Germline APC mutation in familial adenomatous polyposis (FAP) patients promotes gastrointestinal polyposis, including the formation of frequent gastric fundic gland polyps (FGPs). In this study, we investigated how dysregulated Wnt signaling promotes FGPs and why they localize to the corpus region of the stomach. We developed a biobank of FGP and surrounding non-polyp corpus biopsies and organoids from FAP patients for comparative studies. Polyp biopsies and polyp-derived organoids exhibited enhanced Wnt target gene expression. Polyp-derived organoids with intrinsically upregulated Wnt signaling showed poor tolerance to further induction, suggesting that high Wnt restricts growth. Targeted genomic sequencing revealed that most gastric polyps did not arise via APC loss-of-heterozygosity. Studies in genetic mouse models demonstrated that heterozygous Apc loss increased epithelial cell proliferation in the corpus but not the antrum, while homozygous Apc loss was not maintained in the corpus yet induced hyperproliferation in antrum. Our findings suggest that heterozygous APC mutation in FAP patients may be sufficient to drive polyp formation in the corpus region while subsequent loss-of-heterozygosity to further enhance Wnt signaling is not tolerated. This finding contextualizes the abundant yet benign nature of gastric polyps in FAP patient corpus compared to the rare, yet adenomatous polyps in the antrum.
Kevin P. McGowan, Elizabeth Delgado, Theresa M. Keeley, Elise S. Hibdon, Danielle Kim Turgeon, Elena M. Stoffel, Linda C. Samuelson