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

ALDH1B1 expressed in the intestinal epithelium metabolises acetaldehyde to acetate, protecting against acetaldehyde-induced DNA damage. MSH2 is a key component of the DNA mismatch repair (MMR) pathway involved in Lynch syndrome (LS)-associated colorectal cancers. Here, we show that defective MMR (dMMR) interacts with acetaldehyde, in a gene/environment interaction, enhancing dMMR-driven colonic tumour formation in a LS murine model of Msh2 conditional inactivation (Lgr5-CreER; Msh2flox/-, or Msh2-LS) combined with Aldh1b1 inactivation. Conditional (Aldh1b1flox/flox) or constitutive (Aldh1b1-/-) Aldh1b1 knockout alleles combined with the conditional Msh2flox/- intestinal knockout mouse model of LS (Msh2-LS) received either ethanol, which is metabolised to acetaldehyde, or water. We demonstrated that 41.7% of ethanol-treated Aldh1b1flox/flox Msh2-LS mice and 66.7% of 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 control mice. 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 those in water-treated controls. Hence, ALDH1B1 loss increases acetaldehyde levels and DNA damage that interacts with dMMR to accelerate colonic, but not small intestinal, tumour formation.

Automated summary

This study found that defective MMR interacts with acetaldehyde, enhancing colonic tumor formation. Loss of ALDH1B1 increases acetaldehyde levels and DNA damage that interacts with dMMR to accelerate colonic tumor formation.