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TD GALVEZ CARVAJAL Laura.Pdf UNIVERSIDAD DE MÁLAGA FACULTAD DE MEDICINA Departamento Medicina y Dermatología Tesis Doctoral IDENTIFICACIÓN DE UNA FIRMA DE EXPRESIÓN GÉNICA MEDIANTE EL SISTEMA DE ANÁLISIS NCOUNTER COMO MARCADOR PRONÓSTICO DE RECAÍDA EN PACIENTES CON TUMORES DE CÉLULAS GERMINALES NO SEMINOMA ESTADIO I Laura Gálvez Carvajal Málaga, 2020 AUTOR: Laura Gálvez Carvajal http://orcid.org/0000-0002-7952-598X EDITA: Publicaciones y Divulgación Científica. Universidad de Málaga Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial- SinObraDerivada 4.0 Internacional: http://creativecommons.org/licenses/by-nc-nd/4.0/legalcode Cualquier parte de esta obra se puede reproducir sin autorización pero con el reconocimiento y atribución de los autores. No se puede hacer uso comercial de la obra y no se puede alterar, transformar o hacer obras derivadas. Esta Tesis Doctoral está depositada en el Repositorio Institucional de la Universidad de Málaga (RIUMA): riuma.uma.es Revisión por Unicheck Cargado: 02/12/2020 | Verificado: 02/12/2020 Parte Matches Cita Referencia sustituida 0.7% Matches 22% Citas 0% Referencias Matches Web fuentes 153 1 www.laproteina.es 0.09% https://www.laproteina.es/tienda/3956-pure-bcaa-r811-300-gr.html 2 documentop.com 0.09% https://documentop.com/investigar-con-y-para-la-sociedad-uca_59fa65801723dd386241e125.html 3 mafiadoc.com 0.07% https://mafiadoc.com/utilizacion-de-material-didactico-con-recursos-de-ajedrez-para-la-_599c8d241723dd0f406ee02b.html 4 accessmedicina.mhmedical.com 0.04% https://accessmedicina.mhmedical.com/content.aspx?sectionid=114914497 5 panelvida.blogspot.com 0.04% https://panelvida.blogspot.com/2011_12_14_archive.html 6 www.slideshare.net 0.04% https://www.slideshare.net/ArturoLennon/oncologa23 7 www.psicoeureka.com.py 0.04% https://www.psicoeureka.com.py/sites/default/files/publicaciones/eureka-13-2_0.pdf 8 www.fundacioncsz.org 0.04% http://www.fundacioncsz.org/ArchivosPublicaciones/183.pdf 9 helvia.uco.es 0.03% http://helvia.uco.es/xmlui/bitstream/handle/10396/11794/2014000000920.pdf.txt?sequence=3 10 www.aecc.es 0.03% https://www.aecc.es/sites/default/files/migration/actualidad/publicaciones/documentos/glosario.pdf Page 1 Dr. Emilio Alba Conejo Catedrático de Medicina de la Universidad de Málaga. Director del Centro de Investigaciones Médico-Sanitarias (CIMES) de la Universidad de Málaga. Dr. Alfonso Sánchez Muñoz Profesor del Departamento Medicina y Dermatología de la Universidad de Málaga AUTORIZAN a Dña. Laura Gálvez Carvajal a la lectura y defensa de esta memoria de Tesis Doctoral titulada: “Identificación de una firma de expresión génica mediante el sistema de análisis nCounter como marcador pronóstico de recaída en pacientes con tumores de células germinales no seminoma estadio I”. Asimismo, los directores de esta Tesis Doctoral certifican que las publicaciones que la avalan no han sido utilizadas en Tesis anteriores y han sido generadas, parcial o totalmente, a partir de resultados y metodología desarrolladas durante la realización de la Tesis Doctoral de Dña. Laura Gálvez Carvajal. Y para que así conste a los efectos oportunos, firman el presente documento en Málaga a 10 de enero de 2020. Dr. Emilio Alba Conejo Dr. Alfonso Sánchez Muñoz 1 AGRADECIMIENTOS En primer lugar, me gustaría agradecer a mi tutor y codirector de tesis, Emilio Alba, la gran oportunidad que me brindó al confiar en mí para llevar a cabo este bonito proyecto de investigación. A mis dos codirectores de tesis, Emilio Alba y Alfonso Sánchez, me gustaría expresar mi más sincera gratitud por todo el apoyo aportado, resolución de cualquier inconveniente surgido durante los últimos años, así como, por todos los comentarios y recomendaciones constructivas que no sólo me construyeron como investigadora sino que también contribuyeron a mi crecimiento personal. Mención importante en los agradecimientos, merecen todos los pacientes y sus familiares que dieron su consentimiento para formar parte del proyecto de investigación, donando las muestras tumorales para este, así como otros proyectos de investigación. Esta Tesis Doctoral no hubiese sido posible sin el equipo de investigación del Centro de Investigaciones Médico Sanitarias (CIMES) de Málaga, al que agradezco profundamente todo el trabajo realizado y amabilidad con el que resolvieron todas mis dudas sobre metodología de trabajo y otras múltiples consultas, con especial atención a Martina Álvarez, Ángela Santonja, Alicia Garrido, M. Rosario Chica y Rocío Lavado. Tampoco hubiese sido posible el adecuado análisis de los resultados obtenidos sin la gran colaboración de los bioestadísticos / bioinformáticos Julio Montes, Aurelio Moya y a Marco del Rey y Emilio Alba Linero del equipo Foqum. Gracias por introducirme un poco en el complejo mundo del análisis bioinformático, con todas aquellas explicaciones que me permitieron comprender todo el estudio estadístico y bioinformático realizado. Y por último, aunque no menos importante, expresar mi más profundo agradecimiento a mi familia. Sin el constante apoyo y facilidades para poder trabajar fuera de mi horario laboral, no hubiese sido posible realizar este trabajo. RESUMEN INTRODUCCIÓN Actualmente para el 15-20% de los pacientes con tumores de células germinales (TCG) mestastásicos las opciones curativas son limitadas, estando en investigación la respuesta a terapias dirigidas (1). Como estrategias postorquiectomía en los pacientes con tumores de células germinales no seminoma (TCGNS) estadio I son válidas la quimioterapia adyuvante, la linfadenectomía retroperitoneal y la vigilancia activa. La infiltración linfovascular es el factor pronóstico más aceptado y asociado al riesgo de recaída en TCGNS (aumentándolo hasta en un 50%) (2–5). El tratamiento quimioterápico adyuvante en estos pacientes con estadio I basado en la presencia de infiltración linfovascular supone el sobretratamiento del restante 50%, con la consiguiente toxicidad aguda y a largo plazo, por lo que se requieren marcadores más fidedignos de recaída. En los tumores de células germinales testiculares (TCGT) los estudios de expresión génica se encuentran en etapas muy iniciales de investigación. METODOLOGÍA Y OBJETIVO Previo al presente estudio se realizó un trabajo de revisión bibliográfica sobre terapias dianas en pacientes con TCG. Las publicaciones encontradas presentaban una causística reducida y heterogénea, sobre todo, centradas en estadios avanzados, sin demostrar una efectividad razonable con los tratamientos diana estudiados (6). Este hecho puso de manifiesto la necesidad de centrar el presente trabajo en estadios iniciales, focalizando la investigación en identificar aquellos pacientes con mayor riesgo de recaída, los cuales serían candidatos a un tratamiento adyuvante. Se ha realizado un estudio de casos y controles de carácter retrospectivo, donde se han incluido 54 pacientes con tumores de células germinales no seminoma (TCGNS) I estadio I, pertenecientes a varios centros de España, que no habían recibido quimioterapia adyuvante tras la orquiectomía. El objetivo del estudio fue encontrar un conjunto de genes cuyas variaciones en la expresión estuviese relacionado con el riesgo de recaída. De los pacientes incluidos, el 48% (n=26) lo constituían pacientes con recaída y el restante 52% (n=28) pacientes sin recaída. Se han analizado retrospectivamente las variaciones en los perfiles de expresión de grupos de genes realizados con las trece rutas canónicas del cáncer, utilizando el panel PanCancer con el sistema de análisis nCounterTM de Nanostring (7). Los resultados obtenidos fueron evaluados mediante clusterización y análisis estadístico con herramientas bioinformáticas adecuadas para identificar una firma génica cuya variación en la expresión estuviese relacionada con la recaída. RESULTADOS Se obtuvo un modelo de nueve genes resultante del análisis bioinformático (MPL, Col24a1, NR4A1, FOSL1, CREB5, FANCB, LAMB4, ZBTB16, CALML3) con capacidad de predecir el riesgo de recaída en los pacientes con TCGNS estadio I sin tratamiento adyuvante con AUC de 0.8. De esta firma de nueve genes, cuatro están relacionados con la vía de señalización PI3K (Col24a1, NR4A1, CREB5, LAMB4). Respecto a la expresión diferencial individual de cada gen, se detectaron varios genes con expresión diferencial próxima a la significación estadística entre ambos grupos de pacientes (destacando AKT3, BAIAP3, ZBTB16, RASGRP1, KIT, IL13RA2, ITGA3, ACVR1B, TGFB3, HHEX, CCNA1, NR4A1, PLA2G10, FGF7 y GADD45A), así como un modelo de red de coexpresión con una correlación con la recaída de 0.39 (p=0.003) constituido por 31 genes de los que cinco tenían una expresión diferencial próxima a la significación estadística (IL13RA2, CCNA1, PLA2G10, GADD45A, RRAS2). Del modelo de nueve genes obtenido con el análisis bioinformático, destaca FOSL1 con una correlación con la recaída de 0.43 y, NR4A1 y ZBTB16 con una expresión diferencial próxima a la significación estadística (0.075 en ambos casos). II CONCLUSIONES MÁS RELEVANTES 1). En TCGNS estadio I tratados con orquiectomía sin tratamiento adyuvante se ha identificado una firma génica de nueve genes (MPL, Col24a1, NR4A1, FOSL1, CREB5, FANCB, LAMB4, ZBTB16, CALML3) que permite seleccionar aquellos pacientes con alta probabilidad de recaída. 2). La posible aplicabilidad clínica de esta firma génica requiere una validación en una cohorte igual de homogénea pero con un mayor número de pacientes. 3). Hasta la fecha no existe una terapia diana con validez demostrada en pacientes con TCG. III LISTA DE ABREVIATURAS ADN Ácido desoxirribonucleico.
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