Intestinal tumour modelling and DNA damage: investigating the interaction of deficient DNA mismatch repair and ethanol in colorectal carcinogenesis.

Lynch Syndrome (LS) confers inherited cancer predisposition due to germline mutations in one of the DNA mismatch repair (MMR) genes. MMR is a DNA-damage repair pathway involved in the removal of base mismatches and insertion/deletion loops caused by several endogenous and exogenous factors. Loss of MMR through somatic alteration of the wild-type allele in LS results in defective MMR (dMMR). Ethanol and its metabolite acetaldehyde, are classified as group one carcinogens by the IARC. Aldehydes are very reactive molecules that constitute a serious threat to cellular integrity by causing a range of DNA lesions. However, DNA repair pathways responsible for correcting such lesions remains unknown. We hypothesized that MMR is involved in the repair of certain forms of ethanol/acetaldehyde-induced DNA damage. In this study, we aim to determine if there is a gene-environment interaction between dMMR and ethanol/acetaldehyde that accelerates colorectal tumourigenesis. We used a conditional Msh2 knockout mouse model that mimics the LS patients’ pattern of MMR gene inactivation. The LS model mice (6-8 weeks of age) were fed either with 20% ethanol in drinking water or normal drinking water. Most of the ethanol-treated mice demonstrated large intestinal hyperproliferation, adenoma formation and, in some cases, invasive adenocarcinoma within 7 months (6/10), compared with one case of intestinal tumour formation after 16.5 months in the water-treated mice (1/10). The quantification of the dMMR crypts in LS mouse colon has shown an increased number of dMMR foci in ethanol-treated mice compared with the control group. Preliminary results indicate that long-term ethanol treatment induced acceleration of dMMR-driven large intestinal tumour formation. Possible mechanisms may include ethanol-induced mucosal crypt epithelial proliferation and ethanol/acetaldehyde mediated DNA damage that would usually be repaired, at least in part, by DNA MMR.