Inflammation is an essential trigger for POLE-driven ultramutated colorectal cancer
Pathogenic variants in the exonuclease (proofreading) domain of DNA polymerase e (POLE) result in colorectal cancers (CRC) with high tumor mutational burden (TMB). Here, we investigated the role of POLE in colorectal tumorigenesis using a conditional mouse model expressing the PoleP286R pathogenic driver in intestinal epithelial cells. These mice developed invasive adenocarcinomas in the small intestine with incomplete penetrance and extremely long latency but did not spontaneously develop colorectal tumors. However, induction of colitis with dextran sulfate sodium resulted in a striking phenotypic shift to colorectal adenocarcinomas at high frequency. Molecular and histological analyses revealed hyperactivation of Wnt/beta-catenin, NF-kappaB, ERK and STAT3 pathways, leading to cell cycle deregulation. Whole genome sequencing demonstrated exceptionally high TMB (>100 mutations/megabase) and characteristic trinucleotide signatures, consistent with human POLE tumors. Additionally, recurrent mutations in Apc and Ctnnb1 underscored the role of Wnt signaling. Intestinal organoids from Pole mutant mice grew more rapidly, accompanied by increased expression of pro-proliferative genes. These findings highlight POLE as a gatekeeper of intestinal genomic integrity and identify inflammation as the key driver that unleashes POLE-mutant CRC. Furthermore, this work establishes a mechanistically-faithful preclinical platform for studying the molecular pathogenesis of CRC and advancing therapeutic drug discovery.