Identificación de los cambios en los perfiles de metilación de DNA y de expresión génica, asociados a la respuesta clínica al tratamiento quimioterapéutico en pacientes pediátricos con leucemia linfoide aguda tipo B

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dc.contributor.advisorCombita Rojas, Alba Lucia
dc.contributor.advisorLopez Kleine, Liliana
dc.contributor.authorTorres Llanos, Yulieth Ximena
dc.contributor.cvlacYulieth Ximena Torres Llanosspa
dc.contributor.googlescholarYULIETH XIMENA TORRES LLANOSspa
dc.contributor.orcid0000-0002-2859-6980spa
dc.contributor.researchgroupBiología del cáncer. Instituto Nacional de Cancerologíaspa
dc.date.accessioned2023-06-29T14:29:58Z
dc.date.available2023-06-29T14:29:58Z
dc.date.issued2023-03
dc.descriptionilustracionesspa
dc.description.abstractLas leucemias linfoides agudas de células B (LLA-B) son las enfermedades neoplásicas más comunes en niños. Las tasas de supervivencia en la población pediátrica hispana son más bajas en comparación con la supervivencia en niños no hispanos. Por tanto, es necesario encontrar biomarcadores predictivos de respuesta al tratamiento y de pronóstico de recaída y muerte en esta población. El objetivo de este estudio fue identificar biomarcadores de respuesta al tratamiento de inducción, que también pudiesen predecir la recaída y la muerte, a través de la identificación de genes diferencialmente metilados y expresados entre pacientes que respondieron o no a la quimioterapia de inducción. Se extrajeron muestras de DNA y RNA de 46 muestras de médula ósea de niños hispanos recién diagnosticados con LLA-B. Treinta y dos muestras fueron utilizadas como cohorte descriptiva (27 de diagnóstico y 5 post quimioterapia), en la cual se hicieron los análisis de secuencia de RNA y metilación de DNA para elegir los genes candidatos a biomarcadores de respuesta al tratamiento. Por su parte, 18 muestras se utilizaron para validar el set de genes seleccionados del anterior análisis. El mRNA fue secuenciado en el equipo NextSeq500 de Illumina. El DNA fue previamente tratado con bisulfito de sodio y posteriormente se hibridó a los chips de metilación Illumina Infinium EPIC. Los análisis de expresión y metilación diferencial se hicieron a través de la comparación de los perfiles entre respondedores y no respondedores al día 15, al final de la quimioterapia de inducción. Se encontró que DAPK1, CNKSR3, MIR4435-HG2, CTHRC1, NPDC1, SLC45A3, ITGA6 y ASCL2 se sobreexpresaban en los pacientes no respondedores, y también se evidenció que tenían CpGs hipometiladas, dichos hallazgos fueron comunes en todos los grupos analizados. Se hicieron análisis de regresión logística y curvas ROC, se determinó que la sobreexpresión de MIR4435-2HG, DAPK1, ASCL2, SCL45A3, CNKSR3 y NPDC1 puede predecir la falla en la respuesta al día 15 y la refractariedad. Además, con alta sensibilidad y especificidad se evidenció que una mayor expresión de MIR4435-2HG aumenta la probabilidad de falla terapéutica y el riesgo de fallecer. A su vez, se observó que DAPK1, CNKSR3 y MIR4435-2HG también se sobreexpresan en muestras de recaída. Finalmente, la sobreexpresión de MIR4435-2HG en conjunto con la detección de la enfermedad mínima residual positiva se asocian con una menor supervivencia, y la alta expresión de MIR4435-2HG, DAPK1 y ASCL2 mejoran la clasificación de riesgo de los pacientes con cariotipo normal. En conclusión, en este estudio se observó que la expresión de MIR4435-2HG es un potencial biomarcador predictivo y pronóstico en niños hispanos con LLA-B, y su detección en el momento del diagnóstico podría mejorar las tasas de supervivencia en nuestros pacientes. (Texto tomado de la fuente)spa
dc.description.abstractAunque las tasas de supervivencia de la leucemia linfoblástica aguda de células B (LLAB) han mejorado en los últimos años, los niños hispanos siguen teniendo peores tasas de supervivencia. El objetivo de este proyecto fue identificar biomarcadores de respuesta al tratamiento, que también pueden predecir la recaída y la muerte, mediante la identificación de genes metilados y expresados diferencialmente entre los pacientes que respondieron o no respondieron al tratamiento de inducción. Se realizaron ensayos de metilación de DNA y secuenciación de mRNA en 27 médulas óseas de niños hispanos con LLA-B. Se compararon la expresión génica y la metilación diferencial entre los pacientes que respondieron y los que no respondieron el día 15 y al final de la quimioterapia de inducción. DAPK1, CNKSR3, MIR4435-HG2, CTHRC1, NPDC1, SLC45A3, ITGA6 y ASCL2 estaban sobreexpresados e hipometilados en los pacientes no respondedores. La sobreexpresión de DAPK1, ASCL2, SCL45A3, NPDC1 e ITGA6 puede predecir la falla de respuesta al día 15 y la refractariedad. Además, una mayor expresión de MIR4435-2HG aumenta la probabilidad de no respuesta, muerte y riesgo de muerte. MIR4435-2HG también se sobreexpresa en muestras de recaída. Por último, la sobreexpresión de MIR4435-2HG, junto con la enfermedad mínima residual positiva, se asocian a una peor supervivencia, y junto con la sobreexpresión de DAPK1 y ASCL2, podría mejorar la clasificación del riesgo de los pacientes con cariotipo normal. MIR4435-2HG es un biomarcador predictivo potencial en niños con LLA-Beng
dc.description.degreelevelDoctoradospa
dc.description.degreenameDoctor en Ciencias Biomédicasspa
dc.description.methodsEstudio descriptivo analítico en paciente con diagnóstico de novo de leucemia linfoide B. Se extrajeron muestras de DNA y RNA de 46 muestras de médula ósea de niños hispanos recién diagnosticados con LLA-B. Treinta y dos muestras fueron utilizadas como cohorte descriptiva (27 de diagnóstico y 5 post quimioterapia), en la cual se hicieron los análisis de secuencia de RNA y metilación de DNA para elegir los genes candidatos a biomarcadores de respuesta al tratamiento. Por su parte, 18 muestras se utilizaron para validar el set de genes seleccionados del anterior análisis. El mRNA fue secuenciado en el equipo NextSeq500 de Illumina. El DNA fue previamente tratado con bisulfito de sodio y posteriormente se hibridó a los chips de metilación Illumina Infinium EPIC. Los análisis de expresión y metilación diferencial se hicieron a través de la comparación de los perfiles entre respondedores y no respondedores al día 15, al final de la quimioterapia de inducción. Los genes seleccionados fueron validados por RT-qPCR. Posteriormente, se hicieron regresiones logísticas y regresiones de Cox para determinar la capacidad predicitiva de cada gen, así como su asociación con el aumento del riesgo de muerte.spa
dc.description.researchareaBiomarcadores predictivos de respuesta al tratamiento en leucemias linfoides agudasspa
dc.format.extent132 páginasspa
dc.format.mimetypeapplication/pdfspa
dc.identifier.instnameUniversidad Nacional de Colombiaspa
dc.identifier.reponameRepositorio Institucional Universidad Nacional de Colombiaspa
dc.identifier.repourlhttps://repositorio.unal.edu.co/spa
dc.identifier.urihttps://repositorio.unal.edu.co/handle/unal/84105
dc.language.isospaspa
dc.publisherUniversidad Nacional de Colombiaspa
dc.publisher.branchUniversidad Nacional de Colombia - Sede Bogotáspa
dc.publisher.facultyFacultad de Medicinaspa
dc.publisher.placeBogotá,Colombiaspa
dc.publisher.programBogotá - Medicina - Doctorado en Ciencias Biomédicasspa
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dc.rights.accessrightsinfo:eu-repo/semantics/openAccessspa
dc.rights.licenseAtribución-NoComercial-SinDerivadas 4.0 Internacionalspa
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/spa
dc.subject.ddc610 - Medicina y salud::616 - Enfermedadesspa
dc.subject.decsNeoplasiasspa
dc.subject.decsNeoplasmseng
dc.subject.decsInsuficiencia del tratamientospa
dc.subject.decsTreatment Failureeng
dc.subject.proposalLeucemia linfoide agudaspa
dc.subject.proposalExpresión génicaspa
dc.subject.proposalMetilación de DNAspa
dc.subject.proposalBiomarcadores predictivosspa
dc.subject.proposalAcute lymphoid leukemiaeng
dc.subject.proposalGene expressioneng
dc.subject.proposalDNA methylationeng
dc.subject.proposalPredictive biomarkers
dc.titleIdentificación de los cambios en los perfiles de metilación de DNA y de expresión génica, asociados a la respuesta clínica al tratamiento quimioterapéutico en pacientes pediátricos con leucemia linfoide aguda tipo Bspa
dc.title.translatedIdentification of changes in DNA methylation and gene expression profiles associated with clinical response to chemotherapeutic treatment in pediatric patients with type B acute lymphoid leukemiaeng
dc.typeTrabajo de grado - Doctoradospa
dc.type.coarhttp://purl.org/coar/resource_type/c_bdccspa
dc.type.coarversionhttp://purl.org/coar/version/c_ab4af688f83e57aaspa
dc.type.contentTextspa
dc.type.driverinfo:eu-repo/semantics/masterThesisspa
dc.type.redcolhttp://purl.org/redcol/resource_type/TMspa
dc.type.versioninfo:eu-repo/semantics/acceptedVersionspa
dcterms.audience.professionaldevelopmentEstudiantesspa
dcterms.audience.professionaldevelopmentInvestigadoresspa
dcterms.audience.professionaldevelopmentMaestrosspa
dcterms.audience.professionaldevelopmentPúblico generalspa
oaire.accessrightshttp://purl.org/coar/access_right/c_abf2spa
oaire.awardtitleIdentificación de los cambios en los perfiles de metilación de DNA y de expresión génica, asociados a la respuesta clínica al tratamiento quimioterapéutico en pacientes pediátricos con leucemia linfoide aguda tipo Bspa
oaire.fundernameInstituto Nacional de Cancerologíaspa

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