目的 评估宫颈脱落细胞配对盒家族1（paired box1,PAX1）和连接黏附分子3（junctional adhesion molecule 3,JAM3）基因甲基化作为联合生物标志物对高级别宫颈上皮内瘤变（cervical intraepithelial neoplasia,CIN）的预测效能。方法 本研究纳入2023年7月至2024年12月在长沙市妇幼保健院同时接受人乳头瘤病毒（human papillomavirus, HPV）分型、液基细胞学（thinprep cytologic test,TCT）、PAX1和JAM3基因甲基化检测和阴道镜病理检查的受试者（n=144）。采用甲基化特异性PCR对宫颈细胞中PAX1和JAM3基因的甲基化水平进行定量检测,并将HPV分型结果与两基因甲基化（二分类变量）纳入联合预测与判别分析模型。结果 在病理确诊的CIN2+（n=16）患者中,PAX1和JAM3基因甲基化阳性率分别为68.8%和56.3%,显著高于CIN1组（6.4%、6.4%）和慢性宫颈炎组（1.2%、1.2%）（P<0.001）。在高危型HPV感染者中,甲基化阳性者进展为CIN2+的优势比（OR）为6.32（95%CI：3.45~11.28）。联合模型显示,当HPV16/18阳性且任一基因甲基化阳性时,CIN2+的阳性预测值为96.9%（95%CI：82.4~94.3）,且F1值显著优于单一HPV检测（59.1%）（P<0.01）。结论 PAX1/JAM3双基因甲基化联合HPV分型检测可显著提升CIN2+的早期识别能力（AUC=0.8789）,为临床决策提供了可靠依据,并有望为细胞学结论不确定病例的分流管理提供更为明确的建议。
Abstract
Objective To evaluate the predictive power of paired box1(PAX1) and junctional adhesion molecule 3(JAM3) gene methylation as combined biomarkers for high-grade cervical intraepithelial neoplasia (CIN). Methods From July 2023 to December 2024, patients who received HPV typing testing, liquid-based cytology (TCT) testing, PAX1 and JAM3 gene methylation testing, and colposcopy pathology at Changsha Maternal and Child Health Hospital were included in this study (n=144). Methylation-specific PCR was used to quantitatively detect the methylation levels of PAX1 and JAM3 genes in cervical cells, and the combined prediction and discriminant analysis of cervical lesions were carried out by combining dichotomous variables such as HPV typing, PAX1 gene methylation and JAM3 gene methylation. Results Among the 16 pathologically confirmed CIN2 patients, the positive rates of PAX1 and JAM3 gene methylation (68.8% and 56.3%, respectively) were significantly higher than those in the CIN1 group (6.4%, 6.4%) and chronic cervicitis group (1.2%, 1.2%) (P<0.001). Among patients with high-risk HPV infection, the risk ratio for progression to CIN2 was 6.32(95% CI: 3.45-11.28) in those with positive methylation. The combined detection model showed that when HPV16/18 was positive and any gene methylation was positive, the positive predictive value of CIN2 was 96.9% (95%CI: 82.4-94.3), and the F1 value was significantly better than that of single HPV detection (59.1%) (P<0.01). Conclusion PAX1/JAM3 dual gene methylation combined with HPV typing can significantly improve the early identification ability of high-grade cervical lesions (AUC=0.8789), provide a reliable basis for molecular typing for clinical decision-making, and is especially suitable for the shunt management of cytologically uncertain cases.
关键词
宫颈上皮内瘤变 /
甲基化 /
配对盒家族1 /
连接黏附分子3
Key words
cervical intraepithelial neoplasia /
methylation /
power of paired box1 /
junctional adhesion molecule3
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基金
长沙市卫健委2023年度一般课题 “HPV分型检测与PAX1、SOX1和FAM19A4基因甲基化检测对宫颈病变筛查价值的研究”（KJ-B2023097）
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