Genetic Changes of Both p53 AlÃ-elesAssociated with the Conversion from Colorectal Adenoma to Early Carcinoma in Familial Adenomatous Polyposis and Non-Familial Adenomatous Polyposis Patients1

Mutation and loss of heterozygosity (LOH) in the p53 gene were analyzed in 274 colorectal tumors of 4 histopathological grades. Among 160 tumors from 40 familial adenomatous polyposis patients, none of 58 adenomas with moderate dysplasia had pS3 mutations, whereas 8% (3 of 37) of severe adenomas, 15% (6 of 40) of ini rain IKusa I carcinomas, and 40% (10 of 25) of invasive carcinomas had p53 mutations. Only 3% (1 of 33) of severe adenomas showed both mutation and LOH, while 25% (6 of 24) of intramucosal carcinomas and 40% (10 of 25) of invasive carcinomas had both mutation and LOH. All intramucosal and invasive carcinomas that had mutations lost the other alÃ-eleof the p53 gene. In 114 tumors from 86 non-familial adenomatous polyposis patients, sim ilar results were obtained; no adenoma showed both mutation and LOH, but both alterations occurred in intramucosal and invasive carcinomas. As regards specificity in 56 mutations detected in the present study, the frequently affected codons were codons 175, 238, 245, 248, 273, and 282, 4 of these amino acids being arginine, and 72% (39 of 54) of all mutations were GC to AT transition. Although expression into p53 polyadenylated RNA was high in every invasive carcinoma irrespective of the presence of mutation or LOH, there was a correlation between mutation and protein level; immunostaining of p53 protein was negative in almost all adenomas, but it was positive in 86% of invasive carcino mas exhibiting p53 mutation. These data suggest that genetic changes on both alÃ-elesof the p53 gene through mutation and LOH, which result in abnormal protein accumulation, are involved in the conversion of adenoma to early carci noma. Also, carcinoma cells with p53 mutations existing within ade noma tissues are detectable by immunostaining, even in formalin-fixed, paraffin-embedded specimens.