宿主DNA甲基化标志物在宫颈癌筛查中的应用:ZNF671的关键贡献与联合模型评价
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1南方医科大学药学院,广东 广州 510515 ; 2.中国药科大学工学院,江苏 南京 210009 ; 3.东部战区总医院临床药学科,江苏 南京 210002

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国家自然科学基金(22474058,61901527);江苏省“十四五”医学重点学科建设单位(JSDW202250);医院临床诊疗新技术项目(22LCZLXJS15)


Application of host DNA methylation biomarkers in cervical cancer screening:key contribution of ZNF671 and evaluation of a combined diagnostic model
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1School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515 ; 2.School of Engineering,ChinaPharmaceutical University,Nanjing 210009 ; 3.Department of Clinical Pharmacy,General Hospital of Eastern TheaterCommand,Nanjing 210002 ,China

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    摘要:

    目的:探讨宿主基因 SOX1、JAM3、ZNF671 和 DLX1 的 DNA 甲基化水平在人乳头瘤病毒(human papillomavirus, HPV)16/18阳性人群中对宫颈上皮内瘤变2级及以上(cervical intraepithelial neoplasia 2 or worse,CIN2+)的诊断价值,构建风险分层模型,为优化宫颈癌筛查策略提供依据。方法:收集2023年4月—2024年5月在东部战区总医院就诊的HPV16/18阳性女性宫颈脱落细胞样本共141例,采用基于亚硫酸氢盐转化的焦磷酸测序技术检测上述4个基因的DNA甲基化水平。根据组织病理学结果分组,比较 DNA 甲基化水平在不同病变等级(正常、低级别组织学、高级别组织学、癌症)中的差异。进一步以 CIN2+作为阳性结局,通过Logistic回归构建预测模型,评估模型在训练集和测试集中的诊断效能。结果:4个宿主基因的DNA 甲基化水平均随病变程度加重而升高,CIN2+组显著高于CIN1-组(P < 0.001),均具有较高的诊断特异性。ZNF671在单基因分析中表现最佳,其曲线下面积(area under the curve,AUC)为0.741,联合SOX1构建的模型在训练集与测试集中的AUC分别为0.801和0.745,特异性可达87%,优于任意单一基因。结论:SOX1、JAM3、ZNF671和DLX1的DNA甲基化水平与宫颈病变严重程度密切相关,具有潜在的分流价值。尤其是在HPV16/18阳性人群中,ZNF671表现出良好的CIN2+预测性能,可作为识别癌前病变的辅助决策工具;联合SOX1构建的模型可进一步提高诊断效能。

    Abstract:

    Objective:To investigate the diagnostic value of DNA methylation levels of the host genes SOX1,JAM3,ZNF671,and DLX1 for cervical intraepithelial neoplasia grade 2 or worse(CIN2+)in women positive for human papillomavirus(HPV)16/18,and to construct a risk stratification model to optimize cervical cancer screening strategies. Methods:Cervical exfoliated cell samples were collected from HPV16/18-positive women attending the General Hospital of Eastern Theater Command between April 2023 and May 2024. DNA methylation levels of the four host genes were measured using bisulfite-converted pyrosequencing. Samples were grouped according to histopathological diagnosis(normal,low - grade histology,high - grade histology,cancer),and intergroup methylation differences were compared. Logistic regression was used to construct a predictive model for CIN2+,and its diagnostic performance was assessed in both training and testing datasets. Results:The methylation levels of all four host genes increased progressively with lesion severity and were significantly higher in the CIN2 + group than in the CIN1- group(P < 0.001),demonstrating high diagnostic specificity. Among them,ZNF671 exhibited the best performance as a single biomarker,with an area under the curve(AUC)of 0.741. The combined model of ZNF671 and SOX1 achieved AUCs of 0.801 and 0.745 in the training and testing sets,respectively,with a specificity up to 87%,outperforming any individual gene. Conclusion:The DNA methylation levels of SOX1,JAM3,ZNF671,and DLX1 are closely associated with the severity of cervical lesions and exhibit potential value for triage. In particular,ZNF671 shows strong predictive performance for CIN2 + in HPV16/18 - positive women,and may serve as an auxiliary biomarker for identifying precancerous lesions. The combined model incorporating SOX1 further improves diagnostic accuracy.

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王韫格,刘云龙,王玲菲,户文静,周国华,武海萍.宿主DNA甲基化标志物在宫颈癌筛查中的应用:ZNF671的关键贡献与联合模型评价[J].南京医科大学学报(自然科学版),2025,(9):1242-1250

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  • 收稿日期:2025-05-05
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  • 在线发布日期: 2025-09-11
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