conclusion, regardless of race or geography, methylation of PAX1 or ZNF582 is highly specific for detecting CIN2+/CIN3+ lesions in hrHPV-positive or cytologically abnormal scrapings. Triage testing using these markers might significantly reduce immediate colposcopies.