从基于人群的宫颈癌筛查计划中的 hrHPV 阳性自样本中确定甲基化面板作为检测 CIN3+ 的替代分流方法。

IF 5.7 2区 医学 Q1 Medicine Clinical Epigenetics Pub Date : 2023-06-15 DOI:10.1186/s13148-023-01517-6
J de Waard, A Bhattacharya, M T de Boer, B M van Hemel, M D Esajas, K M Vermeulen, G H de Bock, E Schuuring, G B A Wisman
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引用次数: 0

摘要

背景:荷兰人口宫颈癌筛查计划(PBS)包括高危人乳头瘤病毒(hrHPV)初筛检测和细胞学分流检测。除了由全科医生(GP)进行宫颈刮片检查外,妇女还可自行取样,以提高参与率。由于无法对自我取样材料进行细胞学检查,因此需要由全科医生收集 hrHPV 阳性妇女的宫颈样本。本研究旨在设计一个甲基化标记小组,以检测荷兰 PBS 中 hrHPV 阳性自采样本中的 CIN3 或更差(CIN3+),作为细胞学检查的替代分流检测方法:方法:从文献中筛选出 15 个对 CIN3+ 具有高灵敏度和特异性的宿主 DNA 甲基化标记,并使用定量甲基化特异性 PCR(QMSP)对来自 208 名 CIN2 或更低的 hrHPV 阳性自身样本的 DNA 进行了分析(结果:15 个宿主 DNA 甲基化标记对 CIN3+ 具有高灵敏度和特异性):对 15 个单独甲基化标记的 QMSP 分析显示,DNA 甲基化水平在 0.5 之间。)决策树模型显示,最佳和最稳健的面板包含 ANKRD18CP、LHX8 和 EPB41L3,训练集的 AUC 为 0.83,测试集的 AUC 为 0.84。检测 CIN3+ 的灵敏度在训练集中为 82%,在测试集中为 84%,特异性分别为 74% 和 71%。此外,所有癌症病例(5 例)均被识别出来:结论:ANKRD18CP、LHX8 和 EPB41L3 的组合在真实的自采样材料中显示出良好的诊断性能。在荷兰 PBS 计划中,该检测板可替代使用自采样的妇女的细胞学检测,避免了 hrHPV 阳性自采样检测后的额外全科医生就诊。
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Identification of a methylation panel as an alternative triage to detect CIN3+ in hrHPV-positive self-samples from the population-based cervical cancer screening programme.

Background: The Dutch population-based cervical cancer screening programme (PBS) consists of primary high-risk human papilloma virus (hrHPV) testing with cytology as triage test. In addition to cervical scraping by a general practitioner (GP), women are offered self-sampling to increase participation. Because cytological examination on self-sampled material is not feasible, collection of cervical samples from hrHPV-positive women by a GP is required. This study aims to design a methylation marker panel to detect CIN3 or worse (CIN3+) in hrHPV-positive self-samples from the Dutch PBS as an alternative triage test for cytology.

Methods: Fifteen individual host DNA methylation markers with high sensitivity and specificity for CIN3+ were selected from literature and analysed using quantitative methylation-specific PCR (QMSP) on DNA from hrHPV-positive self-samples from 208 women with CIN2 or less (< CIN2) and 96 women with CIN3+. Diagnostic performance was determined by area under the curve (AUC) of receiver operating characteristic (ROC) analysis. Self-samples were divided into a train and test set. Hierarchical clustering analysis to identify input methylation markers, followed by model-based recursive partitioning and robustness analysis to construct a predictive model, was applied to design the best marker panel.

Results: QMSP analysis of the 15 individual methylation markers showed discriminative DNA methylation levels between < CIN2 and CIN3+ for all markers (p < 0.05). The diagnostic performance analysis for CIN3+ showed an AUC of ≥ 0.7 (p < 0.001) for nine markers. Hierarchical clustering analysis resulted in seven clusters with methylation markers with similar methylation patterns (Spearman correlation> 0.5). Decision tree modeling revealed the best and most robust panel to contain ANKRD18CP, LHX8 and EPB41L3 with an AUC of 0.83 in the training set and 0.84 in the test set. Sensitivity to detect CIN3+ was 82% in the training set and 84% in the test set, with a specificity of 74% and 71%, respectively. Furthermore, all cancer cases (n = 5) were identified.

Conclusion: The combination of ANKRD18CP, LHX8 and EPB41L3 revealed good diagnostic performance in real-life self-sampled material. This panel shows clinical applicability to replace cytology in women using self-sampling in the Dutch PBS programme and avoids the extra GP visit after a hrHPV-positive self-sampling test.

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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
期刊最新文献
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