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. 2015 Apr 14;112(8):1398-404.
doi: 10.1038/bjc.2015.104. Epub 2015 Mar 24.

Activating GNAS and KRAS mutations in gastric foveolar metaplasia, gastric heterotopia, and adenocarcinoma of the duodenum

A Matsubara  1 , R Ogawa  2 , H Suzuki  3 , I Oda  3 , H Taniguchi  1 , Y Kanai  2 , R Kushima  1 , S Sekine  4
Affiliations

Activating GNAS and KRAS mutations in gastric foveolar metaplasia, gastric heterotopia, and adenocarcinoma of the duodenum

A Matsubara et al. Br J Cancer. .

Abstract

Background: Heterotopic gastric-type epithelium, including gastric foveolar metaplasia (GFM) and gastric heterotopia (GH), is a common finding in duodenal biopsy specimens; however, there is still controversy regarding their histogenetic backgrounds.

Methods: We analysed a total of 177 duodenal lesions, including 66 GFM lesions, 81 GH lesions, and 30 adenocarcinomas, for the presence of GNAS, KRAS, and BRAF mutations.

Results: Activating GNAS mutations were identified in 27 GFM lesions (41%) and 23 GH lesions (28%). The KRAS mutations were found in 17 GFM lesions (26%) and 2 GH lesions (2%). A BRAF mutation was found in only one GFM lesion (2%). These mutations were absent in all 32 normal duodenal mucosa specimens that were examined, suggesting a somatic nature. Among the GFM lesions, GNAS mutations were more common in lesions without active inflammation. Analyses of adenocarcinomas identified GNAS and KRAS mutations in 5 (17%) and 11 lesions (37%), respectively. Immunohistochemically, all the GNAS-mutated adenocarcinomas diffusely expressed MUC5AC, indicating gastric epithelial differentiation.

Conclusions: A significant proportion of GFM and GH harbours GNAS and/or KRAS mutations. The common presence of these mutations in duodenal adenoma and adenocarcinoma with a gastric epithelial phenotype implies that GFM and GH might be precursors of these tumours.

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Figures

Figure 1
Figure 1
Histology of gastric foveolar metaplasia, gastric heterotopia, and normal duodenal mucosa. (A–C) Gastric foveolar metaplasia. Gastric foveolar-type epithelium exhibiting remarkable hyperplasia (A). Note the surface papillary projections lined by gastric foveolar-type epithelium. The lining epithelium shows an apical mucin cap (arrowheads; B), which is positive for periodic-acid Schiff (PAS) staining (C). (D, E) Gastric foveolar metaplasia with active inflammation. Note the intraepithelial neutrophils (arrowheads; D). Epithelium showing PAS-positive apical mucin (E). (F, G) Gastric heterotopia. Oxyntic glands (arrowheads) are present beneath the gastric foveolar-type epithelium showing foveolar hyperplasia (F). Closely packed oxyntic glands consisting of parietal and chief cells (G). (H, I) Normal duodenal mucosa. Villi lined by intestinal epithelium with a brush border. Goblet cells are intermingled with the absorptive cells (H). The brush border is positive for PAS staining (purple, arrowheads), whereas the goblet cells are positive for Alcian blue (blue, arrows; I). Scale bars indicate 400 μm in (A and F) and 100 μm in (B–E and G–I).
Figure 2
Figure 2
GNAS and KRAS mutations in gastric foveolar metaplasia and gastric heterotopia. (A) Representative GNAS and KRAS mutations identified in gastric foveolar metaplasia, gastric heterotopia, and adenocarcinoma of the duodenum. (B) GNAS mutations in each epithelial component of gastric heterotopia. An identical missense mutation is present in both the foveolar epithelium and oxyntic glands. Missense mutations are indicated by arrowheads. GNAS was sequenced using reverse primers.
See this image and copyright information in PMC

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