INTRODUCCIN
Chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia in western countries. It is associated with a variety of chromosomal and molecular alterations, which may be associated with clinical and evolutionary features of the disease. Among these, mutations of TP53 gene or deletion 17p [...
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| Formato: | Tesis de maestría acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2019
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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_7015 http://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_7015.dir/7015.PDF |
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I28-R145-HWA_7015 |
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dspace |
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Universidad de Buenos Aires |
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I-28 |
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R-145 |
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Repositorio Digital de la Universidad de Buenos Aires (UBA) |
| language |
Español |
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spa |
| topic |
Genes TP53 Genes MDM2 Cáncer Leucemia linfocítica crónica LLC Ciencias de la vida |
| spellingShingle |
Genes TP53 Genes MDM2 Cáncer Leucemia linfocítica crónica LLC Ciencias de la vida Mercado Guzmán, Zema Verónica INTRODUCCIN |
| topic_facet |
Genes TP53 Genes MDM2 Cáncer Leucemia linfocítica crónica LLC Ciencias de la vida |
| description |
Chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia in western countries. It is associated with a variety of chromosomal and molecular alterations, which may be associated with clinical and evolutionary features of the disease. Among these, mutations of TP53 gene or deletion 17p [del(17p13)], are associated with inactivation of the p53 pathway, exhibiting an adverse prognosis. The frequency of TP53 mutations is relatively low in newly diagnosed CLL patients, but increases significantly with disease progression. TP53 gene plays a central role in cancer suppression and the maintenance of genome stability, controlling DNA damage response, proliferation and apoptosis. Different authors have reported that polymorphisms in TP53 or its regulators MDM2 or NQO1 may also lead to the inactivation of the p53 signaling pathway, being its study in CLL of great interest since it could play an important role in the development and clinical evolution of patients.
The aim of this work was to study the relationship of polymorphisms in genes of the p53 pathway with susceptibility and prognostic factors in Argentine patients with CLL. We have analyzed 89 patients and 122 healthy controls. Three polymorphisms in TP53: SNP213 G>C (rs1042522), IVS3 16 bp indel (rs17878362) and IVS6+62A>G (rs1625895); 2 in MDM2: SNP309T>G (rs2279744), MDM2 indel1518 (rs3730485) and SNP NQO1 609C>T (rs1800566) were studied by PCR methods. Analysis of genetic models by logistic regression has shown that the polymorphisms studied are not associated with the risk of developing CLL. The TP53 213-CC (OR=6.98, CI 1.25-38.9, p=0.016) and MDM2 309-GG (OR=8.97, CI 11.55-52.0, p=0.007) genotypes have been associated with increased risk of abnormal karyotypes. In addition, the TP53 213-CC, TP53 IVS3-ins/ins, MDM2 309-GG and NQO1 609-TT genotypes represented an increased risk for del(17p13). Our data indicate that genetic variability in the p53 pathway does not modulate the risk of developing CLL but it is related to the acquisition of chromosomal alterations specific to the pathology. Attenuation of the p53 pathway due to variant genotypes probably leads to the failure of DNA repair resulting in genomic instability, which in turn would contribute to the emergence of specific CLL chromosomal alterations. |
| author2 |
Slavutsky, Irma |
| author_facet |
Slavutsky, Irma Mercado Guzmán, Zema Verónica |
| format |
Tesis de maestría Tesis de maestría acceptedVersion |
| author |
Mercado Guzmán, Zema Verónica |
| author_sort |
Mercado Guzmán, Zema Verónica |
| title |
INTRODUCCIN |
| title_short |
INTRODUCCIN |
| title_full |
INTRODUCCIN |
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INTRODUCCIN |
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INTRODUCCIN |
| title_sort |
introduccin |
| publisher |
Facultad de Farmacia y Bioquímica |
| publishDate |
2019 |
| url |
http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=afamaster&cl=CL1&d=HWA_7015 http://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_7015.dir/7015.PDF |
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AT mercadoguzmanzemaveronica introduccin AT mercadoguzmanzemaveronica analisisdepolimorfismosenlosgenestp53ymdm2eleucemialinfociticacronica |
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1807326945702051840 |
| spelling |
I28-R145-HWA_70152024-03-07 INTRODUCCIN Chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia in western countries. It is associated with a variety of chromosomal and molecular alterations, which may be associated with clinical and evolutionary features of the disease. Among these, mutations of TP53 gene or deletion 17p [del(17p13)], are associated with inactivation of the p53 pathway, exhibiting an adverse prognosis. The frequency of TP53 mutations is relatively low in newly diagnosed CLL patients, but increases significantly with disease progression. TP53 gene plays a central role in cancer suppression and the maintenance of genome stability, controlling DNA damage response, proliferation and apoptosis. Different authors have reported that polymorphisms in TP53 or its regulators MDM2 or NQO1 may also lead to the inactivation of the p53 signaling pathway, being its study in CLL of great interest since it could play an important role in the development and clinical evolution of patients. The aim of this work was to study the relationship of polymorphisms in genes of the p53 pathway with susceptibility and prognostic factors in Argentine patients with CLL. We have analyzed 89 patients and 122 healthy controls. Three polymorphisms in TP53: SNP213 G>C (rs1042522), IVS3 16 bp indel (rs17878362) and IVS6+62A>G (rs1625895); 2 in MDM2: SNP309T>G (rs2279744), MDM2 indel1518 (rs3730485) and SNP NQO1 609C>T (rs1800566) were studied by PCR methods. Analysis of genetic models by logistic regression has shown that the polymorphisms studied are not associated with the risk of developing CLL. The TP53 213-CC (OR=6.98, CI 1.25-38.9, p=0.016) and MDM2 309-GG (OR=8.97, CI 11.55-52.0, p=0.007) genotypes have been associated with increased risk of abnormal karyotypes. In addition, the TP53 213-CC, TP53 IVS3-ins/ins, MDM2 309-GG and NQO1 609-TT genotypes represented an increased risk for del(17p13). Our data indicate that genetic variability in the p53 pathway does not modulate the risk of developing CLL but it is related to the acquisition of chromosomal alterations specific to the pathology. Attenuation of the p53 pathway due to variant genotypes probably leads to the failure of DNA repair resulting in genomic instability, which in turn would contribute to the emergence of specific CLL chromosomal alterations. Fil: Mercado Guzmán, Zema Verónica. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Buenos Aires, Argeentina Slavutsky, Irma Facultad de Farmacia y Bioquímica Fundia, Ariela Mercado Guzmán, Zema Verónica 2019-12-20 La leucemia linfocítica crónica (LLC) es la leucemia de adultos más frecuente en occidente, caracterizada por la acumulación de linfocitos B maduros en sangre periférica, médula ósea, órganos linfoides y bazo, y por presentar un curso clínico variable, siendo de gran interés el estudio de factores genéticos como los polimorfismos en la vía de p53 ya que pueden cumplir un rol importante en la etiología y la evolución clínica de la LLC. El gen TP53 desempeña un papel central en la supresión del cáncer, el mantenimiento de la estabilidad del genoma, el control de la respuesta al daño del ADN, la proliferación y la apoptosis. La pérdida de la función de este gen en la LLC debido a la deleción del cromosoma 17p o a mutaciones genéticas, se asocia a un pronóstico adverso. La frecuencia de las mutaciones de TP53 es relativamente baja en pacientes con LLC recién diagnosticados, pero aumenta considerablemente con la progresión de la enfermedad. Se ha reportado que los polimorfismos en el gen TP53 o en sus reguladores MDM2 o NQO1 llevan a la inactivación de la vía de señalización p53. El objetivo de este trabajo fue estudiar la relación de los polimorfismos en genes de la vía p53 con la susceptibilidad y los factores pronóstico en pacientes argentinos con LLC. Se analizaron 89 pacientes y 122 controles sanos. En todos los pacientes se realizó de rutina el estudio citogenético y de FISH (hibridación de fluorescencia in situ), así como el estado mutacional de IGHV. Se estudiaron 3 polimorfismos en TP53: SNP213 G>C (rs1042522), IVS3 16 bp indel (rs17878362) y IVS6+62A>G (rs1625895); 2 en MDM2: SNP309T>G (rs2279744), MDM2 indel1518 (rs3730485) y el SNP NQO1 609C>T (rs1800566) por diferentes técnicas de PCR. En el grupo control se confirmó que las frecuencias genotípicas de cada polimorfismo estaban en EHW (p>0,05). El análisis de los modelos genéticos por regresión logística demostró que los polimorfismos estudiados no se asocian con el riesgo a desarrollar LLC. Teniendo en cuenta el modelo recesivo, se encontró que los genotipos TP53 213-CC (OR=6,98; IC: 1,25-38,9; p=0,016) y MDM2 309-GG (OR=8,97; IC: 11,55-52,0; p=0,007) se asociaron con mayor riesgo de cariotipos anormales. Además, los pacientes con los genotipos TP53 213-CC, TP53 IVS3-ins/ins, MDM2 309-GG y NQO1 609-TT presentaron mayor riesgo para la del17p13. No se observaron asociaciones significativas con el estado mutacional de IGHV y los factores de pronóstico clínico. Nuestros datos indican que la variabilidad genética en la vía p53 no modula el riesgo a desarrollar LLC pero está relacionada con la adquisición de alteraciones cromosómicas específicas de la patología. La atenuación de la vía p53 debida a genotipos variantes probablemente conduce a una reparación deficiente del daño en el ADN que resulta en inestabilidad genómica, lo que a su vez contribuiría a la aparición de alteraciones cromosómicas específicas de la CLL. application/pdf Cerrone, Gloria Cotignola, Javier Silberstein Cuña, Susana Genes TP53 Genes MDM2 Cáncer Leucemia linfocítica crónica LLC 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/ Ciencias de la vida Análisis de polimorfismos en los genes TP53 y MDM2 e leucemia linfocítica crónica 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_7015 http://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_7015.dir/7015.PDF |