Departamento de Medicina Preventiva y Salud Pública Antonio Clemente PICORNELL COMPANY

247 Pages·2013·7.93 MB·English

UNIVERSIDAD AUTÓNOMA DE MADRID
FACULTAD DE MEDICINA
Departamento de Medicina Preventiva y Salud Pública

PhD Thesis

ESTUDIO PAN-GENÓMICO PRONÓSTICO EN EL CÁNCER DE VEJIGA
—
GENOME-WIDE PROGNOSTIC STUDY IN BLADDER CANCER

Antonio Clemente PICORNELL COMPANY

Madrid, 2013

La Dra. Núria Malats Riera, Jefa del Grupo de Epidemiología Genética y Molecular del
Centro Nacional de Investigaciones Oncológicas (CNIO), como Directora.

CERTIFICA:
Que Don Antonio Clemente Picornell Company, Licenciado en Biología por la Universidad
Complutense de Madrid, ha realizado la presente Tesis Doctoral “Estudio pan-genómico
pronóstico en el cáncer de vejiga” y que a su juicio reúne plenamente todos los requisitos
necesarios para optar al Grado de Doctor, a cuyos efectos será presentada en la
Universidad Autónoma de Madrid, autorizando su presentación ante el Tribunal
Calificador.

Y para que así conste se extiende el presente certificado,
Madrid, abril 2013.

Vº Bº de la Directora:
Dra. Núria Malats Riera

To Montse

To my parents and my brother

Acknowledgements

To my PhD. Thesis director, Núria Malats for her instruction and support during the last
four years.
To all the patients from the Spanish Bladder Cancer (SBC)/EPICURO Study, the
monitors that enrolled them and the MDs that took part in the different phases of the
study.
To all the researchers and collaborators for trying to make a better world through our
hard work.
To Gonzalo Gómez, David G. Pisano, Alfonso Valencia and Francisco Real for guiding
me during my first steps into the field of cancer research at the CNIO.
To the postdocs Andre, Roger and Evangelina for sharing their astonishing knowledge
and free time outside of the lab.
To my predoc colleages Gaëlle, Matt, Salman and Silvia for sharing knowledge,
experiences, frustrations and happy moments.
To my PhD. tutor Fernando Artalejo, from the Department of Preventive Medicine and
Public Health, for its invaluable help both in epidemiologic and bureaucratic issues.
To everybody that has ever helped me during my research.
To my parents and brother for their never-ending love and support.
To Montse for sharing our lives together.

CONTENTS
SUMMARY I
RESUMEN V
ABBREVIATIONS XI
CHAPTER 1: INTRODUCTION 1
Part I: Bladder cancer .............................................................................................. 1
1.1.1. An overview of bladder cancer ..................................................... 1
1.1.2. UCB symptoms, diagnosis and treatment .................................... 3
1.1.3. Evolution and prognosis of UCB ................................................. 6
Part II. The role of the inherited genetics .............................................................. 13
1.2.1. Germline genetic susceptibility markers for UCB ..................... 13
1.2.2. Germline genetic prognostic markers for UCB .......................... 15
1.2.3. Fundamentals of genome-wide studies ...................................... 19
1.2.4. Genome-wide association studies of UCB ................................. 22
1.2.5. Genome-wide prognostic studies in the literature ...................... 26
1.2.6. Gene set analysis in post-genome-wide results .......................... 29
CHAPTER 2: HYPOTHESIS AND OBJECTIVES 31
CHAPTER 3: MATERIALS AND METHODS 33
A. Population and clinical & follow-up information......................................... 33
A.1. Spanish Bladder Cancer (SBC)/EPICURO Study ............................... 33
A.2. Texas Bladder Cancer (TXBC) Study ................................................. 36
A.3. International Series for NMIBC .......................................................... 38
B. Genotyping ................................................................................................... 39
B.1. Genotyping in SBC/EPICURO GWAS Study .................................... 39
B.2. Genotyping in TXBC GWAS Study ................................................... 40
B.3. Genotyping in the Validation Phase of NMIBC .................................. 41
C. Endpoints of interest ..................................................................................... 41
3.1. Independent SNPs associated with UCB clinical outcomes ......................... 44
3.1.1. Independent SNPs associated with NMIBC clinical outcomes .. 44
3.1.2. Independent SNPs associated with MIBC clinical outcomes ..... 46
3.2. Biological pathways associated with UCB clinical outcomes...................... 48
3.3. SNP-SNP interactions associated with UCB clinical outcomes ................... 53
CHAPTER 4: RESULTS 61
4.1. Independent SNPs associated with UCB clinical outcomes ......................... 61
4.1.1. Independent SNPs associated with NMIBC clinical outcomes .. 61
4.1.2. Independent SNPs associated with MIBC clinical outcomes ..... 68
4.2. Biological pathways associated with UCB clinical outcomes...................... 75
4.3. SNP-SNP interactions associated with UCB clinical outcomes ................... 87
CHAPTER 5: DISCUSSION 93
5.1. Independent SNPs associated with UCB clinical outcomes ......................... 93
5.2. Biological pathways associated with UCB outcomes ................................ 100
5.3. SNP-SNP interactions associated with UCB clinical outcomes ................. 107
5.4. Future plans and directions in the prognostic study of UCB ...................... 111
CONCLUSIONS 115
CONCLUSIONES 117
SUPPLEMENTARY TABLES 119
SUPPLEMENTARY FIGURES 143
REFERENCES 183
PUBLISHED PAPERS 203