Association between PEG3 DNA methylation and high-grade cervical intraepithelial neoplasia

Claire Bosire,Francine Overcash,Jennifer S Smith,Adriana C Vidal,David Skaar,Rex Bentley,Anne Ford,Margaret Gradison,Fidel Valea,Zhiqing Huang,Cathrine Hoyo,Susan K Murphy,Kimberly S H Yarnall,Dereje Jima

doi:10.1186/s13027-021-00382-3

Abstract

BackgroundEpigenetic mechanisms are hypothesized to contribute substantially to the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer, although empirical data are limited.MethodsWomen (n = 419) were enrolled at colposcopic evaluation at Duke Medical Center in Durham, North Carolina. Human papillomavirus (HPV) was genotyped by HPV linear array and CIN grade was ascertained by biopsy pathologic review. DNA methylation was measured at differentially methylated regions (DMRs) regulating genomic imprinting of the IGF2/H19, IGF2AS, MESTIT1/MEST, MEG3, PLAGL1/HYMAI, KvDMR and PEG10, PEG3 imprinted domains, using Sequenom-EpiTYPER assays. Logistic regression models were used to evaluate the associations between HPV infection, DMR methylation and CIN risk overall and by race.ResultsOf the 419 participants, 20 had CIN3+, 52 had CIN2, and 347 had ≤ CIN1 (CIN1 and negative histology). The median participant age was 28.6 (IQR:11.6) and 40% were African American. Overall, we found no statistically significant association between altered methylation in selected DMRs and CIN2+ compared to ≤CIN1. Similarly, there was no significant association between DMR methylation and CIN3+ compared to ≤CIN2. Restricting the outcome to CIN2+ cases that were HR-HPV positive and p16 staining positive, we found a significant association with PEG3 DMR methylation (OR: 1.56 95% CI: 1.03–2.36).ConclusionsWhile the small number of high-grade CIN cases limit inferences, our findings suggest an association between altered DNA methylation at regulatory regions of PEG3 and high grade CIN in high-risk HPV positive cases.

Highlights

Epigenetic mechanisms are hypothesized to contribute substantially to the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer, empirical data are limited
We previously reported that aberrant methylation at Differentially methylated region (DMR) that regulate the expression of imprinted genes including Insulin-like Growth Factor 2, Paternally Expressed Gene 1/Mesoderm-Specific Transcript (PEG1/MEST) and Paternally Expressed Gene 3 (PEG3) were independent predictors of CIN2/3 and invasive cervical cancer (ICC) in a cross-sectional study of Tanzanian women with CIN and ICC [15, 16]
We reported a negative association between CIN1 regression and methylation at Insulin-Like Growth Factor 2, Antisense (IGF2AS) and Paternally Expressed Gene 10 (PEG10) DMR in a study of CIN1 cases drawn from the Duke University Cervical Intraepithelial Neoplasia Cohort Study (CINCS) [17]

Summary

Introduction

Epigenetic mechanisms are hypothesized to contribute substantially to the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer, empirical data are limited. Screening and treatment of cervical intraepithelial neoplasia (CIN) has significantly reduced invasive cervical cancer (ICC) incidence and mortality [1]. Current cervical cancer screening guidelines include cytology-based screening, with the addition of high-risk human papillomavirus (HPV) testing in women 30 years and older to increase sensitivity for the detection of high grade CIN (CIN2+) or cancer [4]. Cytology-based tests have relatively low single-use sensitivity for detecting CIN2+ which could delay appropriate treatment [5, 6]. Besides a strategy to triage HPV positive women, molecular markers that can improve the prediction of progression of CIN to ICC are needed. It is important to identify molecular markers to triage HPV positive women using self-sampling devices in the absence of cervical cytology

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Discussion

Conclusion