DNMT3A MUTATIONS IN ACUTE MYELOID LEUKAEMIA WITH INTERMEDIATE-RISK KARYOTYPE - INCIDENCE AND CORRLEATION WITH OTHER GENE MUTATIONS
(Abstract release date: 05/19/16)
EHA Library. How G. 06/09/16; 132489; E940
Dr. Gee Fung How
Contributions
Contributions
Abstract
Abstract: E940
Type: Eposter Presentation
Background
Acute myeloid leukaemia is an aggressive heterogeneous haematopoietic disease. It is characterized by an increased proliferation of haematopoietic progenitor cells that have lost the ability to differentiate. In the last 15 years, major advances have been made in the disease with the discovery of many genetic abnormalities affecting cell proliferation, differentiation, apoptosis or cell cycle regulation. Some of these molecular markers confer good prognosis while others have been found to be adverse prognostic factors. Of the molecular markers, DNMT3A (DNA N-methyltransferase 3A) gene mutation is found to be an independent poor prognostic marker in most studies.
Aims
In this study, we evaluated the mutation status of DNMT3A in AML patients with intermediate-risk cytogenetics, in particular, those with normal karyotype. The incidence of DNMT3A mutations was correlated with the mutation status of other genes like FLT3, NPM1, IDH1 and IDH2 which were also determined.
Methods
For the detection of DNMT3A mutations, exon 26 of the gene was PCR amplified and direct sequencing of the amplicons was performed to detect mutation hotspots in this exon in a cohort of 93 patients.
Results
A total of 16(17%) patients were identified with R822 mutations in DNMT3A exon 26. R882H was the predominant mutation in these patients (n=10) while the remaining 6 had R822C. Of these 16 patients, 14 (87.5%) of them were also NPM1-mutated while 9 had FLT3/ITDs as well. The close association of DNMT3A mutations with NPM1 mutations was significant (p=0.048) while that with FLT3/ITDs was not quite statistically significant (and p=0.084). IDH mutations were detected in only 3 patients with R882 mutations (IDH1 R132H, n=1; IDH2 R140Q, n=2).The relation between DNMT3A mutations and other patient characteristics were determined by the Mann Whitney U test (continuous variables) and the Fisher exact test (categorical variables) (details in Table 1). The platelet counts were significantly higher in the DNMT3A -positive patients than in the patients without DNMT3A mutation (p=0.0125). DNMT3A mutations were also significantly enriched in patients with the FAB M5 subtype (12/22, 55%, p=<0.0001). Other clinical parameters showed no significant difference between the DNMT3A-positive group and the wild type group.Interestingly, in a patient who was separately investigated, FLT3/ITDmut, NPM1mut and DNMT3A R882C were detected at diagnosis but while FLT3/ITD was not detected on follow-up at relapse, an IDH2 R140Q was observed. The R882C status, however, remained unchanged. Previous larger study series have demonstrated the stability of DNMT3A during the course of disease.
Conclusion
Within the normal karyotype and other intermediate risk AMLs, we did not observe any significant correlation of DNMT3A mutations with white blood cell counts, FLT3/ITD or IDH mutations, contrary to what was observed in other studies which involved AMLs across all cytogenetic risk groups.We hope the findings from this preliminary study would help improve our understanding of the association of DNMT3A mutations with other gene mutations in intermediate risk AMLs. Further work is needed to investigate the significance of the DNMT3A exon 26 mutations, in particular, the R882 mutations, as a prognostic predictor and the role of screening of these mutations for further risk-stratification of intermediate risk AMLs, particularly in normal karyotype AML.
Session topic: E-poster
Keyword(s): AML, Mutation
Type: Eposter Presentation
Background
Acute myeloid leukaemia is an aggressive heterogeneous haematopoietic disease. It is characterized by an increased proliferation of haematopoietic progenitor cells that have lost the ability to differentiate. In the last 15 years, major advances have been made in the disease with the discovery of many genetic abnormalities affecting cell proliferation, differentiation, apoptosis or cell cycle regulation. Some of these molecular markers confer good prognosis while others have been found to be adverse prognostic factors. Of the molecular markers, DNMT3A (DNA N-methyltransferase 3A) gene mutation is found to be an independent poor prognostic marker in most studies.
Aims
In this study, we evaluated the mutation status of DNMT3A in AML patients with intermediate-risk cytogenetics, in particular, those with normal karyotype. The incidence of DNMT3A mutations was correlated with the mutation status of other genes like FLT3, NPM1, IDH1 and IDH2 which were also determined.
Methods
For the detection of DNMT3A mutations, exon 26 of the gene was PCR amplified and direct sequencing of the amplicons was performed to detect mutation hotspots in this exon in a cohort of 93 patients.
Results
A total of 16(17%) patients were identified with R822 mutations in DNMT3A exon 26. R882H was the predominant mutation in these patients (n=10) while the remaining 6 had R822C. Of these 16 patients, 14 (87.5%) of them were also NPM1-mutated while 9 had FLT3/ITDs as well. The close association of DNMT3A mutations with NPM1 mutations was significant (p=0.048) while that with FLT3/ITDs was not quite statistically significant (and p=0.084). IDH mutations were detected in only 3 patients with R882 mutations (IDH1 R132H, n=1; IDH2 R140Q, n=2).The relation between DNMT3A mutations and other patient characteristics were determined by the Mann Whitney U test (continuous variables) and the Fisher exact test (categorical variables) (details in Table 1). The platelet counts were significantly higher in the DNMT3A -positive patients than in the patients without DNMT3A mutation (p=0.0125). DNMT3A mutations were also significantly enriched in patients with the FAB M5 subtype (12/22, 55%, p=<0.0001). Other clinical parameters showed no significant difference between the DNMT3A-positive group and the wild type group.Interestingly, in a patient who was separately investigated, FLT3/ITDmut, NPM1mut and DNMT3A R882C were detected at diagnosis but while FLT3/ITD was not detected on follow-up at relapse, an IDH2 R140Q was observed. The R882C status, however, remained unchanged. Previous larger study series have demonstrated the stability of DNMT3A during the course of disease.
Conclusion
Within the normal karyotype and other intermediate risk AMLs, we did not observe any significant correlation of DNMT3A mutations with white blood cell counts, FLT3/ITD or IDH mutations, contrary to what was observed in other studies which involved AMLs across all cytogenetic risk groups.We hope the findings from this preliminary study would help improve our understanding of the association of DNMT3A mutations with other gene mutations in intermediate risk AMLs. Further work is needed to investigate the significance of the DNMT3A exon 26 mutations, in particular, the R882 mutations, as a prognostic predictor and the role of screening of these mutations for further risk-stratification of intermediate risk AMLs, particularly in normal karyotype AML.
Session topic: E-poster
Keyword(s): AML, Mutation
Abstract: E940
Type: Eposter Presentation
Background
Acute myeloid leukaemia is an aggressive heterogeneous haematopoietic disease. It is characterized by an increased proliferation of haematopoietic progenitor cells that have lost the ability to differentiate. In the last 15 years, major advances have been made in the disease with the discovery of many genetic abnormalities affecting cell proliferation, differentiation, apoptosis or cell cycle regulation. Some of these molecular markers confer good prognosis while others have been found to be adverse prognostic factors. Of the molecular markers, DNMT3A (DNA N-methyltransferase 3A) gene mutation is found to be an independent poor prognostic marker in most studies.
Aims
In this study, we evaluated the mutation status of DNMT3A in AML patients with intermediate-risk cytogenetics, in particular, those with normal karyotype. The incidence of DNMT3A mutations was correlated with the mutation status of other genes like FLT3, NPM1, IDH1 and IDH2 which were also determined.
Methods
For the detection of DNMT3A mutations, exon 26 of the gene was PCR amplified and direct sequencing of the amplicons was performed to detect mutation hotspots in this exon in a cohort of 93 patients.
Results
A total of 16(17%) patients were identified with R822 mutations in DNMT3A exon 26. R882H was the predominant mutation in these patients (n=10) while the remaining 6 had R822C. Of these 16 patients, 14 (87.5%) of them were also NPM1-mutated while 9 had FLT3/ITDs as well. The close association of DNMT3A mutations with NPM1 mutations was significant (p=0.048) while that with FLT3/ITDs was not quite statistically significant (and p=0.084). IDH mutations were detected in only 3 patients with R882 mutations (IDH1 R132H, n=1; IDH2 R140Q, n=2).The relation between DNMT3A mutations and other patient characteristics were determined by the Mann Whitney U test (continuous variables) and the Fisher exact test (categorical variables) (details in Table 1). The platelet counts were significantly higher in the DNMT3A -positive patients than in the patients without DNMT3A mutation (p=0.0125). DNMT3A mutations were also significantly enriched in patients with the FAB M5 subtype (12/22, 55%, p=<0.0001). Other clinical parameters showed no significant difference between the DNMT3A-positive group and the wild type group.Interestingly, in a patient who was separately investigated, FLT3/ITDmut, NPM1mut and DNMT3A R882C were detected at diagnosis but while FLT3/ITD was not detected on follow-up at relapse, an IDH2 R140Q was observed. The R882C status, however, remained unchanged. Previous larger study series have demonstrated the stability of DNMT3A during the course of disease.
Conclusion
Within the normal karyotype and other intermediate risk AMLs, we did not observe any significant correlation of DNMT3A mutations with white blood cell counts, FLT3/ITD or IDH mutations, contrary to what was observed in other studies which involved AMLs across all cytogenetic risk groups.We hope the findings from this preliminary study would help improve our understanding of the association of DNMT3A mutations with other gene mutations in intermediate risk AMLs. Further work is needed to investigate the significance of the DNMT3A exon 26 mutations, in particular, the R882 mutations, as a prognostic predictor and the role of screening of these mutations for further risk-stratification of intermediate risk AMLs, particularly in normal karyotype AML.
Session topic: E-poster
Keyword(s): AML, Mutation
Type: Eposter Presentation
Background
Acute myeloid leukaemia is an aggressive heterogeneous haematopoietic disease. It is characterized by an increased proliferation of haematopoietic progenitor cells that have lost the ability to differentiate. In the last 15 years, major advances have been made in the disease with the discovery of many genetic abnormalities affecting cell proliferation, differentiation, apoptosis or cell cycle regulation. Some of these molecular markers confer good prognosis while others have been found to be adverse prognostic factors. Of the molecular markers, DNMT3A (DNA N-methyltransferase 3A) gene mutation is found to be an independent poor prognostic marker in most studies.
Aims
In this study, we evaluated the mutation status of DNMT3A in AML patients with intermediate-risk cytogenetics, in particular, those with normal karyotype. The incidence of DNMT3A mutations was correlated with the mutation status of other genes like FLT3, NPM1, IDH1 and IDH2 which were also determined.
Methods
For the detection of DNMT3A mutations, exon 26 of the gene was PCR amplified and direct sequencing of the amplicons was performed to detect mutation hotspots in this exon in a cohort of 93 patients.
Results
A total of 16(17%) patients were identified with R822 mutations in DNMT3A exon 26. R882H was the predominant mutation in these patients (n=10) while the remaining 6 had R822C. Of these 16 patients, 14 (87.5%) of them were also NPM1-mutated while 9 had FLT3/ITDs as well. The close association of DNMT3A mutations with NPM1 mutations was significant (p=0.048) while that with FLT3/ITDs was not quite statistically significant (and p=0.084). IDH mutations were detected in only 3 patients with R882 mutations (IDH1 R132H, n=1; IDH2 R140Q, n=2).The relation between DNMT3A mutations and other patient characteristics were determined by the Mann Whitney U test (continuous variables) and the Fisher exact test (categorical variables) (details in Table 1). The platelet counts were significantly higher in the DNMT3A -positive patients than in the patients without DNMT3A mutation (p=0.0125). DNMT3A mutations were also significantly enriched in patients with the FAB M5 subtype (12/22, 55%, p=<0.0001). Other clinical parameters showed no significant difference between the DNMT3A-positive group and the wild type group.Interestingly, in a patient who was separately investigated, FLT3/ITDmut, NPM1mut and DNMT3A R882C were detected at diagnosis but while FLT3/ITD was not detected on follow-up at relapse, an IDH2 R140Q was observed. The R882C status, however, remained unchanged. Previous larger study series have demonstrated the stability of DNMT3A during the course of disease.
Conclusion
Within the normal karyotype and other intermediate risk AMLs, we did not observe any significant correlation of DNMT3A mutations with white blood cell counts, FLT3/ITD or IDH mutations, contrary to what was observed in other studies which involved AMLs across all cytogenetic risk groups.We hope the findings from this preliminary study would help improve our understanding of the association of DNMT3A mutations with other gene mutations in intermediate risk AMLs. Further work is needed to investigate the significance of the DNMT3A exon 26 mutations, in particular, the R882 mutations, as a prognostic predictor and the role of screening of these mutations for further risk-stratification of intermediate risk AMLs, particularly in normal karyotype AML.
Session topic: E-poster
Keyword(s): AML, Mutation
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