Methylation markers for risk-stratification in cervical cancer screening and management of CIN

Cervical cancer is one of the most preventable and treatable forms of cancer. The development of cervical cancer is preceded by cervical intraepithelial neoplasia (CIN). This offers possibilities for screening and treatment before CIN lesions progress to cervical cancer. Novel biomarkers offer the opportunity to improve screening and tailor management. The ultimate goal is to mainly refer women for colposcopy and to consequently only treat women with high-grade CIN (CIN2/3) with a high chance of progression to cervical cancer. Chapter 1 provided a general introduction on cervical carcinogenesis, cervical screening and management of CIN2/3. Part 1.Screening Host-cell DNA methylation markers have shown a good performance in the detection of CIN3 and cervical cancer (CIN3+) in HPV-based cervical screening as a triage test. In Chapter 2, six novel methylation markers were evaluated and compared for the detection of CIN3 and cervical cancer. We showed that all six methylation markers had a high performance. ASCL1 and LHX8 showed complementarity in the detection of CIN3 with an AUC of 0.890, resulting in a sensitivity of 84.0% and specificity of 83.2%. The bi-marker panel detected all 50 cervical cancers. The implementation of HPV-based screening with cytology triage led to an increased colposcopy referral rate. This increase in mainly caused by the direct referral of women with borderline or mild cytological abnormalities. In Chapter 3, we evaluated whether the FAM19A4/miR124-2 methylation test can be applied as an additional triage test in HPV-positive women with borderline or mild dyskaryosis cytology to reduce overreferral. The CIN3+ risk after a positive or negative methylation result was 33.1% and 9.8%, respectively. The direct colposcopy referral rate could be reduced with 66% after additional risk-stratification with FAM19A4/miR124-2 methylation while retaining high CIN3+ sensitivity. In Chapter 4, we determined the long-term performance of the FAM19A4/miR124-2 me