ZNF671 methylation test in cervical scrapings for cervical intraepithelial neoplasia grade 3 and cervical cancer detection

Abstract

Effective triage of high-risk human papillomavirus (hrHPV)+ women is warranted to avoid unnecessary referral and overtreatment. Molecular triage tests have recently begun to impact cervical intraepithelial neoplasia grade 3 (CIN3) or cervical cancer (CC), termed CIN3+, detection. We find that zinc finger protein 671 methylation (ZNF671^m) test has superior performance for CIN3+ detection in all single molecular triage tests, including HPV16/18 genotyping, paired box gene 1 methylation (PAX1^m), and ZNF671^m, in the training set. Using ZNF671^m test instead of Thinprep cytologic test (TCT) as a single triage strategy or as a combined triage strategy with HPV16/18 genotyping has achieved comparable sensitivity but higher specificity for CIN3+ detection among 391 hrHPV+ women in the validation set. Little attention has been paid to the women with hrHPV- status but detected CIN3+. We find that the CIN3+ risk after a negative result could be reduced further by triage using ZNF671^m in hrHPV- patients.

Keywords: ASCUS; CIN3+ detection; DNA methylation; Thinprep cytologic test; ZNF671; cervical cancer; hrHPV.

Graphical abstract

Figure 1

Study protocol ^m, methylation detected by qMSP; ^pyro, methylation detected by bisulfite pyrosequencing.

Figure 2

Pre- and post-test CIN3+ risk after applying different triage strategies in hrHPV+ women or in hrHPV− women (A) Pre- and post-test CIN3+ risk by single triage algorithms in hrHPV+ women (n = 391). (B) Pre- and post-test CIN3+ risk by combined triage algorithms in hrHPV+ women (n = 391). (C) Pre- and post-test CIN3+ risk after triage in hrHPV− women (n = 242). CIN3+ risk: red area, >10%; flesh pink area, between 10% and 5.2%; pink area, between 5.2% and 2.6%; light green area, between 2.6% and 1%; dark green area, <1%. Benchmarks are defined at risk levels of 1% (safe) and 10% (high risk) (applied in Europe) and 2.6% (safe) and 5.2% (high-risk) (applied in the United States) for CIN3+. High-risk zone: red area; medium risk: flesh pink area and pink area; safe zone: light green area and dark green area.