28 Chapter 1 3. To support post-colposcopy management; 4. To support post-treatment management of CIN. Meta-analyses have reported that methylation markers have good diagnostic ability 131, 134. In the setting of HPV triage, methylation sensitivity for CIN2+ and CIN3+ were reported to be 68.6% (95% CI: 62.9-73.8%) and 71.1% (95% CI: 65.7-76.0%), respectively, at a fixed specificity of 70%, and PPV were 53.4% (95% CI: 44.4-62.1%) and 35.0% (95% CI: 28.941.6%), respectively. Among hrHPV-positive women, the relative sensitivity of methylation for CIN2+ was found to be 0.81 (95% CI: 0.63-1.04) when compared to cytology (threshold borderline; atypical squamous cells of undetermined significance (ASC-US), or worse (ASC-US+) and 1.22 (95% CI: 1.05-1.42) when compared to HPV16/18 genotyping, while relative specificity was 1.25 (95% CI: 0.99-1.59) and 1.03 (95% CI: 0.94-1.13), respectively. Additional risk-stratification of hrHPV-positive women with borderline/low-grade cytology (ASC-US/LSIL) by methylation analysis has shown that it can reduce direct colposcopy referral rate with 60%, while retaining high CIN3+ sensitivity 108. Host-cell methylation analysis has been reported as a good tool to rule out cervical cancer whether caused by hrHPV infection prior to vaccination, hrHPV genotypes not covered by the current prophylactic vaccines or characterised by the absence of hrHPV 121. For the management of women with CIN2/3, host-cell methylation analysis has shown valuable in predicting regression, i.e., a methylation-negative test was associated with more clinical regression as compared to women with a methylation-positive result (74.7% versus 51.4% respectively; p value = 0.013) 122. Though highly promising, it is of note that most studies that have examined the use of DNA methylation analysis as a method for (secondary) triage of hrHPV-positive women in screening have been conducted on smaller or selected series from screening or referral populations, such as self-sampling studies focused on non-attendee populations. This highlights the need for additional research using samples from women participating in routine HPV-based screening, which is the focus of this thesis 126, 127, 131, 135-139. 1.5 THESIS OUTLINE The primary objective of this thesis is to evaluate the role of DNA methylation markers in cervical cancer screening. With the global introduction of HPV-based screening in various countries, there is a need for effective triage strategies. These strategies aim to identify hrHPV-positive women with the highest risk of developing cervical cancer while simultaneously minimising unnecessary referrals and avoiding over-treatment of
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