A Pre-Leukemic DNA Methylation Signature in Healthy Individuals at Higher Risk for Developing Myeloid Malignancy.

PURPOSE:DNA methylation alterations are widespread in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), some of which appear to have evolved independently of somatic mutations in epigenetic regulators. While the presence of somatic mutations in peripheral blood can predict the risk of development of AML and MDS, its accuracy remains unsatisfactory. EXPERIMENTAL DESIGN:We performed global DNA methylation profiling in a case-control study nested within Singapore Chinese Health Study to evaluate if DNA methylation alterations were associated with AML/MDS development. Targeted deep sequencing and methylated DNA immunoprecipitation sequencing (MeDIP-seq) were performed on peripheral blood collected a median of 9.9 years prior to diagnosis of AML or MDS, together with age-matched still healthy individuals as controls. RESULTS:Sixty-six individuals who developed AML or MDS displayed significant DNA methylation changes in the peripheral blood compared with 167 age- and gender-matched controls who did not develop AML/MDS during the follow up period. Alterations in methylation in the differentially methylation regions (DMRs) were associated with increased odds of developing AML/MDS. CONCLUSIONS:The epigenetic changes may be acquired independently and prior to somatic mutations that relevant for AML/MDS development. The association between methylation changes and the risk of pre-AML/MDS in these individuals was considerably stronger than somatic mutations, suggesting that methylation changes could be used as biomarkers for pre- AML/MDS screening.