CpG island methylator phenotype of myelodysplastic syndrome identified through genome-wide profiling of DNA methylation and gene expression.

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.