Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors.

Mutation of the adenomatous polyposis coli (APC) gene was analyzed in 500 colorectal tumors from 70 familial adenomatous polyposis (FAP) and 102 non-FAP patients and in normal tissues from 119 FAP patients, using polymerase chain reaction-single-strand conformation polymorphism and direct sequencing methods. These tumors were histopathologically diagnosed. Sixty-eight germ line mutations (62% deletion, 9% insertion, and 29% single-base substitution) and 241 somatic mutations (56% deletion, 12% insertion, and 32% single-base substitution) were detected. All mutations formed stop codons resulting in truncated APC proteins, except for one germ line mutation. Differences were found between somatic and germ line mutations, including 3 new hot spots of mutation at codons 1378, 1450, and 1487-1490, which frequently occurred in somatic mutations but not in germ lines. The frequency of mutation in each histopathological type of FAP tumor was 53% in moderate adenoma, 64% in severe adenoma, 52% in intramucosal carcinoma, and 33% in invasive carcinoma, whereas the loss of heterozygosity including the APC gene increased with development to each histopathological type. A similar tendency was observed in non-FAP tumors. Additionally, we found 10 FAP tumors that had both somatic mutation and loss of heterozygosity. These tumors were assumed to have developed from moderate adenomas with germ line and somatic mutations, followed by deletion of the allele with germ line mutation. These results suggest that inactivation of the APC gene by two mutations is involved in the development of moderate adenoma, and loss of heterozygosity of the APC gene is associated with further development to carcinoma. It was also observed that the distribution of 75 somatic mutations from one FAP patient on the APC sequence was similar to the distribution of 159 somatic mutations from 83 patients with FAP and non-FAP, which suggests that the position of somatic mutation is mostly due to the APC sequence itself.