178 Chapter 8 date the majority, if not almost all, studies on methylation marker triage performance in screening have been performed in unvaccinated cohorts. With the implementation of the bivalent HPV vaccine in the Dutch National Immunisation Program since 2009, the first vaccinated cohorts are currently entering the Dutch screening program. It is relevant to assess whether the current triage methods and thresholds are still optimal for vaccinated populations, and to consider screening based on vaccination status with perhaps separate guidelines for vaccinated and unvaccinated women. The prevalence of vaccine-targeted oncogenic hrHPV types is rapidly decreasing in countries with effective national vaccination programs 87-92. In reference to HPV vaccination, it was noted that the detection of CIN3+ by FAM19A4/ miR124-2 methylation is similar for lesions caused by HPV16/18 and those caused by other hrHPV types 93. In Chapter 4 methylation positivity rate was found not to differ across the various genotypes. Also the high methylation positivity rate in cervical carcinomas was found to be independent of genotype 28. Altogether this supports the continued value of host-cell DNA methylation markers in vaccinated women. The premise is that host-cell methylation positivity provides a means to reduce the false-positive screening results by precisely identifying advanced cervical lesions that require treatment 38. The study described in Chapter 7 was the first study that evaluated DNA methylation on cervical samples from 25-year old HPV-vaccinated women. Methylation levels were consistently low and no significant differences were observed in methylation of viral (HPV16 L1, HPV16 L2, HPV18 L2, HPV31 L1 and HPV33 L2) or host-cell (EPB41L3, FAM19A4 and miR124-2) genes between those with HSIL and LSIL or control group. Despite the lower methylation levels in women under 30, previous studies among unvaccinated women, indicated an increase in methylation with the severity of disease 44. The observed low methylation levels suggest that HSIL cases in these young, vaccinated women likely carry a minimal risk of progression to cervical cancer. Our findings suggest that women vaccinated against HPV with high-grade abnormalities might benefit from active monitoring instead of immediate treatment. However, it is crucial to validate these results in a larger cohort of HPV-vaccinated women with extended follow-up, older age categories and the inclusion of an age-matched control group consisting of unvaccinated women. It is imperative to include vaccinated women in future research studies focusing on screening and triage strategies to obtain a comprehensive understanding of the clinical value of methylation markers in both unvaccinated and vaccinated cohorts of women. Recent studies evaluating DNA methylation in cervical screening samples have also
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