Acetaldehyde and defective mismatch repair increase colonic tumours in a Lynch Syndrome model with Aldh1b1 inactivation.

Defective mismatch repair (dMMR) interacts with acetaldehyde, in a gene/environment interaction, enhancing dMMR-driven colonic tumour formation in a Lynch Syndrome murine model of Msh2 conditional inactivation combined with either conditional or constitutive Aldh1b1 inactivation. ALDH1B1 expressed in intestinal epithelium, metabolises acetaldehyde to acetate, protecting against acetaldehyde-induced DNA damage. MSH2 is a key component of the DNA mismatch repair pathway (MMR), involved in Lynch Syndrome (LS)-associated colorectal cancers. Either conditional-Aldh1b1 (Aldh1b1flox/flox) or constitutive-Aldh1b1 (Aldh1b1-/-) knockout alleles combined with conditional Msh2flox/- intestinal knockout mouse model of LS (Msh2-LS), received either ethanol that is metabolised to acetaldehyde, or water. We demonstrated that 41.7% ethanol-treated Aldh1b1flox/flox Msh2-LS mice and 66.7% Aldh1b1-/- Msh2-LS mice developed colonic epithelial hyperproliferation and adenoma formation, in 4.5 and 6 months respectively, significantly greater than 0% in water-treated controls. Significantly higher numbers of dMMR colonic crypt foci precursors and increased plasma acetaldehyde levels were observed in ethanol-treated Aldh1b1flox/flox Msh2-LS and Aldh1b1-/- Msh2-LS mice compared with water-treated controls. Hence, ALDH1B1 loss increases acetaldehyde levels and DNA damage that interacts with defective MMR to accelerate colonic, but not small intestinal, tumour formation.