ASCL1 and LHX8 methylation in HPV-positive self-collected samples 91 4 INTRODUCTION Primary screening for high-risk (hr) human papillomavirus (HPV) provides better protection against cervical intraepithelial neoplasia grade 3 (CIN3) and cervical cancer (CIN3+) than cervical cytology 1, 2. Consequently, many cervical cancer screening programs nowadays include primary HPV testing. The Netherlands converted to HPV testing with cytology triage in 2017. HPV testing as a primary screening tool offers the opportunity to explore self-sampling as an alternative to clinician sampling for all women invited for screening. Self-sampling is a promising strategy to overcome barriers to cervical cancer screening and to increase coverage 3. Furthermore, self-sampling has gained increased interest during the COVID-19 pandemic 4. HPV self-sampling has demonstrated similar clinical accuracy as HPV testing on clinician-collected samples 5, 6. However, cytology triage currently requires recalling women who are hrHPV-positive on a self-collected sample for clinician-based sampling. Emerging evidence has demonstrated that detection of host-cell DNA methylation represents a promising alternative triage strategy 7, 8, with the potential of being directly applicable to self-collected screening samples. Aberrant DNA methylation is an epigenetic hallmark of cancer 9. DNA hypermethylation of tumour suppressor genes is an early and frequent molecular alteration in cervical carcinogenesis 10. DNA methylation levels of various host-cell genes have been reported to increase with CIN grade and are highest in cervical cancer 8. Recent studies have shown that virtually all cervical cancers are methylation positive 11, 12. Within the group of CIN2/3 lesions, it was found that lesions associated with a long-lasting (≥5 years) hrHPV infection have significantly higher methylation levels compared with lesions with a more recently acquired (<5 years) hrHPV infection 13, 14. Based on these findings, it is assumed that methylation positivity of specific host-cell genes is characteristic of CIN lesions with a high short-term risk of cancer, referred to as advanced CIN2/3 lesions 15. In addition, absence of methylation was found to be associated with regression of CIN2/3 lesions 16, 17. In view of the above, DNA methylation biomarkers have emerged as promising triage tool for HPV-based cervical cancer screening to specifically detect advanced CIN lesions in need of treatment. A meta-analysis on the triage performance of various methylation markers in hrHPV-positive clinician-collected cervical samples reported a pooled sensitivity for CIN3+ of 71.1% (95% CI 65.7-76.0%) at a predefined specificity of 70% 8. There is a growing number of studies reporting on DNA methylation analysis for the direct triage on hrHPV-positive self-collected samples 18-23. However, variable diagnostic performances have been reported, which highlights the need for further investigation.
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