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 beta-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/beta-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 beta-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 beta-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 beta-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.
Abraham
Susan C
SC
Department of Pathology, Division of Gastrointestinal/Liver Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Park
Seun Ja
SJ
Mugartegui
Lilian
L
Hamilton
Stanley R
SR
Wu
Tsung-Teh
TT
D000328:Adult; D000368:Aged; D001483:Base Sequence; D003598:Cytoskeletal Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D005753:Gastric Mucosa / Q000473:pathology*; D017491:Genes, APC; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D011127:Polyps / Q000235:genetics* / Q000473:pathology*; D013272:Stomach Diseases / Q000235:genetics* / Q000473:pathology*; D015534:Trans-Activators / Q000235:genetics; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin