Malcolm Dunlop - Overview

We aim to define the role of defects in DNA mismatch repair genes in colorectal cancer susceptibility and to investigate the consequences of defective mismatch repair in tumours and in normal somatic tissue. In addition to molecular studies, we are carrying out systematic population studies of the contribution of DNA mismatch repair gene mutations to the incidence of colorectal cancer. This work is already informing clinical practice. In other work, we aim to determine molecular correlates of clinical outcome and treatment response, as well as to refine gene prevalence and penetrance. In order to identify new genes, we have assembled a large prospective cohort of early onset colorectal cancer patients for genetic linkage and genetic association studies. We are testing a number of candidate genes that were identified by study of tumour material from the cohort.

In parallel studies, we are investigating the molecular basis of the protective effect of aspirin against colorectal cancer. We previously showed that aspirin induces apoptosis in colorectal cancer cells by a mechanism that is dependent on the NF-kB transcription factor. We are now studying the NF-kB pathway upstream and downstream of nuclear translocation of NF-kB to determine the signals and the effectors of this response. Laboratory molecular studies are complemented by model studies and by clinical studies in patients with rectal cancer, and people prediposed to colorectal cancer by nature of genetic susceptibility. Hence the work on chemoprevention is synergistic with our studies aimed at identifying people carrying cancer predisposition genes.