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.
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