DNA Methylation Tests Show High Accuracy for Cervical Cancer TriageDNA methylation tests show promise for identifying high grade cervical cell changes

BACKGROUND: Human papillomavirus (HPV)-based cervical screening offers stronger protection against cervical intraepithelial neoplasia (CIN) than screening with cytology. DNA methylation tests have been proposed as an alternative triage test to cytology, although there is currently no consensus on the most accurate gene or gene panels ("markers"). METHODS: We conducted a meta-analysis of accuracy of human and HPV methylation markers to detect CIN2 or worse (CIN2+), CIN3+, and cervical cancer (CRD42022299760). We systematically searched three databases to March 2025. We used a bivariate random-effects model to produce pooled sensitivity, specificity, diagnostic odds ratios (DORs), positive and negative likelihood ratios (LR+, LR-) for each marker at each available endpoint. Our primary analysis was in HPV+ women, and secondary analysis included all data regardless of HPV positivity. RESULTS: We included 51 studies exploring 13 methylation markers in 28,977 HPV+ women, and in total 125 studies assessing 32 markers in 49,242 women. For HPV+, the markers with the highest DORs were JAM3 (20.82 [95%CI 14.41-30.08]), C13ORF18 (19.50 [95%CI 11.65-32.65]), and PAX1 (17.13 [95%CI 9.20-31.89]). EPB41L3 had the lowest LR- (0.26 [95%CI 0.19-0.35]). In all women, SOX1 had the highest DOR (29.72 [95%CI 12.84-68.81]), although JAM3 and PAX1 maintained good accuracy (DORs 26.73 [95%CI 19.97-35.77] and 23.96 [95%CI 17.32-33.15]). CONCLUSION: Several methylation markers reported good sensitivity in the detection of CIN3+ whilst maintaining high specificity. These have potential to reduce unnecessary referrals to colposcopy. Methylation markers may permit efficient triage on self-samples which are inappropriate for cytology, although this requires further study ideally in screening cohorts.