Lynch Syndrome (LS) confers inherited cancer predisposition due to germline mutations in a DNA mismatch repair (MMR) gene, e.g. MSH2. MMR is a repair pathway for removal of base mismatches and insertion/deletion loops caused by endogenous and exogenous factors. Loss of MMR through somatic alteration of the wild-type allele in LS results in defective MMR (dMMR). Lifestyle/environmental factors can modify colorectal cancer risk in sporadic and LS patients. Ethanol and its metabolite acetaldehyde are classified as group one carcinogens, and acetaldehyde causes a range of DNA lesions. However, DNA repair pathways responsible for correcting most of such DNA lesions remain uncharacterised. We hypothesised that MMR plays a role in protecting colorectal epithelium from ethanol/acetaldehyde-induced DNA damage. Here, an LS mouse model (intestinal epithelial conditional-knockout for Msh2) was used to determine if there is a gene/environment interaction between dMMR and ethanol/acetaldehyde that accelerates colorectal tumourigenesis in LS. Mice underwent either long-term ethanol-treatment or water-treatment. Most ethanol-treated mice demonstrated colonic hyperproliferation and adenoma formation (with some invasive adenocarcinomas) within 6 months (15/23, 65%), compared with one colonic tumour after 15 months in water-treated mice (1/23, 4%) (p<0.0001, Fisher's exact test). A significantly greater number of dMMR colonic crypt foci precursors were observed in ethanol-treated compared with water-treated mice (p=0.0029, Student's t-test). Moreover, increased plasma acetaldehyde levels were detected in ethanol-treated compared with water-treated mice (p=0.0019, Mann-Whitney U-test), along with significantly increased DNA damage response in the colonic epithelium. Long-term ethanol treatment was associated with significantly increased colonic epithelial proliferation and markedly reduced apoptosis in dMMR adenomas, consistent with enhanced survival of aberrant dMMR relative to MMR-proficient colonic epithelium. In conclusion, there is strong evidence for a gene/environment interaction between dMMR/acetaldehyde, causing acceleration of dMMR-driven colonic tumour formation in this LS model, indicating that advice to limit alcohol consumption should be considered for LS patients.

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