Methylation biomarkers in non-regressive cervical intraepithelial neoplasia grade 2 lesions: an epigenome wide association study
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background
DNA methylation has been proposed as a predictive biomarker. Cervical intraepithelial neoplasia grade 2 (CIN2) was historically the cut-off for surgical treatment, however it is increasingly managed with active surveillance, while there is currently no accurate way to predict which lesions will regress.
Methods
We performed the first Illumina 850k array on DNA from serial liquid based-cytology cervical samples from young women with CIN2 that were managed with active surveillance (n = 58). Linear regression identified differentially-methylated sites at baseline distinguishing regressors from non-regressors with persistent or progressive disease at 24-months. Associations with imminent regression and histological change were also evaluated.
Results
We identified three novel differentially-methylated sites; cg12754953 (ALDH9A1) methylation was significantly increased at baseline in non-regressors, cg18887759 (MED25) methylation was significantly lower in samples from women who regressed within the subsequent 12 months, and cg13556949 (TULP2) methylation increased over time between baseline and 12-months of follow-up in non-regressors as compared to regressors.
Conclusion
Methylation could help guide treatment decisions in women considering active surveillance of CIN2 lesions. ALDH9A1, MED25 and TULP2 may be implicated as genes with possible roles in host response to viral mechanisms. Larger prospective studies are needed to validate these findings.
DNA methylation has been proposed as a predictive biomarker. Cervical intraepithelial neoplasia grade 2 (CIN2) was historically the cut-off for surgical treatment, however it is increasingly managed with active surveillance, while there is currently no accurate way to predict which lesions will regress.
Methods
We performed the first Illumina 850k array on DNA from serial liquid based-cytology cervical samples from young women with CIN2 that were managed with active surveillance (n = 58). Linear regression identified differentially-methylated sites at baseline distinguishing regressors from non-regressors with persistent or progressive disease at 24-months. Associations with imminent regression and histological change were also evaluated.
Results
We identified three novel differentially-methylated sites; cg12754953 (ALDH9A1) methylation was significantly increased at baseline in non-regressors, cg18887759 (MED25) methylation was significantly lower in samples from women who regressed within the subsequent 12 months, and cg13556949 (TULP2) methylation increased over time between baseline and 12-months of follow-up in non-regressors as compared to regressors.
Conclusion
Methylation could help guide treatment decisions in women considering active surveillance of CIN2 lesions. ALDH9A1, MED25 and TULP2 may be implicated as genes with possible roles in host response to viral mechanisms. Larger prospective studies are needed to validate these findings.
Date Issued
2026-07-05
Date Acceptance
2026-03-10
Citation
British Journal of Cancer, 2026, 135 (1), pp.118-126
ISSN
0007-0920
Publisher
Springer Science and Business Media LLC
Start Page
118
End Page
126
Journal / Book Title
British Journal of Cancer
Volume
135
Issue
1
Copyright Statement
© The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41965938
PII: 10.1038/s41416-026-03391-4
Subjects
Adolescent
Female
Humans
Young Adult
Biomarkers, Tumor
Cervix Uteri
Disease Progression
DNA Methylation
Epigenome
Follow-Up Studies
Genome-Wide Association Study
Neoplasm Grading
Uterine Cervical Dysplasia
Aldehyde Dehydrogenase
Mediator Complex
Eye Proteins
Watchful Waiting
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2026-04-11