Figure 6.

Schematic diagram of the proposed model of the MMR/ethanol/acetaldehyde gene–environment interactions in both MMR‐proficient (upper panel) and MMR‐deficient (lower panel) colonic epithelial cells. Upon ethanol/acetaldehyde exposure, in some colonic epithelial stem cells there is DNA base damage that normally would be recognised and repaired by the MMR system, or if unrepaired this base damage may induce replication errors, such as base mismatches or insertion/deletion loops (InDels), during S‐phase of the cell cycle. Here, the MMR‐proficient cell is able to activate DNA mismatch repair of the (MMR‐recognised) base damage, bringing about either cell cycle arrest in the context of mild DNA damage to allow DNA repair or cell death by apoptosis for more severe DNA damage. By contrast, the MMR‐deficient cell (dMMR due to mutant Msh2) is unable to activate the MMR signalling pathway and so there is neither cell cycle arrest nor apoptosis, resulting in aberrant survival of DNA‐damaged cells that can undergo ethanol‐induced subsequent proliferation. The proliferating dMMR stem cells populate the colonic crypt and expand further to form dMMR crypt foci. Stimulated by ethanol to undergo increased proliferation, these cells form hyperproliferative crypts whilst remaining subject to ongoing DNA damage from continued exposure to ethanol/acetaldehyde. These dMMR cells can accumulate mutations reflecting dMMR genomic instability and are consequently at increased risk of tumour formation, thus explaining the acceleration of colonic adenoma formation and increased probability of evolution to adenocarcinoma.