Ethanol‐induced formation of colorectal tumours and precursors in a mouse model of Lynch syndrome

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 and 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. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.