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Background Multiple studies have reported the prognostic impact of DNA methylation changes in acute myeloid leukemia (AML). However, these epigenetic markers have not been thoroughly validated and therefore are still not considered in clinical practice. Hence, we aimed to independently verify results of selected studies describing the relationship between DNA methylation of specific genes and their prognostic potential in predicting overall survival (OS) and event-free survival (EFS). Results Fourteen studies (published 2011–2019) comprising of 27 genes were subjected to validation by a custom NGS-based sequencing panel in 178 newly diagnosed non-M3 AML patients treated by 3 + 7 induction regimen. The results were considered as successfully validated, if both the log-rank test and multivariate Cox regression analysis had a  p -value ≤ 0.05. The predictive role of DNA methylation was confirmed for three studies comprising of four genes:  CEBPA  (OS:  p  = 0.02; EFS:  p  = 0.03),  PBX3  (EFS:  p  = 0.01),  LZTS2  (OS:  p  = 0.05; EFS:  p  = 0.0003), and  NR6A1  (OS:  p  = 0.004; EFS:  p  = 0.0003). For all of these genes, higher methylation was an indicator of longer survival. Concurrent higher methylation of both  LZTS2  and  NR6A1  was highly significant for survival in cytogenetically normal (CN) AML group (OS:  p  &lt; 0.0001; EFS:  p  &lt; 0.0001) as well as for the whole AML cohort (OS:  p  = 0.01; EFS &lt; 0.0001). In contrast, for two studies reporting the poor prognostic effect of higher  GPX3  and  DLX4  methylation, we found the exact opposite, again linking higher  GPX3  (OS:  p  = 0.006; EFS:  p  &lt; 0.0001) and  DLX4  (OS:  p  = 0.03; EFS = 0.03) methylation to a favorable treatment outcome. Individual gene significance levels refer to the outcomes of multivariate Cox regression analysis. Conclusions Out of twenty-seven genes subjected to DNA methylation validation, a prognostic role was observed for six genes. Therefore, independent validation studies are necessary to reveal truly prognostic DNA methylation changes and to enable the introduction of these promising epigenetic markers into clinical practice.

clinical epigenetics

A validation study of potential prognostic DNA methylation biomarkers in patients with acute myeloid leukemia using a custom DNA methylation sequencing panel