Region-specific Wnt signaling responses promote gastric polyp formation in patients with familial adenomatous polyposis
Kevin P. McGowan, Elizabeth Delgado, Theresa M. Keeley, Elise S. Hibdon, D. Kim Turgeon, Elena M. Stoffel, Linda C. Samuelson
Kevin P. McGowan, Elizabeth Delgado, Theresa M. Keeley, Elise S. Hibdon, D. Kim Turgeon, Elena M. Stoffel, Linda C. Samuelson
View: Text | PDF
Research Article Gastroenterology

Region-specific Wnt signaling responses promote gastric polyp formation in patients with familial adenomatous polyposis

Abstract

Germline adenomatous polyposis coli (APC) mutation in patients with familial adenomatous polyposis (FAP) 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 nonpolyp corpus biopsies and organoids from patients with FAP 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 the antrum. Our findings suggest that heterozygous APC mutation in patients with FAP 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 with the rare, yet adenomatous polyps in the antrum.

Authors

Kevin P. McGowan, Elizabeth Delgado, Theresa M. Keeley, Elise S. Hibdon, D. Kim Turgeon, Elena M. Stoffel, Linda C. Samuelson

×

Figure 1

FGP biopsy samples from patients with FAP have increased Wnt target gene expression.

Options: View larger image (or click on image) Download as PowerPoint
FGP biopsy samples from patients with FAP have increased Wnt target gene...
(A) Schematic of Wnt signaling in Wnt OFF, in Wnt ON, and in FAP patients with mutated APC (APC*) exhibiting nuclear localization of β-catenin in the absence of Wnt ligand. (B) Biopsies from paired fundic gland polyps (P) and surrounding nonpolyp (NP) corpus tissue were collected to establish an FAP patient biobank of RNA, DNA, and organoids. (C) Schematic of the APC protein labeled with specific familial mutation sites for the patients in our biobank. Patients with established polyp and nonpolyp organoids are designated. Only patients with known germline mutations are included on this schematic (see Table 1). (D) Relative mRNA abundance of select genes in FAP patient biopsies. qPCR analysis of Wnt target–, cell marker–, and inflammation-related transcripts, with HPRT used as an internal reference transcript. Data are displayed as log2 fold-change (error bars minimum to maximum values, box length IQR, whiskers outliers) relative to patient-matched nonpolyp tissue (nnonpolyp = 20–25 biopsies, npolyp = 21–30 biopsies). Statistical analysis by unpaired parametric Student’s t test (*P < 0.05, **P < 0.005, ***P < 0.001; see Supplemental Figure 1).