Abstract
Clinical and genetic features incompletely predict outcome in acute myeloid leukemia (AML). The value of clinical methylation assays for prognostic markers has not been extensively explored. We assess the prognostic implications of methylC-capture sequencing (MCC-Seq) in patients with de novo AML by integrating DNA methylation and genetic risk stratification. MCC-Seq assessed DNA methylation level in 44 samples. The differentially methylated regions associated with prognostic genetic information were identified. The selected prognostic DNA methylation markers were independently validated in two sets. MCC-Seq exhibited good performance in AML patients. A panel of 12 differentially methylated genes was identified with promoter hyper-differentially methylated regions associated with the outcome. Compared with a low M-value, a high M-value was associated with failure to achieve complete remission (p = 0.024), increased hazard for disease-free survival in the study set (p = 0.039) and poor overall survival in The Cancer Genome Atlas set (p = 0.038). Hematopoietic stem cell transplantation and survival outcomes were not adversely affected by a high M-value (p = 0.271). Our study establishes that MCC-Seq is a stable, reproducible, and cost-effective methylation assay in AML. A 12-gene M-value encompassing epigenetic and genetic prognostic information represented a valid prognostic marker for patients with AML.
Highlights
Acute myeloid leukemia (AML) is a clonal disorder of myeloid hematopoiesis and a predominantly fatal hematopoietic malignancy with high heterogeneity [1]
The current study presents methylC-capture sequencing (MCC-Seq) for the detection of prognostic methylation markers in acute myeloid leukemia (AML) and proposes a panel of 12 different functional DNA methylation genes
By a series of comparative screening, a panel of 12 differentially methylated genes (DMGs) was identified with promoter hyper-differentially methylated regions (DMRs) associated with the outcome
Summary
Acute myeloid leukemia (AML) is a clonal disorder of myeloid hematopoiesis and a predominantly fatal hematopoietic malignancy with high heterogeneity [1]. Genetic heterogeneity has been appreciated since early karyotyping studies; somatic mutations have shown a comprehensive landscape of AML and contributed to disease classification and prognostic stratification [1,2,3]. A precise prognosis for nearly 50% of AML cases with a normal karyotype and patients with no mutations is still difficult to achieve [4]. Aberrant DNA methylation is a common theme and a hallmark of AML [6]. Recent studies on genome-wide DNA methylation have emphasized the importance of dysregulated methylation profile in AML from biological and clinical views [7,8,9,10,11]. The methylation techniques employed in these studies are difficult to apply in routine clinical practice [15]
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