Department of Haematology, Huashan Hospital, Fudan University, Shanghai, China.
Br J Haematol. 2014 Jun;165(5):649-58. doi: 10.1111/bjh.12811. Epub 2014 Mar 6.
The CpG island methylator phenotype (CIMP) is an epigenetic phenomenon and plays an important role in tumourigenesis in various cancers. The identification of aberrant DNA methylation can be exploited for early diagnosis and risk assessment of patients. We identified a CIMP in myelodysplastic syndrome (MDS). Genes were screened for hypermethylation and transcription downregulation through genome-wide DNA methylation profiling and gene expression microarrays. Methylation-specific, real-time, and bisulfite-sequencing polymerase chain reaction were performed to validate selected genes. The hypermethylation of genes as a diagnostic tool for the detection of MDS was evaluated. Kaplan-Meier survival analysis and Cox regression were performed. A draft of an MDS CIMP was established and revised to 6 genes after validation in 20 patients and 20 controls. Further large-scale analysis showed that the majority of 211 MDS patients were hypermethylated in 6 genes. The area under the curve of CIMP was 0·9768 (95% confidence interval 0·9609-0·9928). A combination of 5 or more of the methylated genes showed a specificity of 95% and sensitivity of 91% for the diagnosis of MDS. We found CIMP positivity to be a significantly unfavourable prognostic factor for MDS. These results indicate that the newly established CIMP may improve diagnostic accuracy and prognosis assessment in MDS.
CpG 岛甲基化表型（CIMP）是一种表观遗传现象，在各种癌症的肿瘤发生中起着重要作用。异常 DNA 甲基化的鉴定可用于患者的早期诊断和风险评估。我们在骨髓增生异常综合征（MDS）中鉴定出 CIMP。通过全基因组 DNA 甲基化分析和基因表达微阵列筛选出基因的高甲基化和转录下调。通过甲基化特异性、实时和亚硫酸氢盐测序聚合酶链反应对选定基因进行验证。评估了基因高甲基化为 MDS 检测的诊断工具的价值。进行了 Kaplan-Meier 生存分析和 Cox 回归分析。建立了 MDS CIMP 的草案，并在 20 名患者和 20 名对照中验证后修订为 6 个基因。进一步的大规模分析显示，211 名 MDS 患者中的大多数在 6 个基因中呈高甲基化。CIMP 的曲线下面积为 0.9768（95%置信区间 0.9609-0.9928）。5 个或更多甲基化基因的组合对 MDS 的诊断具有 95%的特异性和 91%的敏感性。我们发现 CIMP 阳性是 MDS 预后不良的显著危险因素。这些结果表明，新建立的 CIMP 可能会提高 MDS 的诊断准确性和预后评估。
