Edinburgh Cancer Research

Mark Arends: Colorectal Cancer Pathology

Research Programme

Roles of alcohol-induced DNA damage, DNA mismatch repair, inflammatory bowel disease and new colorectal tumour genes

High alcohol consumption is associated with an increase in the risk of several cancers, notably cancers of the liver, mouth, pharynx, larynx, oesophagus, breast and bowel, but the mechanisms involved are not well understood. It is known that ethanol is metabolised to acetaldehyde, a highly reactive small molecule that can damage DNA, including formation of cross-links between the two strands of the DNA. In collaboration with KJ Patel (LMB, Cambridge) we have shown that the Fanconi Anaemia DNA repair pathway repairs such acetaldehyde-mediated interstrand cross-links and that defective Fanconi repair leads to bone marrow failure and alcohol-induced neoplasia. Defective DNA mismatch repair (occurring either in ~15% sporadic colorectal cancers or ~3% Lynch Syndrome colorectal cancers with inherited mismatch repair gene mutations) confers a high risk of colorectal cancer. This project seeks to investigate whether DNA mismatch repair pathways are also involved in the repair of alcohol-induced DNA damage in the intestines and whether such defective DNA mismatch repair confers a further increase in susceptibility to colorectal cancer development in combination with alcohol consumption. Increased frequency of hypermutated colorectal cancers with defective DNA mismatch repair are also found in inflammatory bowel disease (IBD) patients, accelerating carcinogenesis by increasing the risk of mutations in cancer-related genes and detailed analysis of this process is likely to lead to identification of new cancer-genes that may allow improvements in IBD surveillance or IBD-cancer treatment.

M.Arends - Research Programme 1
Cre induction in colonic crypts of Lgr5-EGFP-IRES-creERT2 model crossed with mTmG model to monitor Cre recombinase activation: Cre switches on expression of the membrane-tagged green fluorescent protein (GFP) and loss of the tomato red fluorescent protein (RFP) in intestinal stem cells that subsequently populate the crypt. Nuclei stained with blue DAPI DNA-binding dye (Mag x400).