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The Transcriptome of Epithelial Transformation Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2010 The transcriptomic profiling of human colorectal precancerous lesions Cattaneo, Elisa Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-30611 Dissertation Published Version Originally published at: Cattaneo, Elisa. The transcriptomic profiling of human colorectal precancerous lesions. 2010, University of Zurich, Faculty of Science. The Transcriptomic Profiling of Human Colorectal Precancerous Lesions Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch­naturwissenschaftlichen Fakultät der Universität Zürich von Elisa Cattaneo aus Italien Promotionskomitee Prof. Dr. Josef Jiricny (Vorsitz) Prof. Dr. François Verrey Dr. Giancarlo Marra (Leitung der Dissertation) Zürich, 2010 Dedicated to my aunt Maria TABLE OF CONTENT 1. SUMMARY................................................................................................................................................ 4 2. ZUSAMMENFASSUNG............................................................................................................................. 8 3. INTRODUCTION.................................................................................................................................... 12 3.1 COLORECTAL CANCER ......................................................................................................................... 12 3.2 BASIC ANATOMY AND PHYSIOLOGY OF THE LARGE INTESTINE ............................................................... 13 3.3 PATHWAYS TO COLORECTAL CANCER................................................................................................... 16 3.3.1 On the way to cancer................................................................................................................. 16 3.3.2 Breaking convention: The contribution of modern endoscopy and histology......................... 19 3.3.3 Convention­breaking findings from molecular biology ........................................................... 25 3.3.4 Fast track transformation models: inherited syndromes......................................................... 30 3.3.5 Hyperplastic polyposis............................................................................................................... 32 4. MATERIALS AND METHODS............................................................................................................... 34 5. RESULTS ................................................................................................................................................ 53 6. DISCUSSION........................................................................................................................................... 87 7. PERSPECTIVES.................................................................................................................................... 101 8. REFERENCES ....................................................................................................................................... 102 9. ACKNOWLEDGEMENTS..................................................................................................................... 110 10. CURRICULUM VITAE ....................................................................................................................... 111 11. APPENDIXES...................................................................................................................................... 113 11.1 SUPPLEMENTARY DATA .................................................................................................................. 113 11.2 PUBLICATIONS ............................................................................................................................... 175 3 Summary 1. SUMMARY Colorectal tumorigenesis is one of the best known processes of cellular transformation in human beings. Its characterization has moved ahead by leaps and bounds during the last three decades, thanks to major advances in the fields of endoscopy, histology and molecular biology. The carcinogenic process in the colon starts when genetic or epigenetic alterations appear and accumulate in the cells of epithelial crypts. In most cases, the transformation process begins with qualitative, quantitative, and spatial subversion of the Wnt signaling pathway, the physiological regulator of epithelial homeostasis. Other crucial alterations affect key genes involved in different signal transduction pathways, apoptosis, and DNA repair such as mismatch repair. These events, which seem to appear at specific stages of tumor progression, eventually lead to malignant and invasive neoplastic les i o n s. Colorectal cancer was assumed for many years to be a homogenous condition, but recently it turned out to include several distinct clinical, histological, and molecular phenotypes. Such heterogeneity can also be recognized in the lesions believed to be its precursors. Advances in the fields of endoscopy and pathology have provided us with a more accurate classification of preinvasive lesions, which better reflects their relevance in colorectal tumorigenesis. Precancerous colorectal lesions have been thus reclassified into different categories based on their morphological and histological appearance. Macroscopically, thpolypoid nonpolypoid ey are divided into (pedunculated and sessile) and (slightly elevated, completely flat or depressed) lesions. Histologically, they can present classical adenomatous features or a peculiar architecture characterized by infolding of the glandular epithelium (also called serration). Serrated lesions display some molecular alterations usually non detected in adenomas, and they are believed to progress into colorectal cancer by means of a new pathway of tumorigenesis, namely the serrated pathway. The distinction of precancerous colorectal lesions based on their morphology, and the belief that they represent different entities, were the central themes driving the design of this study. In an attempt to identify genes and pathways whose dysregulation might play crucial roles in the transformation 4 Summary process, we performed a comprehensive transcriptomic analysis of nonpolypoid and polypoid colorectal precancerous lesions. Our study represents the first gene expression analysis of a large collection of the two types of precancerous lesions. Furthermore, it was carried out using the Affymetrix exon array platform that allowed us to investigate the expression level of all transcripts of the human genome with unprecedented sensitivity. The in‐depth analysis of our transcriptomics data revealed that the two types of precancerous lesions could be easily segregated into different clusters using several unsupervised and supervised analytical tools. A prominent prevalence of expression changes in genes involved in cell cycle related networks was observed in the polypoid group of lesions, suggesting that a profound dysregulation of the cell cycle is crucial for propulsion of cell proliferation in these lesions. In contrast, nonpolypoid lesions were characterized by an overrepresentation of expression changes in genes involved in growth factor signaling pathways, apoptosis and cell adhesion, suggesting that these lesions might exploit activation of cell survival pathways and avoidance of apoptosis for their progression. We have identified a list of genes whose expression changes are more specifically associated with the polypoid or the nonpolypoid phenotype. These changes will be complemented by additional data from other ‐omics studies (a metabolomics study is in progress in our laboratory) in order to investigate the differences between polypoid and nonpolypoid lesions within a systems biology framework. The data analysis also showed that the transcriptome of nonpolypoid lesions was less dramatically subverted than that of the polypoid lesions (in comparison with normal mucosa samples). In a large proportion of change s, the up‐ or downregulation of transcript levels followed a normal mucosa nonpolypoid polypoid sequence, although expression values in nonpolypoid lesions were always closer to that of the cognate, precancerous group of samples. Certain biological processes, such as Wnt signaling, cytoskeleton remodelling and immune response, were similarly dysregulated in the two groups of lesions.diameter of the lesions degree of In a cytologicalddition, dysplasia supervised analyses identified the and as the two most relevant clinical variables associated with specific patterns of gene 5 Summary expression, as was the case also for polypoid lesions in a previous study conducted in our lab o ratory. In conclusion, although nonpolypoid lesions appear to explore different pathways of transformation, they also share many similarities with polypoid lesions. This was expected, since both precancerous lesions arise and grow in the same organ and are likely forced to overcome a series of similar selection pressures. At this stage of our investigation, we could only suggest that it is wise to apply the same level of clinical surveillance to both types of precancerous lesions. One gene transcript TMIGD1 whose expression transmembrane changes and were immunoglobulin dramatic in domain all the precancerous containing 1 lesions was ( ). In comparison with the transcript levels in the corresponTMIGD1 ding normal 2 mucosa samples,
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