170 Chapter 8 as detect cancers associated with vaccine and non-vaccine targeted HPV types, which is an important characteristic in light of HPV vaccination 38. Host-cell DNA methylation can be readily detected by PCR-based methods 15 in clinician-collected as well as selfcollected cervical samples 39-41, even years before cancer detection 12, 26. Furthermore, it has been demonstrated that DNA methylation can be consistently and reproducibly measured in different laboratory contexts 42. Within the group of high-grade CIN lesions (CIN2/3) host-cell DNA methylation patterns are heterogeneous. About half of CIN2 and three-quarters of CIN3 have a cancer-like methylation pattern 43. CIN2/3 lesions associated with a persistent HPV infection of extended duration (≥5 years; i.e., so-called advanced lesions), manifest significantly increased methylation levels in comparison to CIN2/3 lesions resulting from HPV infections of a more recent onset (<5 years; i.e., early or incident lesions) 16, 25, 26. These findings suggest that methylation positivity is characteristic of advanced cervical precursor lesions with a high short-term risk of progression to cancer 6. This is further supported by the fact that methylation positivity in CIN2/3 lesions appears to be associated with increased p16INK4A/Ki-67 immunoscores and low HPV-E4 expression 28, 44. In addition, the absence of methylation was found associated with a high regression rate of CIN2/3 lesions 45, 46. Altogether this corroborates the value of DNA methylation analysis as a biomarker that distinguishes advanced and likely progressive from early and likely regressive lesions. Considering the above, methylation markers hold great promise as biomarker with substantial clinical utility in cervical cancer screening. In this thesis, we have evaluated methylation analysis for triage of hrHPV-positive women using both clinician-collected and self-collected screening samples, for secondary triage of hrHPV-positive women with ASC-US/LSIL cytology on clinician-collected cervical samples, among women vaccinated for HPV. 8.1.1 TRIAGE IN HPV-BASED SCREENING AND AVENUES FOR IMPROVEMENT Cytology is commonly used as a triage strategy for HPV screen-positive women, but comes with some limitations 47, 48. The subjective nature of microscopic interpretation leads to variation in interpretation, which may impact the accuracy of the test. Cytology detects, with a moderate sensitivity, morphological cellular abnormalities associated with CIN2 lesions, CIN3 lesions and cancer, but cytology cannot clearly differentiate between CIN2/3 with a high risk of progression to cervical cancer and those with a low risk, and may miss a proportion of advanced CIN lesions and cancers. The addition of HPV16/18 genotyping to single cytology triage testing, as used in the US 49, increases the sensitivity
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