Sporadic fundic gland polyps with epithelial dysplasia: Evidence for preferential targeting for mutations in the adenomatous polyposis coli gene

Gastric fundic gland polyps (FGPs) occur in two distinct clinicopathological scenarios: Sporadic and familial adenomatous polyposis (FAP) associated. FAP-associated FGPs arise through somatic second hit alterations of the adenomatous polyposis coli (APC) gene and frequently demonstrate epithelial dysplasia (Am J Pathol 2000, 157:747-754). Sporadic FGPs, in contrast, tend to contain β-catenin gene mutations and only infrequently show dysplasia (Am J Pathol 2001, 158:1005-1010). However, sporadic FGPs with dysplasia have not been previously investigated. We studied 13 sporadic FGPs with surface/foveolar low-grade dysplasia or changes indefinite for dysplasia for alterations in the APC/β-catenin pathway, using chromosome 5q allelic loss assays and direct DNA sequencing of the mutation cluster region in exon 15 of APC and the phosphorylation region in exon 3 of β-catenin. In addition, to evaluate for possible additional genetic alterations in FGPs, all cases were evaluated for microsatellite instability using fluorescent-based amplification of a standard panel of five microsatellite markers. Alterations in APC were present in seven (53.8%) FGPs, including two cases with biallelic APC inactivation (truncating intragenic mutation plus 5q allelic loss), two cases with APC mutation only, and three cases with 5q allelic loss only. In contrast, only two (15.4%) FGPs contained stabilizing β-catenin mutations. All 13 FGPs were microsatellite stable. These results indicate that sporadic FGPs with dysplasia/indefinite for dysplasia are molecularly similar to FAP-associated FGPs, and are dissimilar to the more common sporadic nondysplastic FGPs. Mutations in APC and β-catenin, despite occurring in the same genetic pathway, show differing biological properties, a phenomenon that has previously been demonstrated in colorectal neoplasms. The lack of microsatellite instability in FGPs in this study and of K-ras mutations in a previous study suggests that secondary genetic alterations are rare in both dysplastic and nondysplastic FGPs.