In order to clarify genetic changes in flat adenomas, K-ras codon 12 point mutations were examined in 56 flat adenomas, 81 polypoid adenomas and 42 cancers of colon and rectum. The mutation frequency in flat adenomas was 23% (13/56), significantly lower than that in polypoid adenomas (67%: 54/81) and cancers (76%: 32/42). Even mildly dysplastic adenomas or small (less than 5 mm) adenomas showed higher mutation incidence in polypoid type (62%, 57%) than in flat type (23%, 19%). Among flat adenomas, flat elevated lesions exhibited relatively higher mutation frequency than completely flat or depressed ones. As for cancers, 14 tumors (33%) contained mutations only in a minor tumor cell population, indicating that these mutations occur at a late stage of tumorigenesis. These results suggest that the adenoma-carcinoma sequence through flat adenomas may be different from that through polypoid adenomas, and genetic changes may be heterogeneous in colorectal carcinogenesis.