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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Detalles Bibliográficos
Autor principal: Rubio Longo, Patricia
Otros Autores: Alonso, Cristina N.
Formato: Tesis de maestría acceptedVersion
Lenguaje:Español
Publicado: Facultad de Farmacia y Bioquímica 2015
Materias:
NPM1
CEBPA
Leucemia
Pediatría
Pronóstico
Ciencia de la vida
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
Aporte de:
Repositorio Digital de la Universidad de Buenos Aires (UBA) de Universidad de Buenos Aires
id I28-R145-HWA_1129
record_format dspace
institution Universidad de Buenos Aires
institution_str I-28
repository_str R-145
collection Repositorio Digital de la Universidad de Buenos Aires (UBA)
language Español
orig_language_str_mv spa
topic NPM1
CEBPA
Leucemia
Pediatría
Pronóstico
Ciencia de la vida
spellingShingle NPM1
CEBPA
Leucemia
Pediatría
Pronóstico
Ciencia de la vida
Rubio Longo, Patricia
Determinación de las mutaciones en los genes NPM1 y CEBPA en leucemia mieloblástica aguda pediátrica mediante PCR y genescanning
topic_facet NPM1
CEBPA
Leucemia
Pediatría
Pronóstico
Ciencia de la vida
description 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.
author2 Alonso, Cristina N.
author_facet Alonso, Cristina N.
Rubio Longo, Patricia
format Tesis de maestría
Tesis de maestría
acceptedVersion
author Rubio Longo, Patricia
author_sort Rubio Longo, Patricia
title Determinación de las mutaciones en los genes NPM1 y CEBPA en leucemia mieloblástica aguda pediátrica mediante PCR y genescanning
title_short Determinación de las mutaciones en los genes NPM1 y CEBPA en leucemia mieloblástica aguda pediátrica mediante PCR y genescanning
title_full Determinación de las mutaciones en los genes NPM1 y CEBPA en leucemia mieloblástica aguda pediátrica mediante PCR y genescanning
title_fullStr Determinación de las mutaciones en los genes NPM1 y CEBPA en leucemia mieloblástica aguda pediátrica mediante PCR y genescanning
title_full_unstemmed Determinación de las mutaciones en los genes NPM1 y CEBPA en leucemia mieloblástica aguda pediátrica mediante PCR y genescanning
title_sort determinación de las mutaciones en los genes npm1 y cebpa en leucemia mieloblástica aguda pediátrica mediante pcr y genescanning
publisher Facultad de Farmacia y Bioquímica
publishDate 2015
url 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
work_keys_str_mv AT rubiolongopatricia determinaciondelasmutacionesenlosgenesnpm1ycebpaenleucemiamieloblasticaagudapediatricamediantepcrygenescanning
_version_ 1766017452432424960
spelling I28-R145-HWA_11292019-09-27 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. Fil: Rubio Longo, Patricia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina Facultad de Farmacia y Bioquímica Alonso, Cristina N. Rubio Longo, Patricia 2015-04-15 Introducción: Las mutaciones de NPM1, CEBPA y FLT3 se encuentran en 25-\n35% de las LMA de adultos. Estas mutaciones se correlacionan con el pronóstico\nde la enfermedad, especialmente en LMA con cariotipo normal (CN). Hay pocos\ninformes sobre la incidencia e importancia de estas mutaciones en LMA pediátrica\ny no hay datos de Argentina.\nObjetivo: Describir la incidencia de estas mutaciones y analizar el impacto clínico\ny pronóstico de las mutaciones en nuestra institución.\nPacientes y Métodos: Se analizaron retrospectivamente muestras de 216 niños\ncon LMA. La mediana de edad fue de 7,0 [0,0-17,9] años, incluyendo 44 pacientes\nmenores a un año. El 15% de los pacientes presentaron CN. La detección de\nmutaciones NPM1 y CEBPA fueron realizadas por Gene-Scanning; las mutaciones\nFLT3-ITD y FLT3-TKD fueron estudiadas por RT-PCR y RFLP, respectivamente.\nLos casos positivos se caracterizaron además por secuenciación.\nResultados: La incidencia de las mutaciones estudiadas fueron: NPM1mut:4,2%,\nCEBPAmut:1,9%, FLT3-ITD:10,2% y FLT3-TKD:7,9%. En LMA con CN fueron:\nNPM1mut:24,2%,CEBPAmut:12,1%, FLT3-ITD:15,2% y FLT3-TKD:6,1%. La media\nde edad fue:NPM1mut:13,4 años, CEBPAmut:11,6 años,FLT3-ITD:13,8 años y FLT3-\nTKD: 8,0 años. NPM1 y CEBPA mostraron asociación significativa con CN\n(p<0,00001, p=0,001, respectivamente), mientras que FLT3-ITDse asoció\nconPML/RARA (p<0,0001). Los subtipos FAB observados con mayor frecuencia\nfueron: NPM1mut:M2 (p=0,1322), CEBPAmut:M2 (p=0,0281), FLT3-ITD:M3\n(p=0,0002) y FLT3-TKD:M5 (p=0,3258). Las edades de los pacientes con\nResumen\nPágina 2\nNPM1mut, CEBPAmut y FLT3-ITD fueron significativamente mayores (p=0,0001,\np=0,0368 y p<0,00001 respectivamente). FLT3-TKD fue la única mutación\ndetectada en 11,4% de los pacientes menores de 1 año.\nLas probabilidades de sobrevida libre de eventos (pSLE) y error estándar (EE)\nfueron: LMA Total:48,9(3,8)%, NPM1mut:75,0(15,3)%, CEBPAmut:75,0(21,7)%,\nFLT3-ITD: 59,6(11,1)%, FLT3-TKD: 46,0(16,2)%y NPM1mut/CEBPAmut/FLT3-\nITDneg:80,8(12,2)%(p=0,2002). Las pSLE (SE) de los pacientes\nNPM1mut/CEBPAmut/FLT3-ITDneg con CN fue de 78,8(13,4)%(p=0,0593) y en el\ngrupo de riesgo alto fue de 80,8(12,3)% (p=0,0104).\nConclusiones: Este es el primer reporte de las frecuencias de mutaciones\nenNPM1, CEBPA y FLT3en LMA pediátrica en nuestro país. Las incidencias de\nNPM1mut y CEBPAmut fueron significativamente más altas en la LMA con cariotipo\nnormal. Nuestros datos confirman el pronóstico favorable de LMA con genotipos\nNPM1mut/FLT3-ITDneg y/o CEBPAmut/FLT3-ITDneg, apoyando la postulación de este\ngrupo como un nuevo subtipo de LMA con mejor pronóstico. application/pdf Lazarowski, Alberto Fundia, Ariela Varela, Viviana NPM1 CEBPA Leucemia Pediatría Pronóstico spa Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ Ciencia de la vida Determinación de las mutaciones en los genes NPM1 y CEBPA en leucemia mieloblástica aguda pediátrica mediante PCR y genescanning info:eu-repo/semantics/masterThesis info:ar-repo/semantics/tesis de maestría info:eu-repo/semantics/acceptedVersion 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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