The adenomatous polyposis coli (APC) gene, responsible for familial adenomatous polyposis, is also associated with development of sporadic tumors in digestive system as colon, stomach, or pancreas. In order to investigate whether or not APC mutations occur as an early genetic event during gastric carcinogenesis, we examined somatic mutations of APC in flat adenomas of the stomach. DNAs isolated from flat adenomas were examined by means of an RNase protection analysis coupled with polymerase chain reaction (PCR) followed by DNA sequencing of the PCR products. By screening a mutation cluster region (MCR: codons between 1286 and 1513) of APC in which two-thirds of somatic mutations were detected in colorectal tumors, somatic mutations were found in four of ten flat adenomas: three of which caused truncation of the gene product due to a nonsense mutation or 4-bp deletion; one other was a point mutation that altered amino acid from alanine to threonine. Our results imply that APC plays a crucial role in an early step of gastric carcinogenesis, as was observed in colorectal carcinogenesis.