甲基化水平可能与宫颈癌前病变进展风险相关，并可作为预测宫颈癌前病变进展风险的标志物。我们在异常筛查测试后进行了一项全表观基因组关联研究 (EWAS)，研究 CpG 甲基化与高级宫颈上皮内瘤变 (CIN2 ) 的进展。对 289 名具有正常或 CIN1 登记组织学的阴道镜检查患者的前瞻性美国队列进行了评估。使用 Illumina HumanMmethylation 450K (n = 76) 或 EPIC 850K (n = 213) 阵列分析基线宫颈样本 DNA。参与者按照提供者建议的时间间隔返回，并通过医疗记录进行长达 5 年的随访。我们评估了 9 个宫颈癌相关基因的连续 CpG M 值和进展至 CIN2 的时间。我们使用调整后的区间删失威布尔加速失效时间模型估计了 CpG 特定的时间事件比 (TTER) 和风险比。我们还进行了一项探索性 EWAS，以识别错误发现率 (FDR)<0.05 的新型 CpG。入组时，中位年龄为 29.2 岁； 64.0% 为高危 HPV 阳性，54.3% 为非白人。在随访期间（中位 24.4 个月），15 名参与者进展为 CIN2。对于 CADM1 cg03505501 (TTER = 0.28; 95%CI 0.12, 0.63; FDR = 0.03) 和 RARB Cluster 1 (TTER = 0.46; 95% CI 0.29, 0.71; FDR)，更高的甲基化水平与更短的 CIN2 时间相关 = 0.01）。有证据表明 DAPK1 cg14286732、PAX1 cg07213060 和 PAX1 Cluster 1 存在类似趋势。EWAS 检测到 336 个新的进展相关 CpG，包括位于与 FGF22、TOX、COL18A1、GPM6A、XAB2、TIMP2、GSPT1 基因相关的 CpG 岛中的 CpG 、NR4A2 和 APBB1IP。使用前瞻性事件时间数据，我们检测了 CADM1-、DAPK1-、PAX1- 和 RARB 相关 CpG 与宫颈疾病进展之间的关联，并确定了新的与进展相关的 CpG。甲基化水平新的 CpG 位点可能有助于识别具有较高进展为 CIN2 风险的组织学类型≤CIN1 的个体，并为基于风险的宫颈癌筛查指南提供信息。© 2023。作者。

Methylation levels may be associated with and serve as markers to predict risk of progression of precancerous cervical lesions. We conducted an epigenome-wide association study (EWAS) of CpG methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2 +) following an abnormal screening test.A prospective US cohort of 289 colposcopy patients with normal or CIN1 enrollment histology was assessed. Baseline cervical sample DNA was analyzed using Illumina HumanMethylation 450K (n = 76) or EPIC 850K (n = 213) arrays. Participants returned at provider-recommended intervals and were followed up to 5 years via medical records. We assessed continuous CpG M values for 9 cervical cancer-associated genes and time-to-progression to CIN2+. We estimated CpG-specific time-to-event ratios (TTER) and hazard ratios using adjusted, interval-censored Weibull accelerated failure time models. We also conducted an exploratory EWAS to identify novel CpGs with false discovery rate (FDR) < 0.05.At enrollment, median age was 29.2 years; 64.0% were high-risk HPV-positive, and 54.3% were non-white. During follow-up (median 24.4 months), 15 participants progressed to CIN2+. Greater methylation levels were associated with a shorter time-to-CIN2+ for CADM1 cg03505501 (TTER = 0.28; 95%CI 0.12, 0.63; FDR = 0.03) and RARB Cluster 1 (TTER = 0.46; 95% CI 0.29, 0.71; FDR = 0.01). There was evidence of similar trends for DAPK1 cg14286732, PAX1 cg07213060, and PAX1 Cluster 1. The EWAS detected 336 novel progression-associated CpGs, including those located in CpG islands associated with genes FGF22, TOX, COL18A1, GPM6A, XAB2, TIMP2, GSPT1, NR4A2, and APBB1IP.Using prospective time-to-event data, we detected associations between CADM1-, DAPK1-, PAX1-, and RARB-related CpGs and cervical disease progression, and we identified novel progression-associated CpGs.Methylation levels at novel CpG sites may help identify individuals with ≤CIN1 histology at higher risk of progression to CIN2+ and inform risk-based cervical cancer screening guidelines.© 2023. The Author(s).