Title: Using predisposition genes to understand and prevent colorectal cancer
Funder: Cancer Research UK

Abstract: Background Genetic studies have found many new genes associated with increased cancer, but the roles of most of these have not been explored. We recently identified nearly 40 new colorectal cancer risk polymorphisms (CRC SNPs), most at loci with no established role in cancer. If variation in a gene’s function influences tumour risk, the gene is a strong candidate target for cancer prevention. Aims We shall use our recent results to explore and understand the functions of two selected pathways in colorectal tumorigenesis, bone morphogenetic protein (BMP) signalling and TET-controlled (hydroxy)methylation. The programme’s outputs will contribute important advances in the basic science of CRC predisposition. The work also has the underlying aim of identifying targetable mechanisms of colorectal tumorigenesis with clinical utility in cancer prevention. Methods We previously showed that increasing BMP activity has potential for CRC prevention. Using our latest genetic data and comprehensive functional annotation, we shall identify new CRC susceptibility genes in the BMP pathway, and thus potential targets for CRC chemoprevention. We shall determine whether modulating BMP activity at the dual levels of secreted ligands and feedback repressors in target cells is particularly powerful for tumour prevention, and identify the mechanisms involved, including effects on tissue stem cells. We shall identify the maximum level of BMP activation that is non-toxic to the normal bowel and other tissues, whilst retaining considerable anti-tumour activity. Finally, we shall test whether increased BMP activity prevents colorectal tumorigenesis in the “serrated”, as well as classical, pathway, thus providing comprehensive CRC prevention. We shall also study TET2, a gene that harbours a new CRC risk polymorphism. TET proteins are central to controlling DNA demethylation, but have no characterised role in the common solid cancers. We shall determine how variation in TET2 expression in the normal intestines alters DNA (hydroxy)methylation, downstream gene expression, chromatin structure, and cellular lineages. We shall determine the consequences for colorectal tumorigenesis, the underlying mechanisms and implications for prevention. How the results of this research will be used Our work will generate new fundamental information regarding the role of the BMP pathway and (hydroxy)methylation in intestinal crypt homoeostasis and the effects on colorectal tumorigenesis. We shall test the hypothesis that variation in stem cell numbers underlies much of CRC risk and consider ways to modulate this, especially in individuals with high stem cell levels. We shall take forward promising new gene targets to evaluate their use for CRC chemoprevention.

Lay abstract: Background Genetic studies have found many new genes associated with increased cancer, but the roles of most of these have not been explored. We recently identified nearly 40 new colorectal cancer risk polymorphisms (CRC SNPs), most at loci with no established role in cancer. If variation in a gene’s function influences tumour risk, the gene is a strong candidate target for cancer prevention. Aims We shall use our recent results to explore and understand the functions of two selected pathways in colorectal tumorigenesis, bone morphogenetic protein (BMP) signalling and TET-controlled (hydroxy)methylation. The programme’s outputs will contribute important advances in the basic science of CRC predisposition. The work also has the underlying aim of identifying targetable mechanisms of colorectal tumorigenesis with clinical utility in cancer prevention. Methods We previously showed that increasing BMP activity has potential for CRC prevention. Using our latest genetic data and comprehensive functional annotation, we shall identify new CRC susceptibility genes in the BMP pathway, and thus potential targets for CRC chemoprevention. We shall determine whether modulating BMP activity at the dual levels of secreted ligands and feedback repressors in target cells is particularly powerful for tumour prevention, and identify the mechanisms involved, including effects on tissue stem cells. We shall identify the maximum level of BMP activation that is non-toxic to the normal bowel and other tissues, whilst retaining considerable anti-tumour activity. Finally, we shall test whether increased BMP activity prevents colorectal tumorigenesis in the “serrated”, as well as classical, pathway, thus providing comprehensive CRC prevention. We shall also study TET2, a gene that harbours a new CRC risk polymorphism. TET proteins are central to controlling DNA demethylation, but have no characterised role in the common solid cancers. We shall determine how variation in TET2 expression in the normal intestines alters DNA (hydroxy)methylation, downstream gene expression, chromatin structure, and cellular lineages. We shall determine the consequences for colorectal tumorigenesis, the underlying mechanisms and implications for prevention. How the results of this research will be used Our work will generate new fundamental information regarding the role of the BMP pathway and (hydroxy)methylation in intestinal crypt homoeostasis and the effects on colorectal tumorigenesis. We shall test the hypothesis that variation in stem cell numbers underlies much of CRC risk and consider ways to modulate this, especially in individuals with high stem cell levels. We shall take forward promising new gene targets to evaluate their use for CRC chemoprevention.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS