We are working to identify colorectal susceptibility genes and studying specific aspects of chemoprevention. We using two complementary approaches. We are identifying colorectal cancer susceptibility genes. We are also investigating how aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) reduce colorectal cancer incidence and mortality, focusing on a particular signalling pathway, the Nuclear Factor-KappaB (NFKB) pathway. Identifying colorectal cancer susceptibility genes The genetic theme employs family-based approaches and large-scale association studies. Because there is likely to be considerable genetic heterogeneity and gene-gene interactions that contribute to colorectal cancer incidence, such studies require very large patient and control cohorts. We have assembled such a resource with sufficient statistical power, comprising over 4,500 cancer patients and 3,500 controls. In 2500 cases and 2500 controls we have accrued very detailed information about risk factor exposure for investigation of gene-environment interactions. We are also engaged in defining the role of genes shown previously to be associated with colorectal cancer risk. We are investigating the underlying causes of the observed differences in sex-specific and age-related cancer risk in people with mutations in DNA mismatch repair genes. Genetic linkage approaches in very large families carrying an identical mutation are being used to address these issues, and to define genetic and environmental modifying effects on cancer phenotype. Chemoprevention Our chemoprevention work aims to determine how aspirin and NSAIDs prevent bowel cancer. We are specifically interested in defining the aspirin effect on the NFKB signalling pathway, as we have shown this is critical to the anti-tumour effect of aspirin. We are investigating the molecular effects of the drugs on each component of the NFKB signalling pathway in colorectal cancer cells, using chemical and genetic knockouts of NFKB signalling proteins involved from the initiating signal at the cell surface to the nucleus and sub-nuclear functional organisation. Also we are near to completion of clinical studies trials of aspirin defining the molecular effects of aspirin in human subjects. In longer term clinical trials, we aim to treat with aspirin subjects in whom we stratify colorectal cancer risk using the genetic markers we have identified. Molecular endpoints focussed on clinical as well as NFKB signalling and also clinical intermediate and cancer endpoints in such studies will be used. This article was published on 2024-02-06
