General discussion and future perspectives 171 8 for CIN3+ without the need for repeat testing. However, this triage strategy has a low PPV resulting in a high number of colposcopy referrals 50-52. In the Netherlands, the HPV-based screening program, implemented in 2017, included repeat cytology testing at six months after an hrHPV-positive, cytological negative result to ensure adequate protection 47, 48, 53, 54. However, this approach still led to a nearly two-fold increase in colposcopy referrals and ≤CIN1 diagnoses compared to the previous cytology-based screening program 55, 56. Therefore, in the Dutch screening program, as of July 2022, hrHPV-positive women with low-grade cytology (atypical squamous cells of undetermined significance (ASC-US); or low-grade squamous intraepithelial lesions (LSIL); ASC-US/LSIL) are further triaged by HPV16/18 genotyping. Women with ASC-US/LSIL that are HPV16/18-positive are directly referred for colposcopy, while those with non-HPV16/18 types are invited for repeat testing after 12 months instead of 6 months to allow the chance of spontaneous regression to have a reductive effect on the number of referrals (Figure 8.2A). This revised strategy is expected to result in an overall reduction of about 33% in colposcopy referrals, while retaining sufficient protection 57. Figure 8.2A shows current HPV-based screening in the Netherlands. Since cytology does not perform optimally on self-collected samples, women who test HPV-positive on a self-sample need an additional clinician-collected cervical sample for cytology triage. This additional step may lead to loss to follow-up 58-62. This is underscored by contemporary challenges, including reducing over-referral and overtreatment, the implementation of self-sampling as a primary screening tool, the call for automation, and the inclusion of vaccinated women in the screening program. It is crucial to acknowledge the evolving landscape of emerging triage approaches, including automated digital cytology, protein markers detected by immunostaining (such as p16INK4A, Ki-67, E4), RNA sequencing (as demonstrated by the CervicaDX test from Predica Diagnostics BV, Nijmegen, The Netherlands), microRNA, HPV methylation, and host-cell DNA methylation. Continuous evaluation of these alternatives is essential as the landscape evolves, ensuring the optimisation of cervical cancer screening, leading to improved outcomes, and minimising potential drawbacks associated with current protocols. This thesis focussed on the evaluation of host-cell methylation markers. 8.1.1.1 HOST-CELL DNA METHYLATION ANALYSIS FOR TRIAGE OF HRHPV-POSITIVE WOMEN In a training and validation study (Chapter 2), six novel methylation markers ASCL1, LHX8, ST6GALNAC5, GHSR, SST and ZIC1 demonstrated high performance for the triage of hrHPVpositive women with cross-validated AUCs for CIN3 detection between 0.768 and 0.876.
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