English summary 197 9 Cervical cancer screening is an essential component of preventative health care. Considering the superior performance of HPV testing over cytology, many countries have either switched or are in the process of transitioning toward HPV-based screening. HPV testing has the additional advantage that it can be performed on self-collected samples with similar accuracy. In the Netherlands, a nationwide primary HPV-based screening program was implemented in 2017, including the possibility to participate by self-sampling. However, primary HPV testing has a lower specificity compared to cytology, necessitating a second test, known as a triage test, to identify hrHPV-positive women with clinically relevant disease. Despite the acceptable clinical performance of current triage methods, such as cytology and HPV16/18 genotyping, there is a need for alternative techniques applicable to both clinician-collected and self-collected screening samples. This is especially important in light of current challenges such as over-referral and overtreatment, implementation of self-sampling as a primary screening tool, a call for automation, and the inclusion of vaccinated women in the screening programs. This thesis investigates the potential use of DNA methylation markers as a molecular tool in HPV-based cervical cancer screening. Chapter 1 provides a general introduction, describing the aetiology of cervical cancer, HPV and its role in cervical carcinogenesis, strategies for cervical cancer prevention and introduces host-cell DNA methylation as a potential molecular biomarker for cervical cancer and its precursors. Hypermethylation of promoter regions in host-cell genes is an essential factor in the progression from CIN to cervical cancer. Detection of host-cell DNA methylation may be helpful in identifying cervical cancer and advanced CIN lesions with a high-risk or short-term progression to cervical cancer. Chapter 2 describes the triage performance of six host-cell DNA methylation markers (i.e., ASCL1, LHX8, ST6GALNAC5, GHSR, SST and ZIC1) for detection of CIN3 and cervical cancer in a cross-sectional series of hrHPV-positive clinician-collected cervical samples. The study included samples from controls (≤CIN1; n = 352) and women diagnosed with CIN3 (n = 175) or cervical cancer (n = 50). Methylation levels of all six markers significantly increased with disease severity. Three markers (ASCL1, LHX8 and ZIC1) demonstrated an area under the curve (AUC) > 0.800 in receiver operating characteristic curves (ROC) following leave-one-out cross-validation. The ASCL1/LHX8 bi-marker panel achieved the highest AUC (0.882) and successfully identified 83.4% of CIN3 cases and all cervical cancers with a specificity of 82.4%. Our study demonstrated that all six methylation markers exhibited comparable high performance for triaging hrHPV-positive women
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