SOX1 / PAX1 Methylation for Triage of HPV ‐Positive Women in Cervical Cancer Screening: A Cohort Study

OBJECTIVE: To establish a better triage strategy using SOX1/PAX1 methylation detection for high-risk HPV (hrHPV)-positive women than cytology. DESIGN: A cohort study. SETTING: Population-based cervical cancer (CC) screening cohort. POPULATION: A total of 5684 women were enrolled. METHODS: SOX1/PAX1 methylation was detected by quantitative methylation-specific PCR using cytologic residue from hrHPV-positive women at baseline in a 3-year CC screening cohort. Risk stratification ability was evaluated by the immediate and cumulative cervical intraepithelial neoplasia (CIN) grade 2/3 or worse (CIN2+/3+) risks. MAIN OUTCOME MEASURES: CIN3+ and CIN2+. RESULTS: At baseline, 682 hrHPV-positive women were included with 63 CIN2+ and 39 CIN3+. Over 3 years, 109 CIN2+ and 62 CIN3+ were detected. Methylation demonstrated better risk stratification than cytology among hrHPV-positive women. When compared with current practice triage strategy (Strategy A), post hoc re-triage analysis showed that methylation triage for all hrHPV-positive women (Strategy C) significantly increased sensitivity (97.44%/83.87% vs. 84.62%/64.52%, p = 0.0476/0.014), specificity (83.36%/85.00% vs. 73.41%/73.55%, p = < 0.001/< 0.001), positive predictive value (26.21%/35.86% vs. 16.18%/19.61%, p = 0.022/0.001), and negative predictive value (99.81%/98.14% vs. 98.74%/95.40%, p = 0.040/0.012) in detecting immediate and 3-year cumulative CIN3+. Similar improvements were observed for methylation triaged for HR12-positive (Strategy B) and for combined HPV and cytology primary screening (Strategy D). More importantly, all methylation-based triage strategies reduced colposcopies and postponed follow-up intervals compared to Strategy A over the 3-year period of CC screening. CONCLUSION: SOX1/PAX1 methylation showed better risk stratification compared with cytology and enabled more efficient management of HPV-positive women, though external validation and head-to-head comparisons with other triage methods are needed.