Assessment of six markers for cervical (pre)cancer detection 55 2 SUMMARY POINTS • ASCL1, LHX8, ST6GALNAC5, GHSR, SST and ZIC1 have been discovered by genome-wide approaches as novel DNA methylation markers for CIN3 and cervical cancer detection. • This study was designed to assess and compare the triage performance of these methylation markerswfor the application in HPV-based cervical screening. • A series of HPV-positive cervical samples was tested for methylation of ASCL1, LHX8, ST6GALNAC5, ZIC1, GHSR, SST and ZIC1 and marker performance was compared. • Methylation levels of all six markers in cervical samples increased significantly with underlying disease severity. • The performance for the detection of CIN3 was comparable between markers with cross-validated AUCs > 0.800 for ASCL1, LHX8, and ZIC1. • The bi-marker panel consisting of ASCL1 and LHX8 resulted in the highest crossvalidated AUC of 0.882 for the detection of CIN3. • The bi-marker panel ASCL1/LHX8 detected all cervical cancers independent of HPV genotype or histotype. • Performance of ASCL1 and LHX8 on cervical samples in this study was comparable with earlier results on HPV-positive self-collected samples. • This study confirms the diagnostic potential of six recently identified methylation markers with an equivalent and complementary high diagnostic performance for CIN3+ on HPV-positive cervical samples. • The ASCL1/LHX8 marker panel holds promise for full molecular cervical screening compatible with both clinician-collected and self-collected samples.
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