Molecular and Population Genetics
Previous research
The laboratory works primarily, but not exclusively, on tumours of the large bowel and on tumorigenesis that results from dysregulation of the pathways of cellular energy production. Our past successes include the cloning of genes for three Mendelian cancer syndromes and the mapping of a further such locus. We have provided information that questions and updates the model of tumour suppressor action in tumorigenesis. We have been particularly active in the study of patients with multiple adenomas of the large bowel, in relation to their phenotypes, their underlying genetic causes and the genes which modify the effects of major susceptibility genes. We have demonstrated new pathways of colorectal tumorigenesis, with particular emphasis on the roles of different types of genomic instability in tumour initiation and progression, This work has involved the initiation and development of new technologies, including array-based assessment of copy number changes.
In addition to our work on colorectal cancer, over the last four years, we have become deeply involved in the contribution of changes in fundamental metabolic pathways in relation to tumour growth. This work has stemmed from our identification of mutations in the Krebs cycle enzyme fumarate hydratase as a cause of smooth muscle tumours and renal cancer. We have shown that these mutations cause activation of the hypoxia pathway, although other effects on cell growth and division remain possible. We have many fruitful collaborations within and outside Cancer Research UK and our work would not be possible without these interactions.
Current and future projects
These can be divided into main groups:
- Identification of bowel cancer susceptibility genes using linkage analysis, large-scale association studies and candidate gene testing.
- Identifying germline predictors of colorectal cancer behaviour.
- Studies of bowel cancer in different ethnic groups.
- Investigation of the effects of Wnt pathway activation in colorectal tumours, with particular regard to different combinations of APC mutations and their functional consequences.
- Characterisation of the role of mitotic recombination in causing loss of heterozygosity in tumorigenesis.
- Examining the functional effects of disrupting aerobic metabolism in cells and tissues under normoxia.
