Determinación de las mutaciones en los genes NPM1 y CEBPA en leucemia mieloblástica aguda pediátrica mediante PCR y genescanning
Background: Mutations of NPM1,CEBPA and FLT3 are found in 25 to 35% of\nadult-AML. These mutations correlate with outcome, especially in AML with normal\nkaryotype. There are few reports concerning the incidence and significance of\nthese mutations in childhood-AML and there is no data from Argentin...
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| Formato: | Tesis de maestría acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2015
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=afamaster&cl=CL1&d=HWA_1129 http://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_1129.dir/1129.PDF |
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| Sumario: | Background: Mutations of NPM1,CEBPA and FLT3 are found in 25 to 35% of\nadult-AML. These mutations correlate with outcome, especially in AML with normal\nkaryotype. There are few reports concerning the incidence and significance of\nthese mutations in childhood-AML and there is no data from Argentina.\nObjective: To describe the incidence of these mutations and to analyze the clinical\nand prognostic impact in the outcome in our setting.\nMethods: Samples from 216 children treated with AML protocols were\nretrospectively analyzed. The mean age at diagnosis was 6.8 [0.0-17.9] years,\nincluding 44 patients younger than 1 year of age.Fifteen percent/ Of them,\n15%/presented a normal karyotype (NK). Detection of NPM1 and CEBPA\nmutations was performed by Gene-scanning; FLT3-ITD and FLT3-TKD were\nstudied by RT-PCR and RFLP respectively. Positive cases were further\ncharacterized by sequencing analysis.\nResults: The incidences of the studied mutations were: NPM1mut: 4.2%,\nCEBPAmut: 1.9%, FLT3-ITD: 10.2% and FLT3-TKD: 7.9%. Within the group of AML\nwith NK the incidences were: NPM1mut: 24.2%,CEBPAmut: 12.1%, FLT3-ITD: 15.2%\nand FLT3-TKD: 6.1%. The mean age for each subgroup was: NPM1mut: 13.4 years,\nCEBPAmut: 11.6 years, FLT3-ITD: 13.8 years and FLT3-TKD: 8.0 years. NPM1 and\nCEBPAshowed significant association with NK (p<0.00001 and p=0.001,\nrespectively), and FLT3-ITD with PML-RARA (p<0.0001).The most frequently\nobserved FAB subtypes were: NPM1mut: M2 (p=0.1322), CEBPAmut: M2\n(p=0.0281), FLT3-ITD: M3 (p=0.0002) and FLT3-TKD: M5 (p=0.3258). The age of\nResumen\nPágina 4\npatients with FLT3-ITDmut, NPM1mut and CEBPAmut were significantly higher\n(p=0.0001, p=0.0368 y p<0.00001respectively). FLT3-TKD was the only mutation\ndetected in 11.4% of patients younger than 1 year of age.\nThe event-free survival probabilities (pEFS) and standard error (SE) were: Total\nAML: 48.9(3.8)%, NPM1mut: 75.0(15.3)%, CEBPAmut: 75.0(21.7)%, FLT3-ITD:\n59.6(11.1)%, FLT3-TKD: 46.0(16.2)% y NPM1mut/CEBPAmut/FLT3-ITDneg:\n80.8(12.2)%(p=0.2002). The pEFS (SE) of patients NPM1mut/CEBPAmut/FLT3-\nITDneg with normal karyotype was 78.8(13.4)% (p=0.0593) and for the high risk\ngroup was 80.8(12.3)% (p=0.0104).\nConclusions: This is the first report of the frequencies of NPM1, CEBPA and FLT3\nmutations in childhood AML in our country. The incidences of NPM1mut and\nCEBPAmut were significantly higher in AML with normal karyotype. Our data\nconfirm the favorable prognosis of AML with NPM1mut/FLT3-ITDneg and/or\nCEBPAmut/FLT3-ITDneg genotypes, supporting the notion that they should be\nconsidered as a new AML subset with better outcome. |
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