Gene mutational analysis by NGS and its clinical significance in patients with myelodysplastic syndrome and acute myeloid leukemia

Abstract

Background: In this study, we retrospectively summarized the differences of molecular gene mutations between MDS and AML patients, as well as the young and older age groups of MDS and AML patients. We also analyzed the response of newly diagnosed AML patients to standard DA or IA induction chemotherapy and the relationship between the chemotherapy outcome and the frequency of different gene mutation abnormalities. Methods: NGS assay covering 43 genes was studied in 93 de novo MDS and 325 non-M3 AML patients. Bone marrow samples from all patients underwent gene mutational analysis by NGS. Results: At least one non-synonymous gene mutation was detected in 279 AML patients (85.8%) and 85 MDS patients (91.4%). Contrary to 59 years and younger AML patients, there was a significantly higher incidence of gene mutation in 60 years and older AML patients (2.37 vs 1.94, p = 0.034). Gene mutation incidence in 60 years and older MDS patients increased, but no statistical significance was present (1.95 vs 1.64, p = 0.216). AML patients had a significantly higher gene mutation incidence compared with MDS-MLD patients (2.02 vs 1.63, p = 0.046). Gene mutation incidence was higher in patients with MDS-EB1/EB2 compared with patients with MDS-MLD but there was no statistical significance present (2.14 vs 1.63, p = 0.081). AML patients had significantly higher incidences of CEBPA, FLT3-ITD, DNMT3A, NPM1 and IDH1/2 gene mutations (p = 0.0043, 0.000, 0.030962, 0.002752, and 0.000628, respectively) and a lower incidence of TET2 and U2AF1 gene mutations (p = 0.000004 and 0.000, respectively) compared with MDS patients. Among the individual genes in different age groups, there were significantly higher incidences of RUNX1, IDH2, TP53 and SF3B1 gene mutations (p = 0.0478, 0.0028, 0.0024 and 0.005, respectively) as well as a trend of higher ASXL gene mutation (p = 0.057) in 60 years and older AML patients compared to 59 years and younger patients. There was no statistically significant difference in MDS patients with the different age groups and among the individual genes. Between AML patients and MDS patients among the different gene functional groups, AML patients had a significantly higher incidence of transcriptional deregulation (27.4% vs 15.1%, p = 0.014963), activated signalling (36.3% vs 10.8%, p = 0.000002) related gene mutations as well as a significantly lower incidence of RNA spliceosome (6.15% vs 60.1%, p = 0.000) related gene mutations. Furthermore, among the patients who received either IA or DA regimen

Clinical implications of recurrent gene mutations in acute myeloid leukemia

“…Study results have demonstrated that the DNMT3A R882 mutation disrupts the normal ligation of methyltransferase protein subunits, causing a dominant negative impact on DNMT3A protein function [91,92]. Multiple researchers have confirmed that DNMT3A is frequently mutated in AML patients (13.5-23%) [3,93,94]. DNMT3A plays a unique role in hematopoiesis and AML pathogenesis as the inferior prognostic markers for AML patients [6,95].…”

“…NPM1 is frequently mutated and the incidence occur in up to 30% of AML patients overall and 40-60% of patients with normal karyotypes [3,4,60,69]. Mutated NPM1 (mNPM1) is associated with a higher complete remission, improved OS, and a lower cumulative incidence of relapse [60].…”

“…Furthermore, recurrent somatic mutations in more than 50 genes have been identified in 80-90% of MDS. The most recurrent genetic mutations are involved in the RNA splicing (e.g., SF3B1, SRSF2, U2AF1, ZRSR2, LUC7L2, DDX41) and epigenetic modifications, such as histone modification (e.g., ASXL1, EZH2) and DNA methylation (e.g., TET2, DNMT3A, IDH1/IDH2) [3,119]. TP53 mutation predicts significant adverse clinical outcomes in MDS, however, clinical implications of other gene mutations remain unclear [119].…”

“…Six genes, including FMSlike tyrosine kinase 3 (FLT3), nucleophosmin 1 (NPM1), CCAAT/enhancer binding protein alpha (CEBPA), Runtrelated transcription factor 1 (RUNX1), additional sex combs-like 1 (ASXL1), and tumor protein p53 (TP53), have already been incorporated into the risk categories proposed by the European Leukemia Net (ELN) [2]. Other recurrent gene mutations have been reported in AML patients [3][4][5][6][7][8]. Furthermore, the important roles of recurrent gene mutation in AML pathogenesis had been explored and gene mutation-targeted therapies had been developed [8][9][10][11][12][13][14][15].…”

SPOP accelerates acute myeloid leukemia initiation and development through miR-183-mediated METAP2 inhibition

“…It is a heterogeneous disease accompanied by a warning mortality, where the prognosis status is dependent on cytogenetic and molecular changes as well as patient-related situations, such as age, and complications [2,3]. Furthermore, AML is a genetically heterogeneous malignant disorder of the hematopoietic system, which has been reportedly indicated to accompany with the increase of immature myeloid precursors with injured DNA [4,5]. This aggressive hematologic neoplasm often develops to relapse resulting from drug resistance despite intensive chemotherapy [6].…”