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(American Journal of Pathology. 2002;161:1735-1742.)
© 2002 American Society for Investigative Pathology

Sporadic Fundic Gland Polyps with Epithelial Dysplasia

Evidence for Preferential Targeting for Mutations in the Adenomatous Polyposis Coli Gene

Susan C. Abraham*, Seun Ja Park{dagger}, Lilian Mugartegui{dagger}, Stanley R. Hamilton{dagger} and Tsung-Teh Wu{dagger}

From the Department of Pathology,* Division of Gastrointestinal/Liver Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and the Division of Pathology and Laboratory Medicine,{dagger} University of Texas M.D. Anderson Cancer Center, Houston, Texas

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 ß-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/ß-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 ß-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 bi-allelic 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 ß-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 ß-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.






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Copyright © 2002 by the American Society for Investigative Pathology.