Lynch syndrome (LS), caused by a germline mutation of DNA mismatch repair genes MLH1, PMS2, MSH2 or MSH6, is one of the most common hereditary cancer syndromes, affecting an estimated 175,000 people in the UK alone. Individuals with LS have a lifetime risk of colorectal cancer of up to 80%, as well as increased risk of other cancers, including cancer of the endometrium, small intestine, stomach and skin, amongst others. Epidemiological studies have shown that the colorectal cancer risk in LS is increased by alcohol consumption, although insights into the underlying mechanisms are lacking.
In this issue of DMM, Cerretelli and colleagues addressed this by generating mice with combined loss of Msh2 and Aldh1b1, the gene responsible for detoxification of acetaldehyde – the mutagenic metabolite of alcohol. As expected, mice with Aldh1b1 deletion demonstrated increased acetaldehyde levels following ethanol treatment. Importantly, compound mutant mice, with combined Msh2 and Aldh1b1 deletion, developed colonic tumours when treated with alcohol, while no tumours occurred in mice of identical genotype treated with water, or in mice with functional MSH2 treated with either alcohol or water. Interestingly, in contrast to many mouse intestinal tumour models, analysis of the small intestine revealed no evidence of tumours or pre-neoplastic changes. This may be due to the presence of additional protective mechanisms against acetaldehyde-induced DNA damage at this site, or possibly differences in the gut microbiota, the composition of which is known to be altered as a consequence of ethanol consumption. Investigation of the underlying mechanism of colonic tumour development by immunohistochemical analysis of colonic crypts revealed significantly increased DNA damage, apoptosis and p53 response in compound mutant mice when treated with alcohol, consistent with a genotoxic effect of increased acetaldehyde. This analysis also revealed significantly increased frequency of MSH2-negative colonic crypts in alcohol-treated compound mutants, with evidence of dose dependency, as conditional deletion of Aldh1b1 by Lgr5-Cre, which targets a minority of intestinal stem cells, resulted in fewer MSH2-negative crypts than with constitutive Aldh1b1 knockout.
Collectively, the results of Cerretelli and colleagues provide mechanistic insights into the increased colon cancer risk associated with alcohol consumption in individuals with LS and represent an important additional body of evidence supporting efforts to reduce alcohol consumption in this population. This also encourages further investigation of the differences in colonic and small intestinal phenotype in LS.
DMM Research or Resource articles of particular interest or excellence may be accompanied by a short Editor's choice highlight, selected by a DMM editor and written by either members of the DMM in-house editorial team or an expert in the field. The Editor's choice aims to outline the challenges that the work addresses and how the work advances our insight into disease mechanism, therapy or diagnosis.
