Abstract 228: Loss of <i>TET2</i> and <i>TET3</i> mediated DNA demethylation drives intestinal tumor formation

Abstract Non-mutational epigenetic reprogramming is a widely recognized hallmark of cancer, which emphasizes the relevance of epigenetic modifications for cancer development. The discovery of the CpG island methylator phenotype in colorectal cancer (CRC) and promotor hypermethylation of tumor suppressor genes further raised the interest in DNA methylation changes during tumor development. However, despite decades of cancer epigenetics research, our understanding of the function of aberrant DNA methylation remains limited. Thus, new models are needed to study the link between global DNA methylation changes and tumorigenesis. The Ten-eleven translocator (TET) enzymes are critical mediators of active demethylation by oxidizing the C5-methylcytosine, thereby playing a vital role in regulating DNA methylation. Here, we report an intestinal epithelium-specific TET2/3 double knockout (dko) mouse model, which shows invasive adenocarcinomas in the small intestine at high penetrance. We performed a detailed DNA methylation analysis and identified enhancers as the main target of hypermethylation in the tumors. Additionally, we observed substantial overlap in methylation patterns with the fetal developmental stage of the mouse intestine. Subsequent analysis also revealed a fetal gene expression signature and activation of YAP1 signaling, suggesting oncofetal reprogramming. Since fetal reprogramming is enriched in the serrated route to colorectal cancer, we compared our model with models of the classical (APC) and serrated (BRAF- and KRAS-derived) route of CRC. We found similar methylation patterns between the TET2/3 dko tumors and BRAF- and KRAS-derived tumors. To investigate the clinical relevance of our findings, we collected human small bowel adenomas and integrated their methylation profiles with available datasets of colorectal adenomas and carcinomas. We observed notable similarities between adenomas of the small bowel and serrated adenomas of the colon. This finding further confirms the similarities between our TET-deficient mouse model and the serrated route to colorectal cancer and suggests that non-mutational TET deficiency could be an important driver of intestinal cancer. Citation Format: Oliver Gilliam, Ihab Ansari, Nikolaos Georgakopoulos, Manuel Mastel, Rene Jackstadt, Sebastian Belle, Yehudit Bergman, Frank Lyko. Loss of TET2 and TET3 mediated DNA demethylation drives intestinal tumor formation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 228.