Abstract
Obesity increases the risks of at least 13 types of cancer, including colorectal cancer, though the mechanisms underlying this relationship are unknown. In this thesis, I take a multi-disciplinary approach, integrating genetic epidemiology, intervention trials, and in vitro methods, to gain a deeper understanding of the obesity-cancer risk relationship, with a particular focus on colorectal cancer.Chapter 1 gives an overview of the format of this thesis. Chapters 2 introduces relevant background for this research, and Chapter 3 describes the key methods and data used.
In Chapter 4, I use Mendelian randomization (MR), a genetic epidemiological approach, to demonstrate the importance of adiposity distribution in cancer risk. I show that the adiposity distribution-cancer risk relationship is complex and differs by cancer type.
In Chapter 5, I show that a short-term weight-loss intervention leads to cancer-related changes in colorectal tissue, providing promising evidence that individuals with obesity may be able to mitigate cancer risk through weight loss. I highlight four genes in particular – ABHD11, SMAD9, CHMP2A, and ATP5MC2 – that may have roles in the adiposity-colorectal cancer relationship.
Building on these findings, in Chapter 6 I use in vitro methods to further evaluate the role of one of these genes, ABHD11, in colorectal carcinogenesis. I identify changes to cellular stemness, potentially mediated by metabolic changes, as a possible mechanism explaining the effect of ABHD11 expression on colorectal cancer risk.
In Chapter 7, I combine multi-tissue transcriptome-wide association study (TWAS) methods with a causal inference approach, to identify likely colorectal cancer susceptibility genes. I then investigate these genes for a relationship with colorectal cancer risk factors.
Finally, in Chapter 8, I summarise the previous chapters and discuss the clinical implications of my research and possible future directions.
| Date of Award | 4 Feb 2025 |
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| Original language | English |
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| Supervisor | Emma E Vincent (Supervisor) |