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Susceptibilidad Genética Al Cáncer Gástrico Y Lesiones Precursoras, Y Mecanismos Moleculares Que Intervienen En La Progresión De La Metaplasia Intestinal

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Susceptibilidad Genética Al Cáncer Gástrico Y Lesiones Precursoras, Y Mecanismos Moleculares Que Intervienen En La Progresión De La Metaplasia Intestinal S usceptibilidad genética al cáncer gástrico y lesiones precursoras , y mecanismos moleculares que intervienen en la progresión de la metaplasia intestinal Osmel Companioni Nápoles A questa tesi doctoral està subjecta a la llicència Reconeixement - NoComercial – SenseObraDerivada 3.0. Espanya de Creative Commons . Esta tesis doctoral está sujeta a la licencia Reconocimiento - NoComercial – SinObraDerivada 3.0. España de Creative Commons . Th is doctoral thesis is licensed under the Creative Commons Attribution - NonCommercial - NoDerivs 3.0. Spain License . UNIVERSIDAD DE BARCELONA Facultad de Medicina Programa de Doctorado en Biomedicina SUSCEPTIBILIDAD GENÉTICA AL CÁNCER GÁSTRICO Y LESIONES PRECURSORAS, Y MECANISMOS MOLECULARES QUE INTERVIENEN EN LA PROGRESIÓN DE LA METAPLASIA INTESTINAL Memoria presentada por Osmel Companioni Nápoles para optar al grado de Doctor por la Universidad de Barcelona. Este trabajo se ha realizado bajo la dirección de los Doctores Carlos Alberto González y Núria Sala Serra, en el marco del Programa de Investigación en Epidemiología del Cáncer de la Unidad de Nutrición, Ambiente y Cáncer (UNAC) y el Laboratorio de Investigación Traslacional 1 (LRT1) del Instituto Catalán de Oncología (ICO) y el Instituto de Investigación Biomédica de Bellvitge (IDIBELL). Autor: Osmel Companioni Nápoles Directores: Dr. Carlos Alberto González Dra. Núria Sala Serra A mis padres, hija y amigos A Mayelín AGRADECIMIENTOS A Carlos Alberto González y Nuria Sala Serra por la dirección y el apoyo en la realización del presente trabajo. A Nadia García por su intensa implicación, amistad y estrecha interacción en el trabajo experimental, organización y búsquedas de muestras. A Dori y Nuria Ros con las que compartí muchos intensos momentos de ocio e interacción personal. A otros compañeros de la UNAC y del LRT1 como Ville, Noemie, Omar, Ángela, Silvia San José, Eric, Mireia, Raúl, Xavier Bosch, Ión, Natalia, Gemma, Gorka, Miriam, Gabi, Mar y Elisa. A Miguel Sanz Anquela y Marisa Pardo por la búsqueda y caracterización histológica de biopsias gástricas de metaplasia intestinal en los hospitales de La Princesa, Gregorio Marañón y Hospital General Virgen del Mirón de Soria. A Victoria Andreu por su implicación en la búsqueda de pacientes del proyecto FIS. A Juanita Merchant (Molecular and Integrative Physiology Department de la Universidad de Michigan) por los trabajos de Schlafen5 en líneas celulares, lesiones precursoras y cáncer gástrico. A Catalina Bonet por los análisis y asesoramiento estadístico de los estudios de asociación de cáncer gástrico y lesiones precursoras gástricas, Schlafen5 y la elaboración de base de datos del estudio de seguimiento de lesiones precursoras gástricas; así como a Leila Lujan-Barroso que también colaboró en la misma. A Lara Nonell y Eulalia Puigdecanet por el procesamiento de las muestras y análisis estadísticos del microarray de expresión. A mi madre que tanto contribuyó a mi educación y alentó el espíritu de conocimiento en mí. A mi padre, hija, hermanos, resto de la familia y amigos que siempre tengo presentes por razones esenciales. A Mayelín que ha compartido conmigo un tiempo muy bonito y ha sido muy paciente y comprensiva. Índice ÍNDICE ÍNDICE DE FIGURAS ....................................................................................................................... 1 ÍNDICE DE TABLAS ......................................................................................................................... 3 ABREVIATURAS Y SÍMBOLOS ......................................................................................................... 5 PRESENTACIÓN ............................................................................................................................. 9 INTRODUCCIÓN ........................................................................................................................... 13 1. CÁNCER GÁSTRICO. DESCRIPCIÓN GENERAL Y EPIDEMIOLOGÍA ......................................................................... 15 2. ANATOMÍA E HISTOLOGÍA DEL ESTÓMAGO ................................................................................................... 16 3. TIPOS ANATÓMICOS E HISTOLÓGICOS DEL CÁNCER GÁSTRICO ........................................................................... 19 4. HELICOBACTER PYLORI COMO FACTOR DE RIESGO DEL CÁNCER GÁSTRICO ........................................................... 20 4.1. Infección por Helicobacter pylori. Aspectos epidemiológicos ................................................ 20 4.2. Infección por Helicobacter pylori. Factores de virulencia ...................................................... 21 4.3. Infección por Helicobacter pylori. Mecanismos y consecuencias en el huésped ................... 23 4.4. Infección por Helicobacter pylori. Respuesta inmunitaria ..................................................... 26 5. OTROS FACTORES DE RIESGO DEL CÁNCER GÁSTRICO ...................................................................................... 26 5.1. Dieta ...................................................................................................................................... 26 5.2. Tabaquismo ........................................................................................................................... 27 5.3. Anti-inflamatorios no esteroideos ......................................................................................... 27 6. MECANISMO DE CARCINOGÉNESIS GÁSTRICA ............................................................................................... 27 6.1. Alteraciones moleculares en el cáncer gástrico .................................................................... 29 7. LESIONES PRECURSORAS GÁSTRICAS ........................................................................................................... 31 7.1. Gastritis crónica no atrófica (superficial o activa) ................................................................. 31 7.2. Gastritis atrófica multifocal sin metaplasia intestinal .......................................................... 32 7.3. Metaplasia intestinal ............................................................................................................ 33 7.4. Displasia ................................................................................................................................ 35 7.5. Epidemiología de las lesiones precursoras gástricas ............................................................. 36 7.6. Estudios de seguimiento de lesiones precursoras gástricas .................................................. 36 8. METAPLASIA INTESTINAL ......................................................................................................................... 39 8.1. Riesgo de cáncer gástrico según subtipo histológico, localización anatómica y extensión de la metaplasia intestinal ................................................................................................................ 39 8.2. Alteraciones moleculares en la metaplasia intestinal ........................................................... 40 8.2.1. Factores de transcripción tipo caudal homeobox CDX1 y CDX2 .................................................... 40 8.2.2. Daño oxidativo............................................................................................................................... 41 8.2.3. Supresores tumorales RUNX3 y TP53 ............................................................................................ 41 8.2.4. Vía de señalización celular Sonic hedgehog .................................................................................. 41 8.2.5. Mecanismos epigenéticos ............................................................................................................. 42 8.2.6. Mecanismos de reparación del ADN. Pérdida de heterocigosidad e inestabilidad de microsatélites ................................................................................................................................................................. 42 8.2.7. Aumento de actividad telomerasa ................................................................................................ 42 8.3. Estudios de expresión génica por microarrays en metaplasia intestinal............................... 42 8.4. La familia multigénica Schlafen ............................................................................................ 44 8.5. Rol de los genes Schlafen en la metaplasia intestinal ........................................................... 45 9. SUSCEPTIBILIDAD GENÉTICA ...................................................................................................................... 46 9.1. Proyecto de mapeo de haplotipos humanos HapMap y estudios de asociación genética .... 47 9.2. Estudios de asociación de genes candidatos en cáncer gástrico ........................................... 48 9.2.1. Citoquinas pro-inflamatorias ......................................................................................................... 49 9.2.2. Reconocimiento de Helicobacter pylori y respuesta inmune innata ............................................. 49 Índice 9.3. Estudios de asociación de genoma completo en cáncer gástrico ......................................... 50 9.4 Estudios de asociación en lesiones precursoras gástricas ..................................................... 53 9.4.1. Citoquinas pro-inflamatorias ........................................................................................................
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