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KLF4 Mutation Shapes Pathologic Characteristics of Foveolar-Type Gastric Adenoma in Helicobacter pylori–Naive Patients

      Along with a recent remarkable decrease in Helicobacter pylori–infected individuals, reports of gastric neoplasms in H. pylori–naive patients have been increasing. A sporadic foveolar-type gastric adenoma (FGA) is one such type, and we recently reported that occurrence of this tumor is not rare in H. pylori–naive gastric mucosa and its raspberry-like appearance. This study investigated the genomic features of sporadic FGA. Fresh-frozen sporadic FGA tissue samples from H. pylori–naive patients underwent whole genome analysis performed using a next-generation sequencer. Proliferation ability and apoptotic profiles of human gastric epithelial cells, along with plasmid transfection of candidate variants, were then examined. A mean of 6.65 × 108 total reads were obtained for each sample. Common genetic abnormalities in well-known proliferation driver genes of conventional gastric dysplasia/cancer were not found. However, a common single-nucleotide variation (SNV) was noted within the DNA-binding domain of the tumor suppressor gene KLF4. This novel SNV was located in the zinc finger 2 region, and additional experiments showed that it significantly suppressed proliferation of gastric epithelial cells compared with wild-type KLF4 plasmid transfection cells, although suppression was reduced in early apoptotic phase–related genes. A novel SNV in the KLF4 zinc finger 2 region was commonly found in sporadic FGA tissue samples, which may explain the slow-growing properties of this neoplasm.
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