Abstract Pathogenic variants of DNA polymerase ε (POLE), such as P286R, result in high tumor mutational burden (TMB), particularly in endometrium and colorectal cancer (CRC). Here, we investigated the role of POLE mutations in CRC using a conditional mouse model expressing the PoleP286R mutation in intestinal epithelial cells. We generated LSL-PoleP286R knock-in mice and crossed them with Vilin-Cre mice to obtain intestinal epithelial cell-specific PoleP286R mutant mice (PVC). Spontaneous tumor development in the small intestine and colon of PVC mice was monitored. Additionally, effect of inflammation on POLE-driven colorectal tumorigenesis was monitored following induction of colitis with 2.5% dextran sulfate sodium (DSS). PVC developed invasive adenocarcinoma in the small intestine (SI) with partial penetrance but did not develop any tumor in colon spontaneously. Surprisingly, induction of chronic colitis with DSS resulted in colorectal tumor development with 100% penetrance in PVC mice but not control wild-type mice. Tumors of PVC mice were pathologically diverse, with low-grade and high-grade dysplasia and invasive adenocarcinoma. Whole genome sequencing demonstrated that colorectal tumors of PVC mice bear high TMB, including recurring mutations in Apc and Ctnnb1. Consistently, there was increased expression of proliferative genes, including cMyc, Ccnd1, Ki67, and Lgr5 and higher activation of Wnt/β-catenin, NF-κB, and ERK pathways. Notably, mice expressing intestinal PoleP286R recovered faster from acute DSS-induced mucosal injury, prior to the development of tumors. In vitro organoid culture further confirmed that PoleP286R mutant intestinal organoids grow faster and larger than those from control mice. These findings demonstrate that POLE plays a crucial role in the maintenance of intestinal genomic stability, and inflammation plays an essential role in driving ultra-mutated CRC in the presence of pathogenic POLE variants. Citation Format: Md Kawsar Mustofa, He Zhang, Diego H. Castrillon, Hasan Zaki. Intestinal inflammation triggersPOLE P286R-driven ultramutated colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4685.
Mustofa et al. (Fri,) studied this question.