Sporadic fundic gland polyps: common gastric polyps arising through activating mutations in the beta-catenin gene

Abstract

Fundic gland polyps (FGPs) are the most common gastric polyps. FGPs traditionally have been regarded as nondysplastic hamartomatous or hyperplastic lesions, but their pathogenesis remains unclear. We have recently shown that somatic adenomatous polyposis coli (APC) gene alterations are frequently present in FGPs associated with familial adenomatous polyposis (FAP), raising the possibility that mutations of the beta-catenin gene affecting the APC/beta-catenin pathway might be involved in the pathogenesis of sporadic FGPs. We analyzed somatic beta-catenin gene mutations in 57 sporadic FGPs from 40 patients without FAP and in 19 FGPs from 13 FAP patients. Direct DNA sequencing of exon 3 encompassing the glycogen synthase kinase-3beta phosphorylation region for beta-catenin was used with confirmation by HIN:fI restriction endonuclease digestion. The foveolar epithelium and dilated fundic glands of the polyps were separately microdissected and analyzed in 22 of 57 sporadic FGPs. Activating beta-catenin gene mutations were present in 91% (52 of 57) of sporadic FGPs. Both the foveolar epithelium and the dilated fundic gland epithelium comprising the polyps were shown to have the same somatic beta-catenin mutation in 21 of 22 (95%) sporadic FGPs. In contrast, beta-catenin gene mutations were not present in any of the 19 FAP-associated FGPs (P: < 0.000001). The high frequency of beta-catenin mutations in sporadic FGPs indicates that these lesions arise through activating mutations of the beta-catenin gene. Beta-catenin mutations in gastrointestinal tract polyps have previously only been demonstrated in a subset of adenomatous (dysplastic) or neoplastic polyps. Sporadic FGPs are therefore the only lesions of the gastrointestinal tract to demonstrate beta-catenin mutations while lacking dysplastic morphology.

Figure 1.

Histopathological appearance of FGPs. A: Polyps are composed of cystically dilated fundic glands. B: The dilated fundic glands are lined by attenuated parietal cells, chief cells, and mucous neck cells. The overlying surface/foveolar epithelium (arrowheads) is typically nondysplastic. H&E stain; original magnifications: ×40 (A); ×200 (B).

Figure 2.

Representative somatic β-catenin gene mutations in sporadic FGPs. A: DNA sequencing autoradiograph of a TCT (serine)→TGT (cysteine) mutation (arrow) at codon 37, present in both the surface/foveolar epithelium and the epithelium of the dilated fundic glands from an FGP (patient 17). No β-catenin mutation is present in the corresponding normal, nonpolypoid gastric mucosa from the same patient. B: DNA sequencing autoradiograph of a TCT (serine)→TGT (cysteine) mutation (arrow) at codon 33 in both the surface/foveolar epithelium and the epithelium of the dilated fundic glands from an FGP (patient 13). C: HinfI restriction endonuclease assay to verify the presence of a point mutation in this case and in other representative cases with codon 32 and 33 mutations. DNA samples are from sporadic FGPs from patients 11, 12, 13, and 2 (dilated fundic glands, lanes 3, 6, 9, and 11; overlying surface/foveolar epithelium, lanes 2, 5, and 8) and normal tissue from the respective patients (lanes 1, 4, 7, and 10). The normal 200-bp PCR product for β-catenin contains two HinfI restriction endonuclease sites, yielding 7-bp, 55-bp, and 138-bp DNA fragments after digestion of the wild-type allele (the 7-bp fragment is too small to be visualized on the gel). β-catenin mutations in codons 32 and 33 yield 62-bp and 138-bp fragments after digestion because of ablation of the first HinfI site. A molecular weight marker of 50-bp ladder is in lane M.

Figure 3.

Summary of β-catenin mutations in sporadic FGPs. Schematic of the β-catenin gene, wild-type GSK-3β binding sequence in humans (with serine/threonine phosphorylation sites in bold type), and β-catenin point mutations present in sporadic FGPs. S, serine; Y, tyrosine; L, leucine; D, aspartic acid; G, glycine; I, isoleucine; H, histidine; A, alanine; T, threonine; P, proline; K, lysine; N, asparagine. In addition to the point mutations shown in the diagram, one FGP contained a 15-bp deletion spanning codons 32 to 37.

Figure 4.

Immunohistochemical staining for β-catenin in sporadic FGPs. A: Membranous and cytoplasmic staining for β-catenin are present in the epithelial cells lining the dilated fundic glands of an FGP, but nuclear accumulation of β-catenin is not seen. B: The same pattern of β-catenin staining is seen in the nonpolypoid fundic mucosa from the same patient.