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Integrative Genomic Analyses of Bacterially-Associated Colorectal Cancer

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Integrative Genomic Analyses of Bacterially-Associated Colorectal Cancer Integrative genomic analyses of bacterially-associated colorectal cancer by Katie S. Viljoen Submitted in accordance with the requirements for the degree of Doctor of Philosophy University of Cape Town The University of Cape Town Department of Clinical Laboratory Sciences Division of Medical Biochemistry November 2014 The copyright of this thesis vests in the author. No quotation from it or information derived from it is to be published without full acknowledgement of the source. The thesis is to be used for private study or non- commercial research purposes only. Published by the University of Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author. University of Cape Town Abstract Sporadic colorectal cancer (CRC) has been linked to various lifestyle factors, including the consumption of alcohol and red meat, smoking, and obesity. CRC is one of most extensively characterised cancers, both at a molecular and ‘omic level; nevertheless, the precise mechanism driving CRC initiation remains unknown. To date, numerous studies have identified changes in the microbial profiles of CRCs compared to adjacent normal mucosa and compared to healthy controls; however, CRC-associated bacteria have not been concurrently quantified across a single cohort; nor have the relationships between CRC-associated bacteria, clinicopathological features of CRC and genomic subtypes of CRC been investigated. The main aim of this thesis was therefore to gain insight into the potential contribution of CRC-associated bacteria in the aetiopathogenesis of CRC by leveraging both host genomic and clinicopathological data as well as to investigate patterns of tissue colonisation between different CRC-associated bacteria. The objectives were 1) to quantify, using quantitative-PCR, CRC-associated bacteria in a cohort of 55 paired tumour and adjacent histologically normal samples collected during surgical resection as well as in an additional 18 formalin-fixed paraffin- embedded (FFPE) samples; 2) to determine their relationships to patient age, gender, ethnicity, stage of disease, site of disease and MSI status (Chapter 4); 3) to evaluate the relationship between each bacterium and host gene expression (Chapter 8) and methylation changes (Chapter 6); and 4) to determine genomic subtypes of CRC using unsupervised clustering of gene expression data in the context of patient clinicopathological features and bacterial quantitation data; and 5) to gain a deeper biological understanding of the results from the objectives 1–4 using pathway analyses of the genomic subtypes obtained (Chapter 7). The main finding of this thesis is that a transcriptomic subtype of colorectal cancer, characterised by an increase in CpG island methylation, displays an increased frequency of colonisation by Enterococcus faecalis and by high levels of Fusobacterium. At the pathway-level, this subtype is enriched for pathways related to DNA and protein damage response, infection, inflammation and cellular proliferation; notably, these i findings were confirmed in a well-defined publically available CRC gene expression dataset of colorectal adenocarcinomas (N=155). These findings suggest that specific bacterial colonisation underlies a distinct genomic subtype of colorectal cancer that is characterised by inflammatory-related gene expression changes; these findings however require validation in a larger cohort. In addition, novel associations between colonisation by specific bacteria and host clinicopathological, transcriptomic and DNA methylation features were identified. ii Declaration 1. I know that plagiarism is wrong. Plagiarism is to use another’s work and pretend that it is one’s own. 2. I have used the American Medical Association convention for citation and referencing. Each contribution to, and quotation in, this thesis from the work(s) of other people has been attributed, and has been cited and referenced. 3. This thesis is my own work 4. I have not allowed, and will not allow, anyone to copy my work with the intention of passing it off as his or her own work. 5. I acknowledge that copying some else’s assignment or essay, or part of it, is wrong and declare that this is my own work. Signature _________________ iii Acknowledgements I would like to express my sincere gratitude to my supervisor, Prof Jonathan Blackburn, for his expert guidance, his positive attitude and valuable input that kept me inspired throughout my PhD, and for allowing me to develop my own research ideas. I would like to acknowledge my family and friends for their support and belief in me, and for helping me maintain my sense of humour throughout my PhD. I would also like to thank Ryan Goosen (whose thesis was based on the same CRC cohort presented here) for the moral and technical support during the countless hours spent processing samples and deciphering hospital folders, and for the useful bioinformatics discussions; Jessica Duarte for proofreading my thesis in under a week; and Alvera Vorster for always being prepared to share her technical expertise. Lastly, I would like to thank the Harry Crossley Foundation, the National Research Foundation (NRF) and the German Academic Exchange Service (DAAD), for their generous financial support over the past four years. My sincere thanks also goes to the Cancer Association of South Africa (CANSA) who funded this research project. iv Table of Contents List of Abbreviations ................................................................... 1 Chapter 1: The epidemiology and aetiopathogenesis of colorectal cancer ........................................................................... 3 Abstract ............................................................................................................................................................................. 3 Epidemiology of CRC .................................................................................................................................................. 3 CRC risk factors ............................................................................................................................................... 4 Southern African CRC landscape ............................................................................................................. 4 Physiology of the colon .............................................................................................................................................. 6 Intestinal barrier function .......................................................................................................................... 8 Specialised intestinal epithelial cells. .................................................................................................... 9 CRC aetiopathogenesis ............................................................................................................................................ 13 CRC subtypes ................................................................................................................................................ 13 Stem cells of the colon and CRC initiation......................................................................................... 16 The role of inflammation in cancer ...................................................................................................... 17 Epigenetic influences in cancer ............................................................................................................................ 21 Chapter 2: The infectious link to colorectal cancer ............... 24 Abstract ........................................................................................................................................................................... 24 The role of microbes in cancer .............................................................................................................................. 24 Established oncogenic pathogens ........................................................................................................................ 25 The CRC-associated microbiome ......................................................................................................................... 26 Factors influencing the composition of the colonic microbiome ............................................ 26 CRC-associated bacteria ......................................................................................................................................... 29 Escherichia coli and CRC ........................................................................................................................... 29 Fusobacterium spp. .................................................................................................................................... 32 Streptococcus gallolyticus ........................................................................................................................ 32 Enterococcus faecalis.................................................................................................................................. 33 Enterotoxigenic Bacteroides fragilis (ETBF) .................................................................................... 34 Chapter 3: Study design, clinicopathological characterisation, and sample processing ............................................................... 35 Abstract ..........................................................................................................................................................................
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