Malcolm Dunlop: Colon Cancer Genetics

Research Programme

The over-arching mission of the Colon Cancer Genetics Group is to contribute to a reduction in incidence and mortality from cancer of the large bowel (colorectal cancer).

Colorectal cancer is common, and is second commonest cause of cancer death in the UK after lung cancer, being responsible for 16,000 deaths annually.

To achieve our research aims, we have two main research strands:

1. Elucidating the genetic architecture of colorectal cancer and understanding the biological consequences of the responsible genetic variation.

2. Understanding molecular mechanisms responsible for the chemopreventative properties of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs).

The research focus on the genetic basis of colorectal cancer aims to shed new light on disease causation and to combat the disease through preventative approaches and early detection. Genetic studies include investigation of the effect and contribution of known susceptibility alleles as well as to identify novel cancer predisposition genes. We are engaged in population-based studies, cancer family studies and highly enriched patient groups with extreme phenotype colorectal cancer. We have undertaken a genome-wide scans for low penetrance alleles in colorectal cancer and this has led to the identification of 16 common genetic variants thus far (September 2011). We are now pursuing the basis of cancer susceptibility through functional studies for a number of these associations, including developing model systems to study the effects of genetic variants. We are also applying these findings in risk prediction models to begin to develop population risk stratification approaches. We have embarked on a “next generation” sequencing endeavour to identify novel moderate penetrance, low frequency genetic variants using a targeted approach.

Chemoprevention of colorectal cancer is also a central theme of the group, focussed primarily on the effect of aspirin and other nonsteroidal anti-inflammatory drugs on NF-kappa-B signaling as a key mechanism of the anti-tumour effect of these agents. We are also exploring other signaling pathways using basic molecular and cell biology, animal studies and clinical translational studies in patients.