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Role of ASXL1 and TP53 mutations in the molecular classification and prognosis of acute myeloid leukemias with myelodysplasia-related changes.

Devillier R, Mansat-De Mas V, Gelsi-Boyer V, Demur C, Murati A, Corre J, Prebet T, Bertoli S, Brecqueville M, Arnoulet C, Recher C, Vey N, Mozziconacci MJ, Delabesse E, Birnbaum D - Oncotarget (2015)

Bottom Line: ASXL1 mutations (n=26, 21%) were associated with a higher proportion of marrow dysgranulopoiesis (mutant vs. wild-type: 75% vs. 55%, p=0.030) and were mostly found in intermediate cytogenetic AML (23/26) in which they predicted inferior 2-year overall survival (OS, mutant vs. wild-type: 14% vs. 37%, p=0.030).In multivariate analysis, the presence of either ASXL1 or TP53 mutation was the only independent factor associated with shorter OS (HR, 95%CI: 2.53, 1.40-4.60, p=0.002) while MLD, MDS-related cytogenetics and previous MDS history did not influence OS.We conclude that ASXL1 and TP53 mutations identify two molecular subgroups among AML-MRCs, with specific poor prognosis.

View Article: PubMed Central - PubMed

Affiliation: Hematology Department, Institut Paoli Calmettes, Marseille, France.

ABSTRACT
Acute myeloid leukemias (AML) with myelodysplasia-related changes (AML-MRC) are defined by the presence of multilineage dysplasia (MLD), and/or myelodysplastic syndrome (MDS)-related cytogenetics, and/or previous MDS. The goal of this study was to identify distinct biological and prognostic subgroups based on mutations of ASXL1, RUNX1, DNMT3A, NPM1, FLT3 and TP53 in 125 AML-MRC patients according to the presence of MLD, cytogenetics and outcome. ASXL1 mutations (n=26, 21%) were associated with a higher proportion of marrow dysgranulopoiesis (mutant vs. wild-type: 75% vs. 55%, p=0.030) and were mostly found in intermediate cytogenetic AML (23/26) in which they predicted inferior 2-year overall survival (OS, mutant vs. wild-type: 14% vs. 37%, p=0.030). TP53 mutations (n=28, 22%) were mostly found in complex karyotype AML (26/28) and predicted poor outcome within unfavorable cytogenetic risk AML (mutant vs. wild-type: 9% vs. 40%, p=0.040). In multivariate analysis, the presence of either ASXL1 or TP53 mutation was the only independent factor associated with shorter OS (HR, 95%CI: 2.53, 1.40-4.60, p=0.002) while MLD, MDS-related cytogenetics and previous MDS history did not influence OS. We conclude that ASXL1 and TP53 mutations identify two molecular subgroups among AML-MRCs, with specific poor prognosis. This could be useful for future diagnostic and prognostic classifications.

No MeSH data available.


Related in: MedlinePlus

Co mutation profile of ASXL1, RUNX1, DNMT3A, NPM1, FLT3-ITD and TP53 genes in the 125 patients with AML-MRC: Karyotypes: normal (light grey), abnormal non-complex (dark grey) and complex (black)Cytogenetics risk group: intermediate (light blue) and unfavorable (dark blue). MLD: green bars indicate the presence of criteria for MLD and grey bars are samples that were not evaluable for MLD. These latter had at least one other criteria for AML-MRC to enrolled them in this study. MDS = myelodysplastic syndrome; MLD = multilineage dysplasia.
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Figure 1: Co mutation profile of ASXL1, RUNX1, DNMT3A, NPM1, FLT3-ITD and TP53 genes in the 125 patients with AML-MRC: Karyotypes: normal (light grey), abnormal non-complex (dark grey) and complex (black)Cytogenetics risk group: intermediate (light blue) and unfavorable (dark blue). MLD: green bars indicate the presence of criteria for MLD and grey bars are samples that were not evaluable for MLD. These latter had at least one other criteria for AML-MRC to enrolled them in this study. MDS = myelodysplastic syndrome; MLD = multilineage dysplasia.

Mentions: TP53 mutations were exclusive from all other mutations and all but two (26/28, 93%) were found in CK-AML. Mutations in the other genes were almost exclusively found in NCK-AMLs (Table 2A, Figure 1). In NCK-AMLs, ASXL1 was the most frequently mutated gene (26/83, 31%). These mutations were associated with the absence of MDS-related cytogenetics (MDS-related cytogenetics: yes vs. no: 4/29, 14% vs. 22/54, 41%, p = 0.013). Other mutations were equally distributed whether MDS-related cytogenetics was present or not (Figure 1).


Role of ASXL1 and TP53 mutations in the molecular classification and prognosis of acute myeloid leukemias with myelodysplasia-related changes.

Devillier R, Mansat-De Mas V, Gelsi-Boyer V, Demur C, Murati A, Corre J, Prebet T, Bertoli S, Brecqueville M, Arnoulet C, Recher C, Vey N, Mozziconacci MJ, Delabesse E, Birnbaum D - Oncotarget (2015)

Co mutation profile of ASXL1, RUNX1, DNMT3A, NPM1, FLT3-ITD and TP53 genes in the 125 patients with AML-MRC: Karyotypes: normal (light grey), abnormal non-complex (dark grey) and complex (black)Cytogenetics risk group: intermediate (light blue) and unfavorable (dark blue). MLD: green bars indicate the presence of criteria for MLD and grey bars are samples that were not evaluable for MLD. These latter had at least one other criteria for AML-MRC to enrolled them in this study. MDS = myelodysplastic syndrome; MLD = multilineage dysplasia.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480760&req=5

Figure 1: Co mutation profile of ASXL1, RUNX1, DNMT3A, NPM1, FLT3-ITD and TP53 genes in the 125 patients with AML-MRC: Karyotypes: normal (light grey), abnormal non-complex (dark grey) and complex (black)Cytogenetics risk group: intermediate (light blue) and unfavorable (dark blue). MLD: green bars indicate the presence of criteria for MLD and grey bars are samples that were not evaluable for MLD. These latter had at least one other criteria for AML-MRC to enrolled them in this study. MDS = myelodysplastic syndrome; MLD = multilineage dysplasia.
Mentions: TP53 mutations were exclusive from all other mutations and all but two (26/28, 93%) were found in CK-AML. Mutations in the other genes were almost exclusively found in NCK-AMLs (Table 2A, Figure 1). In NCK-AMLs, ASXL1 was the most frequently mutated gene (26/83, 31%). These mutations were associated with the absence of MDS-related cytogenetics (MDS-related cytogenetics: yes vs. no: 4/29, 14% vs. 22/54, 41%, p = 0.013). Other mutations were equally distributed whether MDS-related cytogenetics was present or not (Figure 1).

Bottom Line: ASXL1 mutations (n=26, 21%) were associated with a higher proportion of marrow dysgranulopoiesis (mutant vs. wild-type: 75% vs. 55%, p=0.030) and were mostly found in intermediate cytogenetic AML (23/26) in which they predicted inferior 2-year overall survival (OS, mutant vs. wild-type: 14% vs. 37%, p=0.030).In multivariate analysis, the presence of either ASXL1 or TP53 mutation was the only independent factor associated with shorter OS (HR, 95%CI: 2.53, 1.40-4.60, p=0.002) while MLD, MDS-related cytogenetics and previous MDS history did not influence OS.We conclude that ASXL1 and TP53 mutations identify two molecular subgroups among AML-MRCs, with specific poor prognosis.

View Article: PubMed Central - PubMed

Affiliation: Hematology Department, Institut Paoli Calmettes, Marseille, France.

ABSTRACT
Acute myeloid leukemias (AML) with myelodysplasia-related changes (AML-MRC) are defined by the presence of multilineage dysplasia (MLD), and/or myelodysplastic syndrome (MDS)-related cytogenetics, and/or previous MDS. The goal of this study was to identify distinct biological and prognostic subgroups based on mutations of ASXL1, RUNX1, DNMT3A, NPM1, FLT3 and TP53 in 125 AML-MRC patients according to the presence of MLD, cytogenetics and outcome. ASXL1 mutations (n=26, 21%) were associated with a higher proportion of marrow dysgranulopoiesis (mutant vs. wild-type: 75% vs. 55%, p=0.030) and were mostly found in intermediate cytogenetic AML (23/26) in which they predicted inferior 2-year overall survival (OS, mutant vs. wild-type: 14% vs. 37%, p=0.030). TP53 mutations (n=28, 22%) were mostly found in complex karyotype AML (26/28) and predicted poor outcome within unfavorable cytogenetic risk AML (mutant vs. wild-type: 9% vs. 40%, p=0.040). In multivariate analysis, the presence of either ASXL1 or TP53 mutation was the only independent factor associated with shorter OS (HR, 95%CI: 2.53, 1.40-4.60, p=0.002) while MLD, MDS-related cytogenetics and previous MDS history did not influence OS. We conclude that ASXL1 and TP53 mutations identify two molecular subgroups among AML-MRCs, with specific poor prognosis. This could be useful for future diagnostic and prognostic classifications.

No MeSH data available.


Related in: MedlinePlus