Genome-wide methylation profiling identifies hypermethylated biomarkers in high-grade cervical intraepithelial neoplasia
Genome-wide methylation profiling identifies hypermethylated biomarkers in high-grade cervical intraepithelial neoplasia
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DOI：
10.4161/epi.22301
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发表时间：
2012-11-01
期刊：
影响因子：
3.7
通讯作者：
van der Zee, Ate G. J.
中科院分区：
文献类型：
--
作者：
Lendvai, Agnes;Johannes, Frank;van der Zee, Ate G. J.
表观遗传修饰，例如DNA启动子异常甲基化，在宫颈癌中经常被观察到。识别允许区分正常宫颈上皮和高度宫颈上皮内瘤变(CIN2/3)的高甲基化区域，或更糟糕的情况，可能会改善当前基于人群的宫颈癌筛查计划。本研究采用全基因组DNA甲基化筛查的方法，对高级别CIN病变的DNA甲基化组进行研究，以确定可用于宫颈肿瘤早期诊断的潜在生物标志物。应用甲基化DNA免疫沉淀(MeDIP)结合DNA微阵列技术，比较高度恶性CIN病变上皮细胞和正常宫颈上皮细胞DNA甲基化情况。鉴定了高甲基化的差异甲基化区域(DMRS)。用BSP和MSP在宫颈组织中验证选择的9例DMR，发现63.2-94.7%的高级别CIN和59.3-100%的宫颈癌存在甲基化。对两个最重要的高级CIN特异性甲基化标志物进行了QMSP，以探索在一大系列宫颈刮片中的测试性能。甲基化频率和相对甲基化水平在正常和癌组织中有显著差异。对宫颈涂片异常患者宫颈刮片中这两种标志物的临床验证证实，甲基化频率和相对水平与潜在CIN病变的严重程度相关，ROC分析具有区别性。这些标记代表COL25A1和KATNAl2，它们在进展过程中观察到的甲基化增加可能暗示在癌症发生中的调节作用。总之，我们新发现的高甲基化DMRS代表了高级别CIN病变中特定的DNA甲基化模式，是早期检测的候选生物标记物。“
Epigenetic modifications, such as aberrant DNA promoter methylation, are frequently observed in cervical cancer. Identification of hypermethylated regions allowing discrimination between normal cervical epithelium and high-grade cervical intraepithelial neoplasia (CIN2/3), or worse, may improve current cervical cancer population-based screening programs. In this study, the DNA methylome of high-grade CIN lesions was studied using genome-wide DNA methylation screening to identify potential biomarkers for early diagnosis of cervical neoplasia. Methylated DNA Immunoprecipitation (MeDIP) combined with DNA microarray was used to compare DNA methylation profiles of epithelial cells derived from high-grade CIN lesions with normal cervical epithelium. Hypermethylated differentially methylated regions (DMRs) were identified. Validation of nine selected DMRs using BSP and MSP in cervical tissue revealed methylation in 63.2-94.7% high-grade CIN and in 59.3-100% cervical carcinomas. QMSP for the two most significant high-grade CIN-specific methylation markers was conducted exploring test performance in a large series of cervical scrapings. Frequency and relative level of methylation were significantly different between normal and cancer samples. Clinical validation of both markers in cervical scrapings from patients with an abnormal cervical smear confirmed that frequency and relative level of methylation were related with increasing severity of the underlying CIN lesion and that ROC analysis was discriminative. These markers represent the COL25A1 and KATNAL2 and their observed increased methylation upon progression could intimate the regulatory role in carcinogenesis. In conclusion, our newly identified hypermethylated DMRs represent specific DNA methylation patterns in high-grade CIN lesions and are candidate biomarkers for early detection."