title: GNAS mutation as an alternative mechanism of activation of the Wnt/β-catenin signaling pathway in gastric adenocarcinoma of the fundic gland type.
abstract: Gastric adenocarcinoma of the fundic gland type (GAFG) is a rare variant of gastric tumor. We have recently reported the frequent accumulation of β-catenin in GAFGs and showed that approximately half of the cases studied harbored at least 1 mutation in CTNNB1/AXINs/APC, leading to the constitutive activation of the Wnt/β-catenin pathway. However, the mechanisms of Wnt signaling activation in the remaining cases are unknown. Accumulating evidence showed that the activating mutation in GNAS promotes tumorigenesis via the activation of the Wnt/β-catenin pathway or the ERK1/2 MAPK pathway. Therefore, we analyzed the mutations in GNAS (exons 8 and 9) and in KRAS (exon 2) in 26 GAFGs. Immunohistochemistry revealed nuclear β-catenin expression in 22 of 26 GAFGs, and 10 (38.5%) of 26 cases harbored at least 1 mutation in CTNNB1/AXINs/APC. Activating mutations in GNAS were found in 5 (19.2%) of 26 GAFGs, all of which harbored R201C mutations. Activating mutations in KRAS were found in 2 (7.7%) of 26 GAFGs, and both of these also contained GNAS activating mutations. Four of 5 cases with GNAS mutation showed nuclear β-catenin expression, and presence of GNAS mutation was associated with β-catenin nuclear expression (P = .01). Furthermore, 3 of these 4 cases did not harbor mutations in CTNNB1, APC, or AXINs, suggesting that mutations in the Wnt component genes and those in GNAS occur almost exclusively. These results suggest that GNAS mutation might occur in a small subset of GAFG as an alternative mechanism of activating the Wnt/β-catenin signaling pathway.
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan; Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Nomura
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan. Electronic address: tysaitou@juntendo.ac.jp.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi 321-0293, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mitomi
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan; Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hidaka
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan; Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Se-yong
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002864:Chromogranins; D004252:DNA Mutational Analysis; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000378:metabolism; D005748:Gastric Fundus / Q000378:metabolism / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D002864:Chromogranins; D051176:beta Catenin; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: APC; AXIN; CTNNB1; GNAS; Gastric adenocarcinoma of the fundic gland type; KRAS; Mutation