54 Chapter 2 Strengths of our study are the large sample size and the evaluation of all six methylation markers on the same sample series allowing direct comparison between markers. Another strength is the evaluation and validation of all models for CIN3 detection, consistent with the purpose of cervical screening. A limitation of our study is the absence of histological confirmation in part of the controls. In a restricted analysis including only controls with histologically proven outcome (n = 127), no difference in prediction performance was obtained (data not shown). Another limitation is that LOOCV was used for validation of the models. Further validation in independent cohorts including CIN2 lesions is warranted. CONCLUSION All six single markers showed an equivalent, high diagnostic performance for CIN3 detection. ASCL1 and LHX8 showed complementarity in the detection of cervical cancer. These markers were originally identified on self-collected samples and have now been demonstrated to have a similar good performance on cervical samples. FUTURE PERSPECTIVE Cervical screening programs, currently based on cytology or primary HPV testing plus cytology and/or HPV genotyping, could be improved by the implementation of methylation-based triage strategies. Methylation analysis of host-cell genes using qMSP provides a promising objective triage strategy for HPV-positive women. This study confirms the triage potential of six methylation markers, supporting full molecular cervical screening compatible with both clinician-collected and self-collected samples. Triage of HPV-positive women by methylation markers enables the detection of clinically relevant CIN lesions, and importantly reduces over referral and overtreatment of women with a low cervical cancer risk. Host-cell methylation-based triage strategies, such as ASCL1/LHX8 methylation testing, detect all cervical cancers independent of HPV genotype, histotype or sample type.
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