Fundic gland polyps in familial adenomatous polyposis - Neoplasms with frequent somatic adenomatous polyposis coli gene alterations

Fundic gland polyps (FGPs) are the most common gastric polyps in patients w ith familial adenomatous polyposis (FAP). FGPs have traditionally been rega rded as nonneoplastic, possibly hamartomatous lesions, but the pathogenesis of FGPs in both FAP and sporadic patients remains unclear. FGPs in FAP can show foveolar dysplasia, and rarely invasive gastric adenocarcinoma has be en reported in patients with FAP and fundic gland polyposis. Using direct g ene sequencing and allelic loss assays at 5q, we analyzed somatic adenomato us polyposis coli (APC) gene alterations in 41 FAP-associated FGPs (20 with foveolar dysplasia, six indefinite for dysplasia, and 15 nondysplastic) an d 13 sporadic FGPs. The foveolar epithelium and dilated fundic glands of th e polyps were separately microdissected and analyzed in 25 of 41 FAP-associ ated FGPs and 13 of 13 sporadic FGPs. Somatic APC gene alterations were ide ntified frequently (21 of 41 cases, 51%) in FAP-associated FGPs, Both the f oveolar epithelium and the dilated fundic gland epithelium comprising the F GPs were shown to carry the same somatic APC gene alteration in 24 (96%) of 25 cases. Furthermore, there was no difference in the frequency of somatic APC gene alterations between FGPs with foveolar dysplasia (10 of 20, 50%), indefinite for dysplasia (four of six, 67%), and nondysplastic (seven of 1 5, 47%) in FAP patients (P = 0.697). In contrast, FGPs from non-FAP patient s show-ed infrequent (one of 13, 8%) APC gene alterations (P = 0.008). Thes e results show that FGPs in FAP patients are pathogenetically distinct from sporadic FGPs, Somatic, second-hit APC gene alterations, which precede mor phological dysplasia in many FAP-associated FGPs, indicate that FGPs arisin g in the setting of FAP are neoplastic lesions.