Genetic factors associated with the aetiology and treatment of colorectal cancer

Susceptibility to colorectal cancer is inevitably linked to both environmental and genetic factors, although the relative contribution of these to disease aetiology remains unclear. For a number of years, in a close collaboration between research groups in the Biomedical Research Centre at the University of Dundee and the CR-UK Genetic Epidemiology Division at the University of Leeds, we have studied the relationship between diet and pharmacogenetic polymorphisms on colorectal cancer susceptibility. As part of this work, to test the hypothesis that different tumour mutations may reflect different disease aetiologies and environmental influences, we have carried out a detailed investigation of mutations that occur in colorectal tumours in the major signalling pathways implicated in the aetiology of this disease, e.g. in the tumour suppressor genes p53 and APC and the oncogene K-Ras. Interestingly, our analysis of a large series of colorectal tumours demonstrated that the Vogelstein model of colorectal cancer development is not representative of the majority of colorectal tumours, as only a minority of our tumours had mutations in all three of the p53, APC and K-Ras genes.

Genetic studies on the role of carcinogen metabolising enzymes in colorectal cancer susceptibility did not support the hypothesis that exposure to heterocyclic amine carcinogens is important in the aetiology of this disease, but did support a causative role for polycyclic aromatic hydrocarbons and similar carcinogens.

Further studies are underway to establish whether risk factors associated with the development of colorectal adenomas can be identified. We have also investigated whether the presence of specific tumour mutations is a prognostic marker for survival in colorectal cancer patients and have shown that the presence of K-Ras mutations, but not APC or p53 mutations, is associated with significantly reduced patient survival