Abstract
Background: The S5-methylation test, as an alternative
classifier to cytology and HPV16/18 genotyping to triage cervical
squamous intraepithelial lesions, has not been widely validated in Asian
countries. Herein, we compared S5 methylation to HPV16/18 and cytology
to detect cervical high-grade squamous intraepithelial lesion (HSIL) in
a screening population who with either HPV infection or abnormal
cytology results or both of them, derived from a multi-central clinical
trial of 2246 Chinese participants. We matched all ≥HSIL+ cases (n=468)
with ≤LSIL controls (n=468) to analyze the effectiveness of methylation.
Methylation of S5 was quantified by pyrosequencing, blinded to cytology,
histological and initial HPV results.
Results: The S5 methylation could distinguish women with ≥HSIL+
from women with ≤LSIL at a high area under the curve (AUC) of 0.80 (95%
CI 0.74-0.85). The sensitivity of S5 methylation (at 2.85 cutoff) for
≥HSIL+ was 76.1% (95% confidence interval [CI] 71.7-79.2) was
higher than HPV16/18 sensitivity (64.9%, 95% CI 58.3-71.7, P =
0.039) or cytology (48.9%, 95% CI 42.8-53.2, P <
0.001). At this cutoff, the specificity of S5 for ≥HSIL+ was (79.9%,
95% CI 76.2-84.9), higher than HPV16/18 (44.8%, 95% CI 40.1-49.4,P < 0.001) and cytology (54.6%, 95%CI 50.7-57.9,P < 0.001). In addition, S5 methylation could provide
predictive information about progression in specific population in
follow-up period.
Conclusion: S5 methylation classifier with high sensitivity and
specificity exceeded HPV16/18 or cytology for detecting women with
≥HSIL+ in a screening Chinese population with HPV infection and/or
abnormal cytology results. Furthermore, S5 methylation is a potential
classifier for predicting progression.
Keywords: Cervical cancer; DNA methylation; S5; triage;
progression; Biomarkers