DNA methylation for the triage of HPV-positive clinician-collected cervical samples 79 3 to the screening population level. Many studies evaluating host-cell DNA methylation markers so far have been performed in referral populations or case-control settings. Histology endpoints were retrieved from the nationwide network and registry of histo- and cytopathology (PALGA), which covers all pathology labs in the Netherlands. The use of the original pathology diagnoses represents routine setting, which underscores the value of our findings for potential future implementation in screening practice. The use of revision diagnoses in the analyses did not change our conclusions, verifying the good performance of methylation analysis as triage tool. A limitation of our study is that our results could possibly be biased because no histology endpoint was available in a number of hrHPV-positive women. This could potentially lead to an underestimation of CIN3+. It is not likely that this would have a marked influence on the outcome given that of all women without a histological endpoint, the far majority was documented with two times normal cytology. In conclusion, this study shows that the individual markers ASCL1, LHX8, ST6GALNAC5, GHSR, ZIC1, SST and the bi-marker panel ASCL1/LHX8 have clinical utility for the detection of CIN3+ in hrHPV-positive women at screening. ASCL1/LHX8 methylation test on cervical screening samples has potential as triage test to identify hrHPV-infected women in need of colposcopy.
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