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
ilustraciones
- Autores:
-
Torres Llanos, Yulieth Ximena
- Tipo de recurso:
- Fecha de publicación:
- 2023
- Institución:
- Universidad Nacional de Colombia
- Repositorio:
- Universidad Nacional de Colombia
- Idioma:
- spa
- OAI Identifier:
- oai:repositorio.unal.edu.co:unal/84105
- Palabra clave:
- 610 - Medicina y salud::616 - Enfermedades
Neoplasias
Insuficiencia del tratamiento
Neoplasms
Treatment Failure
Leucemia linfoide aguda
Expresión génica
Metilación de DNA
Biomarcadores predictivos
Acute lymphoid leukemia
Gene expression
DNA methylation
Predictive biomarkers
- Rights
- openAccess
- License
- Atribución-NoComercial-SinDerivadas 4.0 Internacional
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UNACIONAL2 |
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| dc.title.spa.fl_str_mv |
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 |
| dc.title.translated.eng.fl_str_mv |
Identification of changes in DNA methylation and gene expression profiles associated with clinical response to chemotherapeutic treatment in pediatric patients with type B acute lymphoid leukemia |
| title |
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 |
| spellingShingle |
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 610 - Medicina y salud::616 - Enfermedades Neoplasias Insuficiencia del tratamiento Neoplasms Treatment Failure Leucemia linfoide aguda Expresión génica Metilación de DNA Biomarcadores predictivos Acute lymphoid leukemia Gene expression DNA methylation Predictive biomarkers |
| title_short |
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 |
| title_full |
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 |
| title_fullStr |
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 |
| title_full_unstemmed |
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 |
| title_sort |
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 |
| dc.creator.fl_str_mv |
Torres Llanos, Yulieth Ximena |
| dc.contributor.advisor.none.fl_str_mv |
Combita Rojas, Alba Lucia Lopez Kleine, Liliana |
| dc.contributor.author.none.fl_str_mv |
Torres Llanos, Yulieth Ximena |
| dc.contributor.researchgroup.spa.fl_str_mv |
Biología del cáncer. Instituto Nacional de Cancerología |
| dc.contributor.orcid.spa.fl_str_mv |
0000-0002-2859-6980 |
| dc.contributor.cvlac.spa.fl_str_mv |
Yulieth Ximena Torres Llanos |
| dc.contributor.googlescholar.spa.fl_str_mv |
YULIETH XIMENA TORRES LLANOS |
| dc.subject.ddc.spa.fl_str_mv |
610 - Medicina y salud::616 - Enfermedades |
| topic |
610 - Medicina y salud::616 - Enfermedades Neoplasias Insuficiencia del tratamiento Neoplasms Treatment Failure Leucemia linfoide aguda Expresión génica Metilación de DNA Biomarcadores predictivos Acute lymphoid leukemia Gene expression DNA methylation Predictive biomarkers |
| dc.subject.decs.spa.fl_str_mv |
Neoplasias Insuficiencia del tratamiento |
| dc.subject.decs.eng.fl_str_mv |
Neoplasms Treatment Failure |
| dc.subject.proposal.spa.fl_str_mv |
Leucemia linfoide aguda Expresión génica Metilación de DNA Biomarcadores predictivos |
| dc.subject.proposal.eng.fl_str_mv |
Acute lymphoid leukemia Gene expression DNA methylation |
| dc.subject.proposal.none.fl_str_mv |
Predictive biomarkers |
| description |
ilustraciones |
| publishDate |
2023 |
| dc.date.accessioned.none.fl_str_mv |
2023-06-29T14:29:58Z |
| dc.date.available.none.fl_str_mv |
2023-06-29T14:29:58Z |
| dc.date.issued.none.fl_str_mv |
2023-03 |
| dc.type.spa.fl_str_mv |
Trabajo de grado - Doctorado |
| dc.type.driver.spa.fl_str_mv |
info:eu-repo/semantics/masterThesis |
| dc.type.version.spa.fl_str_mv |
info:eu-repo/semantics/acceptedVersion |
| dc.type.content.spa.fl_str_mv |
Text |
| dc.type.redcol.spa.fl_str_mv |
http://purl.org/redcol/resource_type/TM |
| status_str |
acceptedVersion |
| dc.identifier.uri.none.fl_str_mv |
https://repositorio.unal.edu.co/handle/unal/84105 |
| dc.identifier.instname.spa.fl_str_mv |
Universidad Nacional de Colombia |
| dc.identifier.reponame.spa.fl_str_mv |
Repositorio Institucional Universidad Nacional de Colombia |
| dc.identifier.repourl.spa.fl_str_mv |
https://repositorio.unal.edu.co/ |
| url |
https://repositorio.unal.edu.co/handle/unal/84105 https://repositorio.unal.edu.co/ |
| identifier_str_mv |
Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia |
| dc.language.iso.spa.fl_str_mv |
spa |
| language |
spa |
| dc.relation.references.spa.fl_str_mv |
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Facultad de Medicina |
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Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Combita Rojas, Alba Luciaf71c0a5830cfca8e639fccacbd97c6f9Lopez Kleine, Lilianaf2bb1a1acaac486ce40887caf52c3794Torres Llanos, Yulieth Ximena721410845127187dff156e39a802bba8Biología del cáncer. Instituto Nacional de Cancerología0000-0002-2859-6980Yulieth Ximena Torres LlanosYULIETH XIMENA TORRES LLANOS2023-06-29T14:29:58Z2023-06-29T14:29:58Z2023-03https://repositorio.unal.edu.co/handle/unal/84105Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustracionesLas 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)Aunque 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-BDoctoradoDoctor en Ciencias BiomédicasEstudio 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.Biomarcadores predictivos de respuesta al tratamiento en leucemias linfoides agudas132 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Medicina - Doctorado en Ciencias BiomédicasFacultad de MedicinaBogotá,ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud::616 - EnfermedadesNeoplasiasInsuficiencia del tratamientoNeoplasmsTreatment FailureLeucemia linfoide agudaExpresión génicaMetilación de DNABiomarcadores predictivosAcute lymphoid leukemiaGene expressionDNA methylationPredictive biomarkersIdentificación 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 BIdentification of changes in DNA methylation and gene expression profiles associated with clinical response to chemotherapeutic treatment in pediatric patients with type B acute lymphoid leukemiaTrabajo de grado - Doctoradoinfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMChing-Hon Pui, Leslie L Robison, A. 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Pharmacogenet Genomics 22, 229–235 (2012).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 BInstituto Nacional de CancerologíaEstudiantesInvestigadoresMaestrosPúblico generalLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/84105/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL1020747366 2023.pdf1020747366 2023.pdfTesis de Doctorado en Ciencias Biomédicasapplication/pdf3734741https://repositorio.unal.edu.co/bitstream/unal/84105/3/1020747366%202023.pdfc78af98461965885da1f529703e40c30MD53THUMBNAIL1020747366 2023.pdf.jpg1020747366 2023.pdf.jpgGenerated Thumbnailimage/jpeg7204https://repositorio.unal.edu.co/bitstream/unal/84105/4/1020747366%202023.pdf.jpgb92feeac56e231f5b7d9a2b9dd560221MD54unal/84105oai:repositorio.unal.edu.co:unal/841052024-08-07 23:10:50.056Repositorio Institucional Universidad Nacional de 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