Molecular evaluation of DNMT3A and IDH1/2 gene mutation: frequency, distribution pattern and associations with additional molecular markers in normal karyotype Indian acute myeloid leukemia patients (original) (raw)
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Journal of Hematopathology, 2018
Mutation of the genes encoding DNA methyltransferase 3A (DNMT3A) and isocitrate dehydrogenase 1/2 (IDH 1/2) is among the most commonly occurring mutation found in acute myeloid leukemia (AML) patients. This study was purposed to investigate the frequency of DNMT3A and IDH1/2 gene mutation and the clinical features of Iranian cytogenetically normal acute myeloid leukemia (CN-AML) patients harboring these mutations. Thirty-nine CN-AML patients were recruited at the time of diagnosis. PCR followed by direct sequencing was used to detect the mutations of DNMT3A (R882), IDH1 (R132), and IDH2 (R140 and R172). The results showed that of all CN-AML patients, DNMT3A, IDH1, and IDH2 mutations were observed in five (12.8%), five (12.8%), and five (13.2%) patients, respectively. In addition, the most frequent DNMT3A, IDH1, and IDH2 mutant types were R882C, R132C, and R140Q types, respectively. Our results also described that both DNMT3A and IDH1/2 mutations were not associated with significant change in hemoglobin (Hb) levels, white blood cell (WBC) and platelet count, and bone marrow blast percentage (P > 0.05). There was also no significant difference in the mutation status of DNMT3A and IDH1/2 genes regarding age and gender (P > 0.05). A positive relationship was observed between the co-occurrence of DNMT3A and IDH2 (P = 0.021) and FLT3-ITD and NPM1 (P = 0.044). Increasing sample size and longer follow-up of patients may provide additional data to understand the prognostic significance of the DNMT3A and IDH1/2 mutation in the management of CN-AML patients.
Prognostic significance of DNMT3A mutations in patients with acute myeloid leukemia
Blood Cells, Molecules, and Diseases, 2015
Acute myeloid leukemia (AML) represents a heterogeneous group of malignancies with great variability in clinical course and response to therapy. Several molecular markers have been described that help to classify AML patients into risk groups. Mutations in DNA methyltransferase 3A (DNMT3A) gene were recently demonstrated in AML. Approximately 20% patients with AML carry DNMT3A gene mutations and were associated with a poor clinical outcome but its clinical implications in Egyptian AML patients are largely unknown. The aim of the study was to study the incidence and prognostic impact of DNMT3A mutations in patients with de novo acute myeloid leukemia. A total of 120 patients with de novo AML were examined for mutations in DNMT3A by sequencing. DNMT3A mutations were identified in 34/120 (28%) of AML patients. 15 patients with M4, 14 patients with M5, 3 patient with M2 and 2 patient with M6. DNMT3A mutations were more frequently associated with older age, higher platelet counts and intermediate risk. DNMT3A-mutated patients did not differ regarding complete remission (CR) and disease-free survival (DFS), but had shorter overall survival (OS; P = 0.048) than DNMT3A-wild-type patients. Mutations in DNMT3A independently predicted a shorter OS (P = 0.049) by multivariate analysis. We concluded that DNMT3A mutations are highly frequent in Egyptian patients with AML and are associated with an unfavorable prognosis.
BioMed Research International, 2015
Background. DNA methyltransferase 3A (DNMT3A) mutation was recently introduced as a prognostic indicator in normal karyotype (NK) AML and we evaluated the incidence and prognostic impact of DNMT3A mutations in Korean NK AML patients. Methods. Total 67 NK AML patients diagnosed during the recent 10 years were enrolled. DNMT3A mutations were analyzed by direct sequencing and categorized into nonsynonymous variations (NSV), deleterious mutations (DM), and R882 mutation based on in silico analysis results. Clinical features and prognosis were compared with respect to DNMT3A mutation status. Results. Three novel (I158M, K219V, and E177V) and two known (R736H and R882H) NSVs were identified and the latter three were predicted as DMs. DNMT3A NSVs, DMs, and R882 mutation were identified in 14.9%-17.9%, 10.3%-10.4%, and 7.5% of patients, respectively. DNMT3A mutations were frequently detected in FLT3 ITD mutated patients (P = 0.054, 0.071, and 0.071 in NSV, DMs, and R882 mutation, resp.) but did not affect clinical features and prognosis significantly. Conclusions. Incidences of DNMT3A NSVs, DMs, and R882 mutation are 14.9%-17.9%, 10.3%-10.4%, and 7.5%, respectively, in Korean NK AML patients. DNMT3A mutations are associated with FLT3 ITD mutations but do not affect clinical outcome significantly in Korean NK AML patients.
Blood, 2012
evolution and clinical implications mutations in acute myeloid leukemia: stability during disease DNMT3A http://bloodjournal.hematologylibrary.org/content/119/2/559.full.html Updated information and services can be found at: (892 articles) Myeloid Neoplasia Articles on similar topics can be found in the following Blood collections http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub\_requests
Journal of experimental & clinical cancer research : CR, 2014
Mutations in epigenetic modifiers were reported in patients with acute myeloid leukaemia (AML) including mutations in DNA methyltransferase 3A gene (DNMT3A) in 20%-30% patients and mutations in isocitrate dehydrogenase 1/2 gene (IDH1/2) in 5%-15% patients. Novel studies have shown that mutations in DNMT3A and IDH1/2 influence prognosis, indicating an increasing need to detect these mutations during routine laboratory analysis. DNA sequencing for the identification of these mutations is time-consuming and cost-intensive. This study aimed to establish rapid screening tests to identify mutations in DNMT3A and IDH1/2 that could be applied in routine laboratory procedures and that could influence initial patient management. In this study we developed an endonuclease restriction method to identify the most common DNMT3A mutation (R882H) and an amplification-refractory mutation system (ARMS) to analyse IDH2 R140Q mutations. Furthermore, we compared these methods with HRM analysis and evalu...
Oncotarget, 2015
Acute myeloid leukemia (AML) is a heterogeneous disease. Even within the same NPM1-mutated genetic subgroup, some patients harbor additional mutations in FLT3, IDH1/2, DNMT3A or TET2. Recent studies have shown the prognostic significance of minimal residual disease (MRD) in AML but it remains to be determined which molecular markers are the most suitable for MRD monitoring. Recent advances in next-generation sequencing (NGS) have provided the opportunity to use multiple molecular markers. In this study, we used NGS technology to assess MRD in 31 AML patients enrolled in the ALFA-0701 trial and harboring NPM1 mutations associated to IDH1/2 or DNMT3A mutations. NPM1 mutation-based MRD monitoring was performed by RTqPCR. IDH1/2 and DNMT3A mutations were quantified by NGS using an Ion Torrent Proton instrument with high coverage (2 million reads per sample). The monitoringof IDH1/2 mutations showed that these mutations were reliable MRD markers that allowed the prediction of relapse in the majority of patients. Moreover, IDH1/2 mutation status predicted relapse or disease evolution in 100% of cases if we included the patient who developed myelodysplastic syndrome. In contrast, DNMT3A mutations were not correlated to the disease status, as we found that a preleukemic clone with DNMT3A mutation persisted in 40% of the patients who were in complete remission, reflecting the persistence of clonal hematopoiesis.
DNMT3A Mutations in Patients with Acute Myeloid Leukemia in South Brazil
Advances in hematology, 2012
Acute myeloid leukemia (AML) is a complex and heterogeneous hematopoietic tissue neoplasm. Several molecular markers have been described that help to classify AML patients into risk groups. DNA methyltransferase 3A (DNMT3A) gene mutations have been recently identified in about 22% of AML patients and associated with poor prognosis as an independent risk factor. Our aims were to determine the frequency of somatic mutations in the gene DNMT3A and major chromosomal translocations in a sample of patients with AML. We investigated in 82 samples of bone marrow from patients with AML for somatic mutations in DNMT3A gene by sequencing and sought major fusion transcripts by RT-PCR. We found mutations in the DNMT3A gene in 5 patients (6%); 3 were type R882H [corrected]. We found fusion transcripts in 19 patients, namely, AML1/ETO (n = 5; 6.1%), PML/RARα (n = 12; 14.6%), MLL/AF9 (0; 0%), and CBFβ/MYH11 (n = 2; 2.4%). The identification of recurrent mutations in the DNMT3A gene and their possib...
Quantitative detection of DNMT3A R882H mutation in acute myeloid leukemia
Journal of Experimental & Clinical Cancer Research, 2015
Background: DNMT3A mutations represent one of the most frequent gene alterations detectable in acute myeloid leukemia (AML) with normal karyotype. Although various recurrent somatic mutations of DNMT3A have been described, the most common mutation is located at R882 in the methyltransferase domain of the gene. Because of their prognostic significance and high stability during disease evolution, DNMT3A mutations might represent highly informative biomarkers for prognosis and outcome of disease.