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Integrative Approaches for Gene and Molecular Pathway Analysis in Cancer

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Integrative Approaches for Gene and Molecular Pathway Analysis in Cancer Integrative approaches for gene and molecular pathway analysis in cancer Xavier Solé Acha ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tdx.cat) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR. No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora. WARNING. On having consulted this thesis you’re accepting the following use conditions: Spreading this thesis by the TDX (www.tdx.cat) service has been authorized by the titular of the intellectual property rights only for private uses placed in investigation and teaching activities. Reproduction with lucrative aims is not authorized neither its spreading and availability from a site foreign to the TDX service. Introducing its content in a window or frame foreign to the TDX service is not authorized (framing). This rights affect to the presentation summary of the thesis as well as to its contents. In the using or citation of parts of the thesis it’s obliged to indicate the name of the author. INTEGRATIVEAPPROACHESFORGENEAND MOLECULAR PATHWAY ANALYSIS IN CANCER mètodes integratius per a l’anàlisi de gens i rutes moleculars en càncer Programa de Doctorat en Genètica Departament de Ciències Clíniques Facultat de Medicina Universitat de Barcelona XAVIER SOLÉ ACHA Barcelona, Gener de 2012 INTEGRATIVEAPPROACHESFORGENEAND MOLECULAR PATHWAY ANALYSIS IN CANCER Memòria presentada per XAVIER SOLÉ ACHA Per optar al Grau de DOCTOR Tesi doctoral realitzada sota la direcció del Dr. Víctor Raúl Moreno Aguado i del Dr. Miguel Ángel Genestar Pujana a la Unitat de Biomarcadors i Susceptibilitat de l’Institut Català d’Oncologia. Tesi adscrita al Departament de Ciències Clíniques de la Facultat de Medicina, Universitat de Barcelona. Programa de Genètica, bienni 2001-2003 (RD 778/1998). Víctor Moreno Aguado Xavier Solé Acha Miguel A. Genestar Pujana Co-director Doctorand Co-director Barcelona, Gener de 2012 Xavier Solé Acha: Integrative approaches for gene and molecular pathway analysis in cancer, Tesi Doctoral. ©Universitat de Barcelona, Gener de 2012. Als meus pares. Aquesta tesi existeix gràcies a vosaltres. A mi abuelo Gaspar y a mi tío Ramón. Por la ilusión que sé que les habría hecho verla. GENERALCONTENTS Acknowledgements ix Preface xv Catalan Summary xix Detailed contents xxxvii List of Figures xxxix List of Acronyms xl List of Genes xlii Introduction 1 Rationale 41 Results 45 Closing 95 Addenda 139 vii “You take the blue pill — the story ends, you wake up in your bed and believe whatever you want to believe. You take the red pill — you stay in Wonderland and I show you how deep the rabbit-hole goes”. — Morpheus to Neo, in "The Matrix". AGRAÏMENTS Sempre que he llegit els agraïments de tesis alienes (reconeguem-ho, és la part més llegida de les tesis) he pensat que arribar a aquest moment devia ser quelcom especial. Moment de prendre aire i fer una mirada cap enrere, i alhora inevitablement moment de tancar una etapa i mirar al fu- tur amb il·lusions renovades per encetar la recerca de noves experiències. A més de ser aquest punt d’inflexió, el moment d’escriure els agraï- ments d’una tesi és doblement grat. Per un costat, significa que el dur i llarg procés que suposa aquesta tasca gairebé arriba a la seva fi. Per altra banda, permet agrair-ho com cal a totes les persones que al llarg d’aquesta travessia han ajudat i col·laborat amb la causa. Cal dir que aquesta tesi no és en cap cas fruit i mèrit exclusiu del doctorand, sinó que és la suma de moltes hores d’ajuda de moltes persones. Ja per avançat vull donar unes gràcies immenses a TOTES les persones que hi han contribuït. Per descomptat, la responsabilitat de qualsevol error la té exclusivament la persona que es dirigeix a vosaltres. En primer lloc, vull agrair al Xavier Messeguer l’oportunitat que em va donar de saciar el meu cuquet curiós i poder dur a terme un projecte de bioinformàtica a la Facultat d’Informàtica de Barcelona. Recordo amb molt d’afecte les hores que ens vam passar discutint l’algorisme de MA- LIG i resolent plegats els problemes que anaven sortint. Gràcies a ell em vaig adonar que m’encantava la bioinformàtica, la recerca, i que volia triar la pastilla vermella per veure fins on arribava el cau del conill. I també gràcies a ell vaig acabar treballant a l’ICO. La Universitat necessita pioners com ell. En segon lloc, vull agrair al Víctor Moreno la inestimable oportuni- tat que em va donar al permetre’m treballar en el seu grup a l’Institut Català d’Oncologia, confiant en un informàtic que no havia sentit mai les paraules microarray o les sigles PCR. D’allò fa més d’onze anys. Junts vam desentortolligar el complex camí de l’anàlisi d’arrays, experiència ix gratificant a estones i desesperant moltes altres. Inevitablement, en onze anys també hem viscut travessies pel desert, però al seu costat he pogut aprendre infinitat de coses. És una persona que sorprèn perquè pots parlar amb ell de qualsevol tema i sempre té alguna cosa interessant a aportar. Gràcies per ser un "jefe" tan poc "jefe", per deixar-me fer i desfer segons el meu criteri i per tot el teu suport i confiança. Aquesta tesi de cap manera existiria sense el Miguel Ángel Pujana. Ell em va rescatar en una d’aquestes "travessies pel desert" meves, fet que no li podré agrair mai prou. Ell em va introduir en el món de la biologia molecular del càncer, la Systems Biology, les xarxes i els factors de transcripció, món que ja no he abandonat. Infinites gràcies també per obrir-me les portes del Califano Lab a la Universitat de Columbia, i gràcies per ensenyar-me a mirar els p-valors sempre des del cantó positiu! ;-) Al Gabriel Capellá (Gabi) i al Miguel Ángel Peinado (MAP) els vull agrair la seva col·laboració i el seu suport en tot moment durant els meus primers anys d’estada a l’ICO. Gràcies a tots dos en especial per escoltar-me cada cop que us anava a veure per dir-vos "necessito un tema de tesi"! La Mònica Grau (jefa!) va ser companya d’aventures i desventures en els meus primers anys a l’ICO. Amb ella vaig veure el que era la vocació i el sacrifici per la ciència. Llàstima que determinades circumstàncies la duguessin a canviar de camp. Estic convençut que es va perdre una bona investigadora, però alhora es va guanyar una gran cooperant! ;-) Gràcies per la teva paciència infinita a l’hora de fer-te entendre per un informàtic i explicar-me què era una sonda, un clon, un primer, la RAP-PCR... tantes coses! Per motius personals ara ens veiem poquet, però l’amistat que ens uneix estic convençut que no desapareixerà mai. Molta sort en les teves aventures, saps que sempre estaré a tir de Skype! Recordo el dia que em van dir que una noia mallorquina començava la tesi al laboratori, es deia Antònia Obrador (Antu!). Quan la vaig sentir parlar per primera vegada em va fer molta gràcia el seu accent illenc, i això va ser un fet que es va mantenir amb el temps, sempre que xerrava amb ella aprenia expressions mallorquines noves! ;-) L’Antònia ha estat per mi un exemple de perseverància i de lluita per fer les coses ben fetes quan sovint l’entorn ho posava difícil. De vegades diuen que en les situacions adverses saps qui és un amic de veritat, i l’Antònia sempre va ser allà quan la necessitava. Antu saps que sempre tindràs un amic a Barcelona, o allà on jo pari. Et desitjo el millor perquè t’ho mereixes! x Al Juan Ramón (JR) González li agraeixo la seva amistat i el seu bon humor al llarg dels anys que vam compartir a l’ICO. Els dinars amb ell eren els millors! A l’Elisenda Vendrell li agraeixo també la paciència que va tenir amb mi en les etapes en què moltes de les paraules del lab encara em sonaven a xinès, gràcies! A la Gemma Tarafa li vull agrair que m’ensenyés que els resultats obtinguts a la recerca depenen en gran part de la persona que la duu a terme. Al compis de dinar (David, Esther, Ferran, Sareta).
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