Bukowski Alexandra, Hoyo Cathrine, Graff Misa, Vielot Nadja A, Kosorok Michael R, Brewster Wendy R, Maguire Rachel L, Murphy Susan K, Nedjai Belinda, Ladoukakis Efthymios, North Kari E, Smith Jennifer S
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, NC 27695, United States.
Am J Epidemiol. 2025 Apr 8;194(4):1012-1022. doi: 10.1093/aje/kwae254.
CpG site methylation patterns have potential to improve differentiation of high-grade screening-detected cervical abnormalities. We assessed CpG differential methylation (DM) and differential variability (DV) in high-grade (CIN2+) vs low-grade (≤ CIN1) lesions. In ≤ CIN1 (n = 117) and CIN2+ (n = 31) samples, cervical sample DNA underwent testing with Illumina HumanMethylation arrays. We assessed DM and DV of CpG methylation M-values among 9 cervical cancer-associated genes. We fit CpG-specific linear models and estimated empirical Bayes standard errors and false discovery rates (FDRs). An exploratory epigenome-wide association study (EWAS) aimed to detect novel DM and DV CpGs (FDR < 0.05) and Gene Ontology (GO) term enrichment. Compared to ≤ CIN1, CIN2+ exhibited greater methylation at CCNA1 cluster 1 (M-value difference 0.24; 95% CI, 0.04-0.43) and RARB cluster 2 (0.16; 95% CI, 0.05-0.28), and lower methylation at CDH1 cluster 1 (-0.15; 95% CI, -0.26 to -0.04). CIN2+ exhibited lower variability at CDH1 cluster 2 (variation difference -0.24; 95% CI, -0.41 to -0.05) and FHIT cluster 1 (-0.30; 95% CI, -0.50 to -0.09). EWAS detected 3534 DM and 270 DV CpGs. Forty-four GO terms were enriched with DM CpGs related to transcriptional, structural, developmental, and neuronal processes. Methylation patterns may help triage screening-detected cervical abnormalities and inform US screening algorithms. This article is part of a Special Collection on Gynecological Cancer.
CpG位点甲基化模式有潜力改善高级别筛查发现的宫颈异常的鉴别。我们评估了高级别（CIN2+）与低级别（≤CIN1）病变中的CpG差异甲基化（DM）和差异变异性（DV）。在≤CIN1（n = 117）和CIN2+（n = 31）样本中，宫颈样本DNA使用Illumina HumanMethylation芯片进行检测。我们评估了9个宫颈癌相关基因中CpG甲基化M值的DM和DV。我们拟合了CpG特异性线性模型，并估计了经验贝叶斯标准误差和错误发现率（FDR）。一项探索性全基因组关联研究（EWAS）旨在检测新的DM和DV CpG（FDR < 0.05）以及基因本体（GO）术语富集情况。与≤CIN1相比，CIN2+在CCNA1簇1处表现出更高的甲基化（M值差异0.24；95%CI，0.04 - 0.43）和RARB簇2处（0.16；95%CI，0.05 - 0.28），而在CDH1簇1处甲基化较低（-0.15；95%CI，-0.26至-0.04）。CIN2+在CDH1簇2处（变异差异-0.24；95%CI，-0.41至-0.05）和FHIT簇1处（-0.30；95%CI，-0.50至-0.09）表现出较低的变异性。EWAS检测到3534个DM CpG和270个DV CpG。44个GO术语与转录、结构、发育和神经过程相关的DM CpG富集。甲基化模式可能有助于对筛查发现的宫颈异常进行分类，并为美国的筛查算法提供信息。本文是妇科癌症专题集的一部分。
