MYD88 L265P como factor pronóstico en Linfomas Difusos de Células Grandes B

MYD88 L265P mutation as a prognostic factor in DLBCL patients.\nIntroduction: Diffuse large B-cell lymphoma (DLBCL), the most prevalent non-Hodgkin lymphoma, is clinically and biologically heterogeneous, and up to 40% of patients are not able to reach long-term response with the use of standard ther...

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Autor principal: Jauk, Federico
Otros Autores: García Rivello, Hernán
Formato: Tesis de maestría acceptedVersion
Lenguaje:Español
Publicado: Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica 2022
Materias:
Linfoma difuso de células grandes B
MYD88
Factor pronóstico
Diffuse large B-cell lymphoma
Prognostic factor
Ciencias de la vida
Acceso en línea:http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=afamaster&cl=CL1&d=HWA_6910
https://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_6910.dir/6910.PDF
Aporte de:
Repositorio Digital de la Universidad de Buenos Aires (UBA) de Universidad de Buenos Aires
id I28-R145-HWA_6910
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 Linfoma difuso de células grandes B
MYD88
Factor pronóstico
Diffuse large B-cell lymphoma
MYD88
Prognostic factor
Ciencias de la vida
spellingShingle Linfoma difuso de células grandes B
MYD88
Factor pronóstico
Diffuse large B-cell lymphoma
MYD88
Prognostic factor
Ciencias de la vida
Jauk, Federico
MYD88 L265P como factor pronóstico en Linfomas Difusos de Células Grandes B
topic_facet Linfoma difuso de células grandes B
MYD88
Factor pronóstico
Diffuse large B-cell lymphoma
MYD88
Prognostic factor
Ciencias de la vida
description MYD88 L265P mutation as a prognostic factor in DLBCL patients.\nIntroduction: Diffuse large B-cell lymphoma (DLBCL), the most prevalent non-Hodgkin lymphoma, is clinically and biologically heterogeneous, and up to 40% of patients are not able to reach long-term response with the use of standard therapy.\nMYD88 encodes an adaptor protein of Toll-like and IL-1 receptors. The MYD88 L265P mutation is recurrently detected in DLBCL, especially in the activated B-cell subtype. Its role as a prognostic biomarker has not been clearly defined yet. In our country, there is little data on this topic.\nObjectives: To determine the prevalence and prognostic value of MYD88 L265P in an Argentine DLBCL patients retrospective cohort.\nTo assess association between overall survival and clinical or biological features in this group of patients.\nMaterials and methods: An observational retrospective cohort study was carried out, including cases with first DLBCL diagnosis at the Hospital Italiano de Buenos Aires during 2010-2016. Patients with previous history of low-grade B-Cell lymphomas or immunosuppression, special DLBCL subtypes, and cases with no available tissue for molecular techniques were excluded. Clinical features were collected from institutional electronic medical records. Immunohistochemistry for cell-of-origin classification (Hans? algorithm), and DNA extraction were carried out from formalin-fixed paraffin-embedded tissue. An in-house hydrolysis probe-based real-time PCR for the detection of MYD88 L265P was performed.\nFor overall survival analysis, only patients with comparable therapies were selected.\nResults: 67 patients were analyzed (49,3% female, median age: 66 years). According to Hans? algorithm, 40 patients (59,7%) were considered germinal center subtype, and the remaining 27 patients (40,3%) were considered non-germinal center subtype.\nThe prevalence of MYD88 L265P was 3% (IC95 0,8-10,3%) within the DLBCL cohort (1 germinal center subtype and 1 non-germinal center subtype).\n47 patients with comparable therapeutic approaches were selected for overall survival analysis. No statistically significant differences were found for localization (p=0,75), sex (p=0,82), IPI (p=0,12), stage (p=0,17), cell of origin (p=0,67) or MYD88 L265P status (p=0,31). A shorter overall survival was found in ?60-year-old patients (p=0,047).\nDiscussion and conclusion: Within the analyzed cohort, the number of MD88 L265P-positive cases was surprisingly low (n=2). Our finding was different as compared with the meta-analysis published in 2017 by Lee and colleagues (MYD88 L265P prevalence 16,5%; p=0,001). We could hypothesize that other mutations could be involved in NF-kB activation in non-germinal center DLBCLs, possibly due to population-related predisposition or environmental factors. Neither MYD88 L265P nor cell of origin subtypes were associated with a shortened overall survival. Only the ?60-year-old patients showed a diminished overall survival, being this comparable with international publications.\nThe obtained results are interesting and set out new hypotheses for further investigations.
author2 García Rivello, Hernán
author_facet García Rivello, Hernán
Jauk, Federico
format Tesis de maestría
Tesis de maestría
acceptedVersion
author Jauk, Federico
author_sort Jauk, Federico
title MYD88 L265P como factor pronóstico en Linfomas Difusos de Células Grandes B
title_short MYD88 L265P como factor pronóstico en Linfomas Difusos de Células Grandes B
title_full MYD88 L265P como factor pronóstico en Linfomas Difusos de Células Grandes B
title_fullStr MYD88 L265P como factor pronóstico en Linfomas Difusos de Células Grandes B
title_full_unstemmed MYD88 L265P como factor pronóstico en Linfomas Difusos de Células Grandes B
title_sort myd88 l265p como factor pronóstico en linfomas difusos de células grandes b
publisher Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica
publishDate 2022
url http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=afamaster&cl=CL1&d=HWA_6910
https://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_6910.dir/6910.PDF
work_keys_str_mv AT jaukfederico myd88l265pcomofactorpronosticoenlinfomasdifusosdecelulasgrandesb
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spelling I28-R145-HWA_69102025-07-31 MYD88 L265P mutation as a prognostic factor in DLBCL patients.\nIntroduction: Diffuse large B-cell lymphoma (DLBCL), the most prevalent non-Hodgkin lymphoma, is clinically and biologically heterogeneous, and up to 40% of patients are not able to reach long-term response with the use of standard therapy.\nMYD88 encodes an adaptor protein of Toll-like and IL-1 receptors. The MYD88 L265P mutation is recurrently detected in DLBCL, especially in the activated B-cell subtype. Its role as a prognostic biomarker has not been clearly defined yet. In our country, there is little data on this topic.\nObjectives: To determine the prevalence and prognostic value of MYD88 L265P in an Argentine DLBCL patients retrospective cohort.\nTo assess association between overall survival and clinical or biological features in this group of patients.\nMaterials and methods: An observational retrospective cohort study was carried out, including cases with first DLBCL diagnosis at the Hospital Italiano de Buenos Aires during 2010-2016. Patients with previous history of low-grade B-Cell lymphomas or immunosuppression, special DLBCL subtypes, and cases with no available tissue for molecular techniques were excluded. Clinical features were collected from institutional electronic medical records. Immunohistochemistry for cell-of-origin classification (Hans? algorithm), and DNA extraction were carried out from formalin-fixed paraffin-embedded tissue. An in-house hydrolysis probe-based real-time PCR for the detection of MYD88 L265P was performed.\nFor overall survival analysis, only patients with comparable therapies were selected.\nResults: 67 patients were analyzed (49,3% female, median age: 66 years). According to Hans? algorithm, 40 patients (59,7%) were considered germinal center subtype, and the remaining 27 patients (40,3%) were considered non-germinal center subtype.\nThe prevalence of MYD88 L265P was 3% (IC95 0,8-10,3%) within the DLBCL cohort (1 germinal center subtype and 1 non-germinal center subtype).\n47 patients with comparable therapeutic approaches were selected for overall survival analysis. No statistically significant differences were found for localization (p=0,75), sex (p=0,82), IPI (p=0,12), stage (p=0,17), cell of origin (p=0,67) or MYD88 L265P status (p=0,31). A shorter overall survival was found in ?60-year-old patients (p=0,047).\nDiscussion and conclusion: Within the analyzed cohort, the number of MD88 L265P-positive cases was surprisingly low (n=2). Our finding was different as compared with the meta-analysis published in 2017 by Lee and colleagues (MYD88 L265P prevalence 16,5%; p=0,001). We could hypothesize that other mutations could be involved in NF-kB activation in non-germinal center DLBCLs, possibly due to population-related predisposition or environmental factors. Neither MYD88 L265P nor cell of origin subtypes were associated with a shortened overall survival. Only the ?60-year-old patients showed a diminished overall survival, being this comparable with international publications.\nThe obtained results are interesting and set out new hypotheses for further investigations. Fil: Jauk, Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Buenos Aires, Argentina García Rivello, Hernán Ranuncolo, Stella Maris Jauk, Federico 2022-03-23 Introducción: El linfoma difuso de células grandes B (LDCGB) es una patología heterogénea tanto biológica como clínicamente, en la cual hasta un 40% de los pacientes no alcanza respuestas sostenidas luego de regímenes terapéuticos estándar.\nMYD88 es un gen que codifica para una proteína adaptadora de la vía de los receptores tipo Toll e IL-1. La mutación L265P en dicho gen es un hallazgo recurrente en el LDCGB, y se detecta mayormente en el subtipo célula B activada. Su rol como factor pronóstico para identificar pacientes de alto riesgo no se encuentra definido de manera concluyente. Los datos al respecto en nuestro país son limitados.\nObjetivos: Determinar la prevalencia y el valor pronóstico de MYD88 L265P en una cohorte retrospectiva de pacientes argentinos con diagnóstico inicial de LDCGB.\nEvaluar la asociación de la supervivencia global y variables clínicas/biológicas en este grupo de pacientes.\nMateriales y métodos: Se llevó a cabo un estudio observacional de cohorte retrospectiva, incluyendo casos con diagnóstico inicial de LDCGB en el Hospital Italiano de Buenos Aires entre 2010 y 2016. Se excluyeron casos con antecedentes de linfomas B de bajo grado, subtipos especiales de LDCGB, historia de inmunosupresión, o material insuficiente o no adecuado para estudios moleculares. Se recabaron datos de los pacientes de la historia clínica electrónica institucional. Se llevaron a cabo técnicas de inmunohistoquímica para clasificación según célula de origen (algoritmo de Hans), y la extracción de ADN a partir de material fijado en formol e incluido en parafina. La detección de MYD88 L265P se realizó mediante un ensayo basado en PCR en tiempo real con sondas de hidrólisis de desarrollo propio. Para el análisis de supervivencia global se incluyeron pacientes que recibieron terapias comparables.\nResultados: Se analizaron 67 pacientes (49,3% sexo femenino; mediana de edad 66 años). En base a la clasificación según la célula de origen mediante algoritmo de Hans, 40 pacientes (59,7%) resultaron de tipo centro germinal y los restantes 27 (40,3%) de tipo no-centro germinal. La prevalencia de MYD88 L265P fue del 3,0% (IC95 0,8-10,3%) en la cohorte global de LDCGB (1 caso en el grupo de tipo centro germinal; 1 caso en el grupo de tipo célula B activada). Se seleccionaron 47 pacientes con terapias comparables para estudiar la asociación entre variables y supervivencia global. No se observaron diferencias significativas para la supervivencia global según localización (p=0,75), sexo (p=0,82), IPI (p=0,12), estadio (p=0,17), célula de origen (p=0,67) o presencia de MYD88 L265P (p=0,31). Se observó una supervivencia global menor en pacientes de edad ?60 años (p=0,047).\nDiscusión y conclusiones: En la cohorte estudiada, el número de casos positivos para MYD88 L265P resultó llamativamente bajo (n=2), y evidencia una diferencia significativa cuando se la compara con la cohorte del meta-análisis publicado en 2017 por Lee y cols. (prevalencia MYD88 L265P 16,5%; p=0,001). A partir de esto se hipotetiza que posiblemente debido a factores poblacionales de predisposición o ambientales, mutaciones distintas a MYD88 L265P podrían ser las alteraciones genómicas activadoras de NF-kB en los LDCGB tipo No-CG. MYD88 L265P no se asoció a una disminución de la supervivencia global, como tampoco lo hizo la separación en grupos según célula de origen. Se ha constatado una diferencia significativa en cuanto a la supervivencia global según el grupo etario dicotómico (<60 años vs. ?60 años). Esto es concordante con datos arrojados por fuentes internacionales. Los resultados obtenidos son interesantes y plantean la necesidad de futuras investigaciones, como por ejemplo la evaluación de otros genes involucrados en la vía NF-kB para dilucidar si en nuestra serie de pacientes existen factores ajenos a MYD88 que estimulan la activación de dicha vía, predominantemente en LDCGB de tipo no-centro germinal. application/pdf Narbaitz, Marina Slavutsky, Irma Kusminsky, Gustavo Linfoma difuso de células grandes B MYD88 Factor pronóstico Diffuse large B-cell lymphoma MYD88 Prognostic factor 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 Magíster de la Universidad de Buenos Aires en Biología Molecular Médica MYD88 L265P como factor pronóstico en Linfomas Difusos de Células Grandes B 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_6910 https://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_6910.dir/6910.PDF

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