Triage performance and predictive value of the human gene methylation panel among women positive on self‐collected HPV test: Results from a prospective cohort study

Triaging of women positive for high‐risk human papillomavirus (hrHPV) on self‐collected samples requires a molecular reflex test to avoid recall for cytology or visual tests. We assessed triage performance and predictive value of human gene methylation panel (ZNF671/ASTN1/ITGA4/RXFP3/SOX17/DLX1) alone and with combination of HPV16/18 genotyping in a longitudinal screening study. Out of 9526 women at baseline, 1758 women positive for hrHPV on self‐collected samples followed up yearly were included in the current analysis. Satisfactory risk stratification to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was demonstrated by the methylation panel with an odds ratio (OR) of 11.3 among methylation‐positive women compared to methylation‐negative counterparts. Triaging with methylation panel reduced colposcopy referral rate by 67.2% with sensitivity and specificity of 83.0% and 69.9% to detect CIN2+. The corresponding values for the combining methylation and HPV 16/18 were 96.6% and 58.3%. The cumulative 3‐year incident CIN2+ risk was 6.8% (95% CI: 4.9%‐8.6%) for hrHPV positive women, which was reduced to 4.5% (95% CI: 2.7%‐6.3%) and 2.9% (95% CI: 1.2%‐4.5%) for women negative on methylation triaging alone and negative on the combined strategy. The corresponding risk for women positive for both methylation and HPV 16/18 reached 33.7% (95% CI: 19.0%‐45.8%). Our study demonstrated the satisfactory triage performance and predictive value of the methylation panel, especially in combination with HPV 16/18 genotyping. The substantially lower risk of CIN2+ among the triage negative women over the next 3 years suggests that the interval for repeat HPV test can be safely extended to at least 2 years. What's new? Assays to detect methylation in human papillomavirus (HPV) DNA and human genes are promising for the triage of high‐risk HPV‐positive women. There is scarce evidence, however, on its performance for the triage of self‐collected samples. Here, a human gene methylation panel, alone and in combination with HPV16/18 genotyping, was assessed for predictive performance in a cervical cancer screening cohort in China. Among methylation‐positive women, the panel exhibited satisfactory risk stratification for cervical intraepithelial neoplasia grade 2 or worse, especially when combined with HPV 16/18 genotyping. The findings suggest that methylation testing has high predictive value for clinically relevant cervical lesions.