Université Libre de Bruxelles
FACULTE DE MEDECINE
Debora Fumagalli, MD
Thèse présentée en vue de l’obtention du grade académique
de Docteur en Sciences Médicales
Promoteur de thèse: Professeur Christos Sotiriou
Année académique 2015-2016
Table of Contents
Acknowledgments ... 3
Table of Contents ... 5
List of Tables ... 7
List of Figures ... 9
Abbreviations ... 13
Summary in French ... 16
Introduction ... 19
Inter-tumor heterogeneity ... 21
Intra-tumor heterogeneity ... 26
Spatial heterogeneity ...26 Temporal heterogeneity ... 28Origins of tumor heterogeneity ... 31
The cell of origin ... 31
The cancer stem cell hypothesis & the clonal evolution model ... 32
Beyond the Cancer Genome ... 34
The influence of the tumor microenvironment ... 34
The emerging role of RNA editing ... 35
Breast cancer heterogeneity: the clinical challenges ...39
Aims of my research works ... 40
CHAPTER 1: Intra-tumor heterogeneity ... 43
PART A: Multifocal breast cancers ... 43
Abstract ... 43
Introduction ... 45
Results ...57
Discussion ... 73
PART B: Metastatic ER positive/HER2 negative breast cancer
patients. ... 76
Abstract ... 76
Introduction ... 78
Material and Methods ... 80
Results ...89
Discussion ... 108
Conclusions and Perspectives ...113
CHAPTER 2: Inter-tumor heterogeneity ...115
The role of RNA editing in breast cancer ... 115
Abstract ... 115
Introduction ... 117
Material and Methods ... 119
Results ...127
Discussion ... 164
