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

Abstract

Background Epigenetic mechanisms are hypothesized to contribute substantially to the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer, although empirical data are limited. Methods Women (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. Results Of 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). Conclusions While 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.

Hypomethylation at H19DMR in penile squamous cell carcinoma is not related to HPV infection

“…Furthermore, the hypomethylation observed in our current study seems to be independent of HPV infection, given the similar methylation levels between the HPV+ and HPV- samples considering either p16 INK4a and hrHPV markers. Similarly, H19DMR hypomethylation was not associated with HPV infection in invasive cervical cancer (ICC) [ 45 ] and cervical intraepithelial neoplasia (CIN) [ 46 ]. We previously showed that the 5mC Global DNA methylation mark is increased in penile SCC and is not influenced by HPV infection [ 3 ].…”

Detection of Host Cell Gene/HPV DNA Methylation Markers: A Promising Triage Approach for Cervical Cancer

“…A meta-analysis has validated that increased methylation at the promoters of several genes (CADM1, MAL, miR-124-2, FAM19A4, POU4F3, EPB41L3, PAX1, and SOX1) and HPV16 L1/L2 correlates to CIN lesion, with good performance in the triage of advanced CIN (20). While PEG3 methylation is associated with advanced CIN lesions (98), its efficacy for screening CIN/ICC needs to be further investigated. Because 3q gain is common in ICC, methylation of three genes (GHSR, SST, and ZIC1) is associated with 3q gain as well as the severity of CIN (99).…”