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Updated: May 28, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Prognostic impact of DNMT3A mutations in patients with intermediate cytogenetic risk profile acute myeloid leukemia
Jana Marková1, Petra Michková, Kateřina Burčková
1Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
Objectives:
Recently, mutations in DNMT3A gene have been described in about 25% acute myeloid leukemia (AML) cases, preferentially in monocytic AML. They were found to predict worse overall survival (OS) of mutated patients.
Patients And Methods:
RT-PCR followed by direct sequencing was used to test the presence of DNMT3A mutations in 226 AML patients with an intermediate-risk (IR) cytogenetics.
Results:
Sixty-seven patients of 226 (29.6%) carried a mutation in the DNMT3A gene. Occurrence of DNMT3A mutations was associated with female sex (P = 0.027) and with the presence of FLT3/ITD (P = 0.003), but not with particular FAB subtypes. Patients with DNMT3A mutation had higher initial WBC counts than those without it (P = 0.064) only because of higher incidence of FLT3/ITD within these cases. There was no difference between mutated and wild-type groups in reaching complete remission (CR) (P = 0.380). OS was not affected by DNMT3A mutation (P = 0.251), but OS of patients who reached CR was longer in DNMT3A negative cases (P = 0.025). Patients with DNMT3A mutation had a higher relapse rate (P = 0.007). Patients carrying both the DNMT3A mutation and FLT3/ITD relapsed more often than either patients with single DNMT3A mutation (P = 0.044) or patients with FLT3/ITD only (P = 0.058). DNMT3A mutations were associated with higher relapse rate even within the FLT3/ITD-negative group (P = 0.072). After reaching CR, these two genetic factors were independent predictors of relapse at multivariate analysis (P < 0.001). Only three of 30 'double-mutated' (FLT3/ITD+, DNMT3A+) patients are still alive, all of them having undergone hematopoietic stem cell transplant.
Conclusions:
We have confirmed the high incidence of DNMT3A mutations in patients with AML with IR cytogenetics. Patients with DNMT3A mutations relapse more often and have inferior OS when only patients achieving CR are analyzed. 'Double-mutated' patients have a very poor prognosis.
Insights
DNMT3A gene mutations are common in acute myeloid leukemia (AML) and are linked to higher relapse rates. Patients with both DNMT3A and FLT3/ITD mutations have a very poor prognosis, especially if they achieve complete remission.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- DNMT3A gene mutations are found in approximately 25% of acute myeloid leukemia (AML) cases, particularly in monocytic AML.
- These mutations have been associated with a worse overall survival (OS) in affected patients.
Purpose of the Study:
- To investigate the incidence and prognostic significance of DNMT3A mutations in AML patients with intermediate-risk (IR) cytogenetics.
- To assess the impact of DNMT3A mutations, alone and in combination with FLT3/ITD, on relapse rates and survival outcomes.
Main Methods:
- RT-PCR and direct sequencing were employed to detect DNMT3A mutations in 226 AML patients with IR cytogenetics.
- Statistical analyses were performed to correlate DNMT3A mutation status with clinical characteristics, treatment response, and survival outcomes.
Main Results:
- DNMT3A mutations were identified in 29.6% of the studied AML cohort, associated with female sex and FLT3/ITD presence.
- Patients with DNMT3A mutations exhibited significantly higher relapse rates (P = 0.007).
- The combination of DNMT3A and FLT3/ITD mutations conferred a particularly poor prognosis, with only 3 of 30 'double-mutated' patients surviving, all after stem cell transplant.
Conclusions:
- DNMT3A mutations are frequent in AML with IR cytogenetics and are associated with an increased risk of relapse.
- While overall survival was not significantly impacted in the entire cohort, DNMT3A-mutated patients achieving complete remission had inferior OS.
- 'Double-mutated' (DNMT3A and FLT3/ITD) AML patients face a very poor prognosis, highlighting the importance of combined genetic profiling.
