68 Chapter 3 INTRODUCTION Since a negative high-risk (hr) human papillomavirus (HPV) test provides high reassurance against cervical cancer, many countries have switched from cytology to primary HPVbased screening 1. Women with a positive hrHPV test require additional triage testing as many hrHPV infections are transient and harmless without causing any premalignancy. Cytology is widely used as a triage test, but a variety of molecular tests are presently under investigation as promising alternative since they can offer an objective, non-morphological modality 2-4. Particularly the analysis of DNA hypermethylation of host-cell genes involved in cervical carcinogenesis seems to have great potential 5. Methylation levels of various genes show an increase with cervical intraepithalial neoplasia (CIN) grade and are almost universally high in cervical cancer 6. Currently available data support the capability of DNA methylation tests for triage of hrHPV-positive women in cervical screening 6, 7. Using epigenome-wide screens, we recently identified new host-cell DNA methylation markers that may hold promise for full-molecular screening 8, 9. The utility of these methylation markers ASCL1, LHX8, ST6GALNAC5, GHSR, SST and ZIC1 for the detection of CIN3 and cancer (CIN3+) in clinician-collected cervical samples of hrHPV-positive women was verified in a large training series. The six methylation markers showed good triage performance, with the bi-marker panel ASCL1/LHX8 detecting 89.1% of CIN3 and all 50 cervical cancers at a specificity of 70% 10, providing an optimised sensitivity over reported methylation markers 6 that warrants further investigation. Therefore, the current study was set out to externally validate these methylation markers for detection of CIN3+ in a large, independent hrHPV-positive cohort derived from primary HPV-based screening. We made use of cervical samples of hrHPV-positive women participating in the IMPROVE study that was carried out within the organised population-based screening program in the Netherlands. To evaluate triage performance of the methylation markers in a routine cervical screening setting, CIN diagnosis by pathologists made in daily practice was used. In addition, centralised reviewed diagnosis was included to verify the accuracy of the methylation markers. METHODS STUDY POPULATION This is a post hoc analysis of the IMPROVE trial (NTR5078), a randomised non-inferiority trial
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