176 Chapter 8 ASCL1/LHX8 methylation improved the NPV while maintaining a PPV of > 20%, it still did not reach the 98% threshold. Therefore, the implementation of ASCL1/LHX8 methylation, possibly combined with genotyping, as a single triage moment does not seem acceptable and repeat testing is needed. A similar approach is used in the current Dutch screening programme where women with normal cytology or HPV16/18-negative ASC-US/LSIL are repeated by cytology after one year. For women who participate by self-sampling, a triage strategy could involve recalling those who screen positive for HPV but negative for methylation on their self-collected sample for a clinician-collected cervical sample, either for methylation analysis or cytology after 12 months 8, 16, 64, 72, 73. Figure 8.2B presents a proposal strategy for full molecular cervical cancer screening, for both clinician-collected cervical samples and self-collected samples, using methylation analysis as a triage test for hrHPV-positive women. Future research could focus on the exploration of integrating additional complementary biomarkers and the refinement of repeat testing strategies. 8.1.2 DNA METHYLATION IN COMBINATION WITH CYTOLOGY AND HPV GENOTYPING AS SECONDARY TRIAGE IN HPV-BASED SCREENING Triage of hrHPV-positive women with low-grade cytology (ASC-US/LSIL) by methylation analysis gained interest as an approach for reducing the number of women referred for colposcopy. An extensively evaluated host-cell methylation marker panel to date is FAM19A4/miR124-2 30, 78. The methylation of FAM19A4 and miR124-2, alone or combined, assessed in several studies, reported sensitivities, ranging from 67% to 78%, and specificities, ranging from 61% to 91% 31, 79-82. Retrospective longitudinal evaluation showed that hrHPV-positive but FAM19A4/miR124-2 methylation-negative women had a 14-year CIN3+ risk equal to that of negative cytology triage outcome, and they had a lower risk for cervical cancer 30, 78. Evaluating the long-term performance of hostcell DNA methylation in hrHPV-positive women is crucial for defining the effectiveness of surveillance strategies. Previous retrospective historical cohort analyses show that additional risk-stratification of hrHPV-positive women with low-grade cytological abnormalities by FAM19A4/miR124-2 methylation could substantially reduce the direct colposcopy referral rate (60-66%), while retaining high clinical CIN3+ sensitivity (> 70%) 83, 84. A strategy with HPV16/18 genotyping as an additional triage test in hrHPV-positive women would reduce the colposcopy referrals with 56.8% 83. Comparable results have been reported for PAX1 and ZNF582 37, 85, 86. This indicates that methylation analysis can offer at least similar benefits to HPV16/18 genotyping in terms of reducing unnecessary
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