Abstract
BackgroundMultiple 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).ResultsFourteen 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 < 0.0001; EFS: p < 0.0001) as well as for the whole AML cohort (OS: p = 0.01; EFS < 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 < 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.ConclusionsOut 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.
Highlights
Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by a complex interplay of aberrations at different levels of the genome [1,2,3]
The main weakness is that such works are usually not validated by other researchers and there is not sufficient validation of these potential biomarkers for them to be introduced into clinical practice
For two studies [19, 20], we found the exact opposite effect of DNA methylation on prognosis than originally reported—higher GPX3 and DLX4 methylation—was linked to a better outcome according to our data
Summary
Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by a complex interplay of aberrations at different levels of the genome (i.e., genetic, epigenetic, transcriptomic, and proteomic) [1,2,3]. Only properly introduced and validated genetic lesions altogether with cytogenetics are considered into treatment decision making [4]. This still applies despite growing evidence that some other markers, such as epigenetic factors, may add valuable information about the predicted course of the disease in individual AML patients [3]. Multiple studies have reported the prognostic impact of DNA methylation changes in acute myeloid leukemia (AML). These epigenetic markers have not been thoroughly validated and are still not considered in clinical practice. 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)
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