In order to elucidate the significance of the adenoma-carcinoma sequence in gastric carcinogenesis from a genetic point of view, we examined microsatellite alterations (replication error and loss of heterozygosity) on chromosomes 2p (D2S123), 3p (D3S1317), 5q (D5S409), 9p (IFNA), and 13q (D13S153) as well as p53 gene mutations in 13 adenomas and 23 differentiated adenocarcinomas including 8 early carcinomas of the stomach. Replication error was detected in only one of the adenomas (8%, 1/13) at the D5S409 locus and in none at the other loci, and loss of heterozygosity was also an infrequent event found in one adenoma (14%, 1/7 informative cases) at D5S409 and in none at the other loci. A p53 gene mutation was detected in one (8%, 1/13) of the adenomas. Thus, microsatellite alterations and p53 gene mutations are rare events in adenomas. In differentiated adenocarcinomas, replication error was detected in 4 (17%, 4/23) at single or multiple loci, and loss of heterozygosity was observed frequently at D3S1317 (25%, 3/12), D5S409 (67%, 6/9), and IFNA (26%, 5/19). Mutations in the p53 gene were detected in 9 (39%, 9/23) of the differentiated adenocarcinomas. Microsatellite alterations on several chromosomes and mutations in the p53 gene were frequent in differentiated adenocarcinomas, even those at an early stage. These results suggest that the adenoma-carcinoma sequence is relatively rare in gastric carcinogenesis, and that the majority of differentiated adenocarcinomas of the stomach may develop through a de novo pathway.