Low methylation levels among HPV-vaccinated women with cervical HSIL 157 7 demonstrate mean levels of methylation among unvaccinated women, with LSIL (light pink) and HSIL (dark pink). These mean methylation levels were obtained from previously published data 11, 12, 23. FAM19A4 and miR124-2 both showed low methylation levels in HPV-vaccinated women compared to unvaccinated women with LSIL and HSIL lesions (Figure 7.1A and 7.1B). With host-cell gene EPB41L3, methylation levels were much higher among unvaccinated women with HSIL lesions, while among LSIL cases, levels were similar between vaccinated and unvaccinated women (Figure 7.1C). With the S5-classifier panel, the mean methylation levels of HPV-vaccinated women were also much lower compared to the unvaccinated HSIL S5-classifier methylation levels with a predefined cut-off of 0.8 (Figure 7.1D). However, significantly higher mean methylation level for S5-classifier was recorded in HSIL cases (0.81 (SD ±1.74)) compared to HPV-vaccinated controls (0.11 (SD ±1.04)) (p value = 0.0001). DISCUSSION Our study sheds light on HPV-vaccinated women with long-term follow-up, revealing that HSIL cervical lesions can still be detected in women vaccinated in early adolescence. However, the underlying nature and carcinogenic potential of these lesions remain unclear. With these first DNA methylation results among HPV-vaccinated women, we demonstrate that methylation marker levels in nearly all HPV-vaccinated HSIL cases are similar to controls. This indicates that most cervical lesions among HPV-vaccinated women could regress without treatment. It has been clearly demonstrated that HPV-associated disease remains a major issue, particularly in countries with a low vaccination coverage or without HPV vaccination programs 20, 24. However, screening data are emerging from women in vaccinated cohorts, showing a substantially lower cancer risk compared to unvaccinated women. Modifications to current screening tests and protocols will be necessary to reduce the harms of cervical cancer screening among HPV-vaccinated women 6, 20. In this study, we evaluated HPV-vaccinated women with histologically confirmed LSIL or HSIL cervical lesions. The observed HPV genotypes were in line with previous publications, with HPV52, 59, 51, 58 and 33 being the most prevalent among HSIL cases 20, 25, 26. These HPV genotypes are often detected in the pooled hrHPV type setting and are used for
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