Diagnostic value of FAM19A4/SOX1/PAX1 methylation in non-16/18 high-risk HPV cervical lesions.

PURPOSE: To evaluate clinical performance of FAM19A4, SOX1, and PAX1 methylation testing as a triage method for women ≥30 with positive non-16/18 high-risk HPV (hrHPV).

PATIENTS AND

METHODS

A total of 915 non-16/18 hrHPV-positive patients ≥30 from three hospitals between January and December 2024 were prospectively included. Diagnostic performance of FAM19A4, SOX1, and PAX1 methylation test, cytology, and combined testing were compared. Methylation testing was also evaluated as a triage for patients with ASC-US/LSIL cytology.

RESULTS

Methylation levels of FAM19A4, SOX1, and PAX1 correlated with cervical intraepithelial neoplasia (CIN) severity (P < 0.001). Compared with cytology, selected methylation panels showed comparable sensitivity for CIN3+ (91.18% vs. 79.41%-97.06%; P > 0.05) and significantly higher specificity (23.26% vs. 82.29%-93.51%; P < 0.001). The combined SOX1/PAX1 methylation assay demonstrated superior performance, with a sensitivity of 94.12% (95% CI: 85.83-97.69), specificity of 89.96% (95% CI: 87.76-91.81). In ASC-US/LSIL patients, combining single-gene or multigene methylation testing theoretically reduced the colposcopy referral rate from 100% to as low as 7.63%, and lower the number of referrals needed to detect one CIN3+ from 26.78 to as few as 3.11. A positive methylation result conferred an immediate CIN3+ risk of over 16.39%, while negative results for the gene panels yielded immediate CIN3+ risk below 2.00% when results were negative.

CONCLUSION

FAM19A4, SOX1, and PAX1 methylation testing effectively identifies high-grade cervical lesions and, due to high diagnostic accuracy, may improve stratified management of non-16/18 hrHPV-positive women and reduce unnecessary colposcopy and overtreatment.