158 Chapter 7 triaging women with low-grade pap cytology for repeated testing, suggesting a lower risk of cancer compared to HPV16/18, which often represents abnormal Pap cytology and requires direct referral for colposcopy 27. A large recent systematic review, evaluating the risk of cervical HSIL for unvaccinated women, found that the risk for HPV33 was intermediate, while HPV52 and HPV58 carried only a moderate risk and HPV51 and HPV59 had the least risk 27. Therefore, even when considering only HPV genotyping, HPVvaccinated women with HSIL lesions have low to moderate risk for developing cervical cancer. Natural regression of cervical HSIL lesions is common among young unvaccinated women, with almost half of them resolving spontaneously within two years 28. However, in our cohort of HPV-vaccinated cases, no expectant management was employed, as they were all surgically treated with loop electrosurgical excision procedure (LEEP) according to the clinical case guidelines of Finland. LEEP can cause emotional distress and serious complications during pregnancy, highlighting the need for alternative management strategies. For instance, premature delivery, a consequence of LEEP, contributes to the challenges we face today with premature children that require extensive and costly postnatal care that sometimes becomes life-long care 29, 30. Recent studies have shown that DNA methylation testing has the potential to distinguish unvaccinated women with progressive HSIL lesions from those likely to regress spontaneously. Among women under the age of 30 with follow-up every six months after CIN2 diagnoses, the S5-classifier had the highest association with women showing progressive cervical disease, with an odds ratio (OR) of 3.39 17. Moreover, the hostcell marker panel FAM19A4/miR124-2 reported a high regression rate in women with a CIN2/3 lesion if they had a negative baseline FAM19A4/miR124-2 methylation test 16. Both studies have confirmed that combining methylation testing with HPV genotyping or pap cytology could be used in clinical setting to identify women at genuine risk of progressive disease. Our study is the first to investigate DNA methylation among HPV-vaccinated women, revealing low methylation levels and suggesting a low progression potential for HSIL lesions in this population. We could only detect viral HPV33 methylation, as HPV16, 18 and 31 were not detected among the HPV-vaccinated women. No differences were recorded between the vaccinated LSIL or HSIL cases and vaccinated controls for HPV33 or any of the host-cell genes (EPB41L3, FAM19A4 and miR124-2), indicating low or absent methylation levels. Though methylation is known to be lower in women under the age of 30. Previous studies have shown that methylation levels increase with lesion severity
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