Cancer and Immunogenetics

Previous and current research
The major interests of the laboratory are the fundamental genetics and biology of colorectal cancer and the characterisation and population distribution of HLA and other genetic diversity. We are studying the function of the polyposis or APC and related genes and their involvement in the regulation of cell-cell and cell extracellular matrix adhesion. We are also studying the role of epigenetic changes and searching for new susceptibility genes and mutations in sporadic colorectal and other GI tumours. The mouse Min model for APC in combination with other mutations, enables creation of a model for spontaneous colorectal tumorigenesis in the mouse that mimics the human situation. We have developed novel molecular approaches for the characterisation of HLA types, and SNPs in general, and have an extensive resource for HLA population studies based on Julia Bodmer's organisation of the anthropological component of the 12th International Histocompatibility Testing Workshop, and other national and international collaborations.

Future projects
The mouse models promise to provide a basis for testing therapeutic approaches and their mechanisms, especially using monoclonal antibodies. They are also a basis for evaluating the role of specific genetic changes in colorectal tumorigenesis. We are extending the range of candidate genes for mutation and epigenetic changes in human colorectal and other GI tumours, and exploring further aspects of the function of the APC and related genes such as β-catenin. We are also extending our studies of the basis for chromosome instability in tumours and the stage at which it first occurs. We are developing automated high-throughput procedures for HLA typing at the DNA level, and expect these to be applicable to a wide range of DNA polymorphisms. These will be studied in British and other populations world-wide, which form the basis for controls in case control studies searching for candidate disease susceptibility genes. We are also extending our work on quantitative mathematical models of the cancer process and the role of mutation and selection in the somatic evolution of tumours. In particular, we are studying the role of APC and other cancer gene missense mutations as lower penetrance colon cancer, or adenoma susceptibility factors.

The work of the laboratory continues to combine research on the fundamental genetics and biology of colorectal cancer, with a wide range of human population genetic studies, still emphasising our interest in the HLA system.