Low methylation levels among HPV-vaccinated women with cervical HSIL 149 7 NOVELTY AND IMPACT HPV-vaccinated women with cervical HSIL had infections with HPV genotypes that very rarely cause cancer in this age group and displayed similarly low methylation levels as HPV-vaccinated women with LSIL and HPV-vaccinated controls. Validated data on the progression potential of their lesions are needed for redesigning cervical cancer screening programs for HPV-vaccinated women, including triage. The discovered low methylation levels suggest that HPV-vaccinated women would benefit from active surveillance of their HSIL-lesions rather than immediate treatment. INTRODUCTION Human papillomavirus (HPV) vaccinated birth cohorts of women are now reaching the age for cervical cancer screening programs. Over the past years, many countries have transitioned their cervical cancer screening programs to HPV primary screening, with pap cytology used as the triage test 1, 2. HPV vaccination has led to a reduction in the prevalence of many HPV genotypes targeted by cervical cancer screening, resulting in a lower prevalence of high-risk (hr) HPV and associated cervical lesions among HPVvaccinated women 3-5. This reduction is expected to significantly decrease the positive predictive value of current cervical cancer screening tests. Therefore, it is crucial for cervical cancer screening programs to carefully consider adaptations for HPV-vaccinated women to balance the potential risks and benefits 6, 7. Furthermore, there is an urgent need to explore alternative screening tests that can effectively identify HPV-vaccinated women with a substantial risk of cervical cancer. Methylation of both host-cell and viral genes has shown promising results in identifying unvaccinated women with high-grade lesions and cervical cancer. Methylation levels tend to increase with lesion severity 8-10. Two well-studied marker panels, the QIAsure Methylation Test, including host-cell methylation markers FAM19A4 and miR124-2 11-13 and the S5-classifier, including host-cell methylation marker EPB41L3, and viral genes HPV16-L1, HPV16-L2, HPV18-L2, HPV31-L1 and HPV33-L2 9, have demonstrated accurate detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+), as well as malignancy in unvaccinated women across various geographic contexts and settings (Asia, Europe, Africa and the Americas) 14, 15. Both panels have proven effective in identifying progressive high-grade squamous intraepithelial (HSIL) cervical lesions in unvaccinated women 16, 17. Importantly, implementation of predictive cervical
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