Department of Epidemiology, University of North Carolina at Chapel Hill, NC, 27599.
Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA, 27599.
Int J Cancer. 2018 Aug 1;143(3):552-560. doi: 10.1002/ijc.31350. Epub 2018 Mar 30.
The role of host epigenetic mechanisms in the natural history of low-grade cervical intraepithelial neoplasia (CIN1) is not well characterized. We explored differential methylation of imprinted gene regulatory regions as predictors of the risk of CIN1 regression. A total of 164 patients with CIN1 were recruited from 10 Duke University clinics for the CIN Cohort Study. Participants had colposcopies at enrollment and up to five follow-up visits over 3 years. DNA was extracted from exfoliated cervical cells for methylation quantitation at CpG (cytosine-phosphate-guanine) sites and human papillomavirus (HPV) genotyping. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression to quantify the effect of methylation on CIN1 regression over two consecutive visits, compared to non-regression (persistent CIN1; progression to CIN2+; or CIN1 regression at a single time-point), adjusting for age, race, high-risk HPV (hrHPV), parity, oral contraceptive and smoking status. Median participant age was 26.6 years (range: 21.0-64.4 years), 39% were African-American, and 11% were current smokers. Most participants were hrHPV-positive at enrollment (80.5%). Over one-third of cases regressed (n = 53, 35.1%). Median time-to-regression was 12.6 months (range: 4.5-24.0 months). Probability of CIN1 regression was negatively correlated with methylation at IGF2AS CpG 5 (HR = 0.41; 95% CI = 0.23-0.77) and PEG10 DMR (HR = 0.80; 95% CI = 0.65-0.98). Altered methylation of imprinted IGF2AS and PEG10 DMRs may play a role in the natural history of CIN1. If confirmed in larger studies, further research on imprinted gene DMR methylation is warranted to determine its efficacy as a biomarker for cervical cancer screening.
宿主表观遗传机制在低度宫颈上皮内瘤变（CIN1）自然史中的作用尚不清楚。我们探讨了印迹基因调控区域的差异甲基化作为 CIN1 消退风险的预测因子。共有 164 名 CIN1 患者从杜克大学的 10 个诊所招募到 CIN 队列研究中。参与者在入组时进行了阴道镜检查，并在 3 年内进行了多达 5 次随访。从宫颈细胞脱落物中提取 DNA，用于 CpG（胞嘧啶-磷酸-鸟嘌呤）位点的甲基化定量和人乳头瘤病毒（HPV）基因分型。使用 Cox 回归估计风险比（HR）和 95%置信区间（CI），以量化与非消退（持续 CIN1；进展为 CIN2+；或 CIN1 在单个时间点消退）相比，甲基化对连续两次就诊中 CIN1 消退的影响，调整年龄、种族、高危 HPV（hrHPV）、产次、口服避孕药和吸烟状态。中位参与者年龄为 26.6 岁（范围：21.0-64.4 岁），39%为非裔美国人，11%为当前吸烟者。大多数参与者在入组时为 hrHPV 阳性（80.5%）。超过三分之一的病例消退（n=53，35.1%）。中位消退时间为 12.6 个月（范围：4.5-24.0 个月）。CIN1 消退的可能性与 IGF2AS CpG5（HR=0.41；95%CI=0.23-0.77）和 PEG10 DMR（HR=0.80；95%CI=0.65-0.98）的甲基化呈负相关。印迹 IGF2AS 和 PEG10 DMR 的甲基化改变可能在 CIN1 的自然史中起作用。如果在更大的研究中得到证实，进一步研究印迹基因 DMR 甲基化是值得的，以确定其作为宫颈癌筛查生物标志物的功效。
