Gastric and duodenal adenomas exhibit a significant morphological and phenotypical diversity and are classified into intestinal-type, foveolar-type and pyloric gland adenomas. We analysed the mutations in GNAS, KRAS, BRAF and CTNNB1 and the expressions of mismatch repair (MMR) proteins in 80 gastric and 32 duodenal adenomas with histologically distinct subtypes, as well as in 71 gastric adenocarcinomas. Activating GNAS mutations were found in 22 of the 35 pyloric gland adenomas (PGAs; 63%) but in none of the foveolar-type or intestinal-type adenomas or the adenocarcinomas. Fourteen PGAs (41%), two foveolar-type adenomas (9%), five intestinal-type adenomas (9%) and one adenocarcinoma (1%) had KRAS mutations. BRAF mutations were absent in all the adenomas and adenocarcinomas that were examined. CTNNB1 mutations were only found in two intestinal-type adenomas (4%). Notably, 13 of the 14 KRAS-mutated gastric and duodenal PGAs had concurrent GNAS mutations. The loss of the MMR proteins, which is indicative of microsatellite instability, was observed in one PGA (3%), 12 foveolar-type adenomas (52%), one intestinal-type adenoma (2%) and five adenocarcinomas (7%). These observations indicate that each histological subtype of gastric and duodenal adenomas has a distinct genetic background. In particular, the present study identified the frequent presence of activating GNAS mutations, which are often associated with KRAS mutations, as a characteristic genetic feature of PGAs of the stomach and duodenum.