Mutation of the p53 tumour-suppressor gene in exons 5 through 8 was examined in 118 cases of gastric cancer (59 early gastric cancers and 59 advanced gastric cancers) using PCR-SSCP (polymerase-chain-reaction-single-strand-conformation polymorphism) analysis and direct sequencing. In early gastric cancer, mutations were found in 15 of 41 (37%) cases of the cohesive type, i.e., papillary adenocarcinoma, well to moderately differentiated tubular adenocarcinoma, and poorly differentiated adenocarcinoma with solid nests or focal tubular structures, but were not detected in 18 cases of the non-cohesive type, i.e., signet-ring-cell carcinoma and poorly differentiated adenocarcinoma growing in a scattered manner. In advanced gastric cancer, 25 of 59 (42%) cases of the cohesive type had p53 mutation. No significant association was found between p53 mutation and other histopathological parameters such as macroscopic classification, lymph-node involvement and depth of tumour invasion. Fifteen of 25 (60%) mutations in the advanced gastric-cancer group were accompanied by allele loss at the p53 gene locus. Eighty-three percent of mutations in early gastric cancer and 52% of mutations in advanced gastric cancer showed G:C-to-A:T transition, almost exclusively at CpG dinucleotide mutational hot spots, indicating that the spectrum of p53 mutation was similar to that of colorectal cancer. These data suggest that the p53 mutation occurs selectively in gastric cancer of the cohesive type from the intramucosal cancer stage.