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【文献翻译】人乳头瘤病毒DNA甲基化在宫颈上皮内瘤变中的应用:系统综述和Meta分析

1、背景

病毒DNA甲基化是对HPV筛查阳性女性群体进行分流的新型生物标记。这项系统综述和Meta分析旨在评估甲基化水平如何随疾病的严重程度而变化,并确定其检测宫颈高级别上皮内瘤变(CIN)的诊断试验准确性(DTA)。

Methylation of viral DNA has been proposed as a novel biomarker for triage of human papillomavirus (HPV) positive women at screening. This systematic review and meta-analysis aims to assess how methylation levels change with disease severity and to determine diagnostic test accuracy (DTA) in detecting high-grade cervical intra-epithelial neoplasia (CIN).

2、方法

我们搜索了截至2019年10月,MEDLINE、EMBASE和CENTRAL数据库中有关HPV DNA甲基化水平的研究。提取数据一式两份,必要时向作者要求原数据。所得数据应用随机效应模型和二元混合效应回归模型进行效应估计。

We performed searches in MEDLINE, EMBASE and CENTRAL from inception to October 2019. Studies were eligible if they explored HPV methylation levels in HPV positive women. Data were extracted in duplicate and requested from authors where necessary. Random-effects models and a bivariate mixed-effects binary regression model were applied to determine pooled effect estimates.

3、结果

共有44项研究符合纳入标准,涵盖8819名高危型HPV阳性的女性。高级别CIN组(≥CIN2/HSIL)HPV16 L1基因甲基化发生率显著高于低级别CIN组(≤CIN1/LSIL)(72.7%(95%CI:47.8-92.2) vs. 44.4% (95% CI: 16.0-74.1))。高级别CIN组的平均甲基化水平差异显著高于低级别CIN组(11.3% (95%CI:6.5-16.1))。与低级别CIN组相比,HPV16 L1甲基化与高级别CIN组的相关性更高,合并比值比为5.5(95%CI:3.5-8.5)(p < 0.0001)。HPV16 L1 / L2在预测CIN2+病变中的效果最佳(灵敏度77%(95%CI:63-87),特异性64%(95%CI:55-71)),曲线下面积0.73(95%CI:0.69-0.77))。

44 studies with 8819 high-risk HPV positive women were eligible. The pooled estimates for positive methylation rate in HPV16 L1 gene were higher for high-grade CIN (≥CIN2/high-grade squamous intra-epithelial lesion (HSIL) (95% confidence interval (95%CI:72.7% (47.8–92.2))) vs. low-grade CIN (≤CIN1/low-grade squamous intra-epithelial lesion (LSIL) (44.4% (95%CI:16.0–74.1))). Pooled difference in mean methylation level was significantly higher in ≥CIN2/HSIL vs. ≤CIN1/LSIL for HPV16 L1 (11.3% (95%CI:6.5–16.1)). Pooled odds ratio of HPV16 L1 methylation was 5.5 (95%CI:3.5–8.5) for ≥CIN2/HSIL vs. ≤CIN1/LSIL (p < 0.0001). HPV16 L1/L2 genes performed best in predicting CIN2 or worse (pooled sensitivity 77% (95%CI:63–87), specificity 64% (95%CI:55–71), area under the curve (0.73 (95%CI:0.69–0.77)).

4、结论

HPV甲基化水平与疾病严重程度正相关,HPV16 L1/L2基因的甲基化在诊断感染阳性的高级别CIN中具有较高的准确性。目前该结论的临床应用受到多基因型检测需求和标准化检测的限制。新一代多重HPV测序法正在开发中,未来有望实现快速、自动化、低成本的甲基化检测。

Higher HPV methylation is associated with increased disease severity, whilst HPV16 L1/L2 genes demonstrated high diagnostic accuracy to detect high-grade CIN in HPV16 positive women. Direct clinical use is limited by the need for a multi-genotype and standardised assays. Next-generation multiplex HPV sequencing assays are under development and allow potential for rapid, automated and low-cost methylation testing.

参考文献

Bowden SJ, Kalliala I, Veroniki AA,et al. The use of human papillomavirus DNA methylation in cervical intraepithelial neoplasia: A systematic review and meta-analysis[J]. EBioMedicine. 2019;50:246–259.

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撰稿 | 王建鑫

编辑 | 刘雨奇

责任编辑 | 刘雨奇

审稿 | 樊碧娆 江路

审核 | 陶霞

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声明:该文观点仅代表作者本人,搜狐号系信息发布平台,搜狐仅提供信息存储空间服务。

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