CADM1、MAL 和 miR124 启动子甲基化作为转化型宫颈上皮内病变的生物标志物。
CADM1, MAL, and miR124 Promoter Methylation as Biomarkers of Transforming Cervical Intrapithelial Lesions.
机构信息
Institute Clinic of Gynecology, Obstetrics, and Neonatology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain.
Department of Pathology, Hospital Clínic, University of Barcelona, 08036 Barcelona, Spain.
出版信息
Int J Mol Sci. 2019 May 7;20(9):2262. doi: 10.3390/ijms20092262.
BACKGROUND
Squamous intraepithelial lesions/cervical intraepithelial neoplasias (SIL/CIN) are high-risk human papilloma virus (hrHPV)-related lesions which are considered as high grade (HSIL/CIN2-3) or low grade (LSIL/CIN1) lesions according to their risk of progression to cervical cancer (CC). Most HSIL/CIN2-3 are considered as transforming hrHPV infections, so truly CC precursors, although some clear spontaneously. hrHPV testing has a high sensitivity for the detection of HSIL/CIN2-3 but a relatively low specificity for identifying transforming lesions. We aimed to determine whether the combination of CADM1, MAL and miR124 promoter methylation status assessed in histological samples can be used as a biomarker in the identification of transforming HSIL/CIN lesions.
DESIGN
131 cervical biopsies, including 8 cases with no lesion and a negative hrHPV test result (control group), 19 low-grade (L)SIL/CIN1, 30 HSIL/CIN2, 60 HSIL/CIN3, and 14 CC were prospectively collected. hrHPV was detected and genotyped using the polymerase chain reaction (PCR)-based technique SPF10 HPV LIPA. A multiplex quantitative methylation-specific PCR (qMSP) was used to identify the methylation status of the CADM1, MAL, and miR124 promoter genes.
RESULTS
Significantly higher methylation levels of CADM1, MAL and miR-124 were found in HSIL/CIN2-3 and CC compared with normal and LSIL lesions. DNA methylation of at least one gene was detected in 12.5% (1/8) of normal samples, 31.5% (6/19) of LSIL/CIN1, 83.3% (25/30) of HSIL/CIN2, 81.6% (49/60) of HSIL/CIN3 and 100% (14/14) of CC ( < 0.001). The sensitivity and specificity for HSIL/CIN2-3 and CC of having at least one methylated gene were 84.6% and 74.0%, respectively. The sensitivity and specificity of the combination of at least one methylated gene and a positive hrHPV test were 80.7% and 85.1% for HSIL/CIN2-3 and CC, respectively.
CONCLUSIONS
The methylation rate of CADM1, MAL and miR124 increases with the severity of the lesion. Further research is warranted to evaluate the usefulness of these biomarkers for the identification of transforming HSIL/CIN.
背景
鳞状上皮内病变/宫颈上皮内瘤变（SIL/CIN）是人乳头瘤病毒（HPV）高危型相关病变，根据其进展为宫颈癌（CC）的风险，可分为高级别（HSIL/CIN2-3）或低级别（LSIL/CIN1）病变。大多数 HSIL/CIN2-3 被认为是转化型 HPV 感染，因此是真正的 CC 前体，尽管有些病变可自发消退。HPV 检测对 HSIL/CIN2-3 的检测具有较高的敏感性，但对识别转化病变的特异性较低。我们旨在确定在组织学样本中评估 CADM1、MAL 和 miR124 启动子甲基化状态的组合是否可用作识别转化型 HSIL/CIN 病变的生物标志物。
设计
前瞻性收集了 131 例宫颈活检标本，包括 8 例无病变且 HPV 阴性的病例（对照组）、19 例低级别（LSIL）/CIN1、30 例 HSIL/CIN2、60 例 HSIL/CIN3 和 14 例 CC。采用基于聚合酶链反应（PCR）的 SPF10 HPV LIPA 技术检测和基因分型 HPV。采用多重定量甲基化特异性 PCR（qMSP）检测 CADM1、MAL 和 miR124 启动子基因的甲基化状态。
结果
与正常和 LSIL 病变相比，HSIL/CIN2-3 和 CC 中 CADM1、MAL 和 miR-124 的甲基化水平显著升高。在 8 例正常样本中，有 12.5%（1/8）检测到至少一种基因的 DNA 甲基化，在 19 例 LSIL/CIN1 中，有 31.5%（6/19），在 30 例 HSIL/CIN2 中，有 83.3%（25/30），在 60 例 HSIL/CIN3 中，有 81.6%（49/60），在 14 例 CC 中，有 100%（14/14）（<0.001）。至少有一个基因甲基化对 HSIL/CIN2-3 和 CC 的敏感性和特异性分别为 84.6%和 74.0%。至少有一个甲基化基因和 HPV 阳性检测对 HSIL/CIN2-3 和 CC 的敏感性和特异性分别为 80.7%和 85.1%。
结论
CADM1、MAL 和 miR124 的甲基化率随病变严重程度的增加而增加。需要进一步研究以评估这些生物标志物在识别转化型 HSIL/CIN 中的有用性。
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