Genetic approaches to combating colorectal cancer

Cancer of the large bowel, is a common and frequently fatal disease, affecting 43,000 people in the UK annually and causing ~16,000 deaths. Genes and environment both play a role in development of this cancer. Our research focuses on understanding the interplay of genes and environment on bowel cancer susceptibility and how these cause cancer at a molecular, cellular and whole-person level. We use state-of-the-art technologies to understand the complete picture of genetic and environmental effects on bowel cancer risk and find new genetic changes causally linked with cancer risk. This includes sequencing the entire genetic code (DNA) of human research subjects, and using genotyping arrays to tag parts of the human genetic makeup. We study the effects of these genetic variants in model systems from humans and animals. We aim to identify new ways to prevent cancers forming, and have begun clinical studies in humans to explore the beneficial effects of vitamin D on the lining of the human bowel. We are also able to change the genetic code in cells that we grow from the human bowel (intestinal organoids) using a system called “genome-editing”. This allows us to directly test the effects of genetic signals associated with cancer risk. We can also use genome editing approaches to reverse these effects and test the beneficial effects of drugs, and dietary components, on organoid and animal model systems. In future, we plan to test the effects of these agents in human studies. With our unique blend of discovery science, disease models and ability to translate laboratories findings to the clinic, we are extremely well-placed to make beneficial impact in human health in the field of a common cancer killer through early detection and cancer prevention.

Cancer of the large bowel, or colorectal cancer (CRC), is a common and frequently fatal disease of multifactorial aetiology, affecting 43,000 people in the UK annually and causing ~16,000 deaths, with ~600,000 annual deaths worldwide. Genetic variation and environmental factors contribute to CRC causation. With increasing exposure to environmental risk factors, developing countries are experiencing dramatic increases in CRC incidence. Our research focuses on understanding the complex interplay of genes and environment on CRC susceptibility. Elucidating disease mechanisms not only provides novel insight into cancer causation, but also enables earlier detection and prevention. We employ a range of large-platform approaches to define genetic, and functional genomic, architectures of CRC risk. We establish the role of genetic risk factors through large, well-powered, genome-wide association (GWAS) studies and exome/whole-genome sequencing, then model systems to confirm, and then understand, the molecular genetic mechanisms underlying these genetic associations. Using RNAseq, ATACseq, Capture-C and ChIPseq analysis of normal and tumour human tissues, we explore the molecular and functional consequences of common genetic variation, enabled by our unique patient access, linked with well-curated clinical, pathology and survival data. In case-control and trio studies of extreme early onset CRC, we employ NextGen sequencing to search for rare high penetrance mutations in novel cancer susceptibility genes. Through epidemiological studies and mendelian randomisation, we are exploring the role of environmental risk factors and how these interplay with causal genetic risk factors. Importantly these provide insight to modifiable risk factors that interact with genetic main effects, hence can be considered as “precision-prevention” approaches. Having refined description of genetic and environmental factors in large correlative studies, we are exploiting genome editing approaches (CRISPR) in cultured human and mouse intestinal and tumour organoids to explore the effects of perturbing putative causal pathways. Organoids provide a representative experimental human tissue model, allowing us to explore downstream functional and phenotypic consequences of manipulating genetic sequences - including deletion of putative causal gene(s) and genome editing to replace precise genomic control regions responsible for cancer risk. Using organoid technology, we are beginning to explore effects of multiple common genetic variants, as well as combinations of known key CRC drivers, such as upregulation of wnt signalling. Finally, we are using genome editing approaches to model human common genetic variation in mouse, thereby enabling us to extrapolate to whole-organism environments that are not feasible in humans. With a strong clinical translational emphasis, a key aspect of the Programme is our ability to modify genetic and environmental risk through intervention. Already, modification of genetic risk factors by vitamin D in human organoids and in human subjects treated with vitamin D are showing encouraging beneficial effects on gene expression and phenotypic changes using intestinal organoids. With a unique blend of discovery science, exploring mechanisms, disease models and ability to translate laboratories findings to clinical settings, we are extremely well-placed to make beneficial impact in human health in the field of a common cancer killer.