在组织学宫颈标本上分析宫颈上皮内瘤变和宫颈癌中宿主基因的启动子甲基化。
Promoter hypermethylation analysis of host genes in cervical intraepithelial neoplasia and cervical cancers on histological cervical specimens.
机构信息
Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, Changsha, China.
Department of Clinical Medicine, Harbin Medical University, Harbin, 150081, China.
出版信息
BMC Cancer. 2023 Feb 20;23(1):168. doi: 10.1186/s12885-023-10628-5.
BACKGROUND
DNA methylation is an essential factor in the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer. The aim was to investigate the diagnostic value provided by methylation biomarkers of six tumor suppressor genes (ASTN1, DLX1, ITGA4, RXFP3, SOX17 and ZNF671) for cervical precancerous lesions and cervical cancer.
METHODS
The histological cervical specimens of 396 cases including 93 CIN1, 99 CIN2, 93 CIN3 and 111 cervical cancers were tested for methylation-specific PCR assay (GynTect®) of score and positive rate. Among them, 66 CIN1, 93 CIN2, 87 CIN3 and 72 cervical cancers were further used for paired analysis. A chi-square test was used to analyze the difference of methylation score and positive rate in cervical specimens. The paired t-test and paired chi-square test were for analyzing the methylation score and positive rate in paired CIN and cervical cancer cases. The specificity, sensitivity, odds ratio (OR) and 95% confidence interval (95% CI) of the GynTect® assay for CIN2 or worse (CIN2 +) and CIN3 or worse (CIN3 +) were evaluated.
RESULTS
According to the chi-square test trend, hypermethylation increased with severity of the lesions as defined by histological grading (P = 0.000). The methylation score above 1.1 was more common in CIN2 + than in CIN1. The DNA methylation scores in the paired groups of CIN1, CIN3 and cervical cancer were significant differences (P = 0.033, 0.000 and 0.000, respectively), except for CIN2 (P = 0.171). While the positive rate of GynTect® in each paired group had no difference (all P > 0.05). The positive rate of every methylation marker in the GynTect® assay showed differences in four cervical lesion groups (all P < 0.05). The specificity of GynTect® assay for detection of CIN2 + /CIN3 + were higher than high-risk human papillomavirus test. With CIN1 as a reference, the positive status of GynTect®/ZNF671 were significantly higher in CIN2 + : odds ratio (OR) 5.271/OR 13.909, and in CIN3 + : OR 11.022/OR 39.150, (all P < 0.001).
CONCLUSION
The promoter methylation of six tumor suppressor genes is related to the severity of cervical lesions. The GynTect® assay based on cervical specimens provides diagnostic values for detecting CIN2 + and CIN3 + .
背景
DNA 甲基化是宫颈上皮内瘤变（CIN）进展为宫颈癌的重要因素。本研究旨在探讨六种肿瘤抑制基因（ASTN1、DLX1、ITGA4、RXFP3、SOX17 和 ZNF671）的甲基化生物标志物对宫颈前病变和宫颈癌的诊断价值。
方法
采用甲基化特异性 PCR 检测（GynTect®）评分和阳性率，对 396 例宫颈组织标本（包括 93 例 CIN1、99 例 CIN2、93 例 CIN3 和 111 例宫颈癌）进行检测。其中，66 例 CIN1、93 例 CIN2、87 例 CIN3 和 72 例宫颈癌进一步进行配对分析。采用卡方检验分析宫颈标本中甲基化评分和阳性率的差异。采用配对 t 检验和配对卡方检验分析配对的 CIN 和宫颈癌病例中的甲基化评分和阳性率。采用 GynTect®检测评估 CIN2 或更高级别病变（CIN2+）和 CIN3 或更高级别病变（CIN3+）的特异性、敏感性、比值比（OR）和 95%置信区间（95%CI）。
结果
根据卡方检验趋势，随着组织学分级定义的病变严重程度增加，出现过度甲基化（P=0.000）。CIN2+中甲基化评分高于 1.1 的情况更为常见。CIN1、CIN3 和宫颈癌配对组的 DNA 甲基化评分差异有统计学意义（P=0.033、0.000 和 0.000，分别），但 CIN2 除外（P=0.171）。而 GynTect®在每个配对组中的阳性率没有差异（均 P>0.05）。GynTect®检测中每个甲基化标志物在四个宫颈病变组中的阳性率均有差异（均 P<0.05）。GynTect®检测对 CIN2+和 CIN3+的检测特异性高于高危型人乳头瘤病毒检测。以 CIN1 为参照，GynTect®/ZNF671 的阳性状态在 CIN2+中显著升高：OR 5.271/OR 13.909，在 CIN3+中：OR 11.022/OR 39.150，（均 P<0.001）。
结论
六种肿瘤抑制基因的启动子甲基化与宫颈病变的严重程度有关。基于宫颈标本的 GynTect®检测为检测 CIN2+和 CIN3+提供了诊断价值。
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