Identification of endometrial cancer methylation features using combined methylation analysis methods.
Identification of endometrial cancer methylation features using combined methylation analysis methods.
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DOI：
10.1371/journal.pone.0173242
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Goodfellow PJ
中科院分区：
文献类型：
--
作者：
Trimarchi MP;Yan P;Groden J;Bundschuh R;Goodfellow PJ
DNA甲基化是一种稳定的表观遗传标记，在肿瘤中经常发生改变。鉴于活细胞和通常可用于分析的生物样本中DNA甲基化的稳定性，DNA甲基化特征是用于疾病状态的有吸引力的生物标志物。在某些癌症中，调控元件中甲基化的广泛积累（特别是CpG岛甲基化表型，CIMP）可以在肿瘤发生中发挥重要作用。然而，对于整个基因组的CIMP的高分辨率评估仍然成本高昂，并且需要对于许多感兴趣的组织样品不可用的DNA的量。已经对大量肿瘤进行了全基因组甲基化扫描，并对有限数量的癌症标本进行了更高分辨率的分析。分析这种大型数据集和整合不同研究结果的方法不断发展。开发了一种方法，用于比较肿瘤DNA甲基化组分的全基因组评估结果和更广泛应用的甲基化扫描结果。使用甲基化片段捕获和第二代测序，MethylCap-seq，生成76个原发性子宫内膜癌和12个正常子宫内膜样本的甲基化组。将来自癌症基因组图谱（TCGA）的公开可用的Infinium HumanMethylation 450数据与MethylCap-seq数据进行比较。启动子CpG岛（CGI）甲基化的分析确定了一个亚组的肿瘤与甲基化表型。我们使用了两个阶段的方法来开发一个与“超甲基化状态”相关的13个区域的甲基化特征。在TCGA测试集中，13区甲基化标记的高水平甲基化与错配修复缺陷、高突变率和低体细胞拷贝数改变相关。此外，设计的签名与先前描述的由TCGA设计的甲基化簇显示出良好的一致性。我们鉴定了子宫内膜癌中“超甲基化表型”的甲基化特征，并开发了可能用于鉴定其他癌症中极端甲基化表型的方法。
DNA methylation is a stable epigenetic mark that is frequently altered in tumors. DNA methylation features are attractive biomarkers for disease states given the stability of DNA methylation in living cells and in biologic specimens typically available for analysis. Widespread accumulation of methylation in regulatory elements in some cancers (specifically the CpG island methylator phenotype, CIMP) can play an important role in tumorigenesis. High resolution assessment of CIMP for the entire genome, however, remains cost prohibitive and requires quantities of DNA not available for many tissue samples of interest. Genome-wide scans of methylation have been undertaken for large numbers of tumors, and higher resolution analyses for a limited number of cancer specimens. Methods for analyzing such large datasets and integrating findings from different studies continue to evolve. An approach for comparison of findings from a genome-wide assessment of the methylated component of tumor DNA and more widely applied methylation scans was developed. Methylomes for 76 primary endometrial cancer and 12 normal endometrial samples were generated using methylated fragment capture and second generation sequencing, MethylCap-seq. Publically available Infinium HumanMethylation 450 data from The Cancer Genome Atlas (TCGA) were compared to MethylCap-seq data. Analysis of methylation in promoter CpG islands (CGIs) identified a subset of tumors with a methylator phenotype. We used a two-stage approach to develop a 13-region methylation signature associated with a “hypermethylator state.” High level methylation for the 13-region methylation signatures was associated with mismatch repair deficiency, high mutation rate, and low somatic copy number alteration in the TCGA test set. In addition, the signature devised showed good agreement with previously described methylation clusters devised by TCGA. We identified a methylation signature for a “hypermethylator phenotype” in endometrial cancer and developed methods that may prove useful for identifying extreme methylation phenotypes in other cancers.