Methylation biomarkers in non-regressive cervical intraepithelial neoplasia grade 2 lesions: an epigenome wide association study

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.