A FREQUENT ALTERATION OF P53 GENE IN CARCINOMA IN ADENOMA OF COLON

In general, colorectal carcinoma is thought to originate mainly from a denoma, and this pathway is called the adenoma-carcinoma sequence. Car cinoma in adenoma is an appropriate model for analysis of this mechani sm, because adenoma and carcinoma tissues coexist in the same polyp an d the carcinoma is thought to have originated from the surrounding ade noma. Expression of the p53 protein was analyzed in 36 cases of carcin oma in adenoma in the colon by immunohistochemistry using an anti-huma n p53 monoclonal antibody (PAb1801). Alterations of the p53 gene were analyzed by the polymerase chain reaction for microanalysis of normal mucosa, adenoma, and carcinoma from histological slides. Mutations wer e assessed by polymerase chain reaction-single strand conformation pol ymorphism analysis and identified by DNA sequencing in some cases. Los s of heterozygosity was studied by polymerase chain reaction-restricti on fragment length polymorphism analysis. Positive staining for p53 wa s detected in three (8%) of 37 adenomas and 20 (53%) of 38 focal carci nomas. One (7%) of 15 adenomas with mild dysplasia, three (14%) of 22 adenomas with moderate dysplasia, and 16 (42%) of 38 focal carcinomas had a mutation in exon 5 through exon 8 of the p53 gene. As for alleli c loss in the p53 gene locus, only one adenoma with moderate dysplasia had loss of heterozygosity, whereas six (40%) of 15 focal carcinomas had loss of heterozygosity. Of those tumors (3 of 37 adenomas and 20 o f 38 focal carcinomas) that reacted with PAb1801, 78% (18 of 23) showe d genetic alterations. Among 52 tumors which showed negative staining, five tumors had a p53 mutation and four of them were nonsense mutatio ns. Putting all of these results together, 71% (24 of 31) of the cases underwent p53 gene and protein alterations during the conversion from adenoma to focal carcinoma. These data clearly indicate that genetic alterations of p53 are involved mainly in the malignant transformation from adenoma to focal carcinoma in colon carcinogenesis. In addition, some cases show heterogeneity of the p53 gene in carcinoma in adenoma of the colon. There may be other pathways than p53 responsible for ma lignant change in the colon.