Mice deficient in beta(2)-microglobulin and interleukin 2 (beta(2)m(null) x IL-2(null)) spontaneously develop colon cancer in the setting of chronic ulcerative colitis (UC). We investigated mutations of the Apc and p53 genes and microsatellite instability in colonic adenocarcinomas arising in this model. Mutations of the Apc and p53 genes in the regions corresponding to mutation hot spots in human colorectal cancer were determined by sequencing in 11 colonic adenocarcinomas. Microsatellite instability was determined in matched normal and neoplastic DNA at five loci. All 11 adenocarcinomas harbored Apc mutations. Of these 11 tumors, 5 harbored truncating mutations. A total of 67 Apc mutations were found in these 11 tumors; 59 were missense mutations, whereas 8 were frameshift or nonsense mutations. Six of the 11 adenocarcinomas harbored p53 mutations. A total of seven p53 mutations were found in these 11 tumors; all mutations were transitions, 4 of which were C:G-->T:A transitions occurring in codon 229 at cytosine-guanine dinucleotides. Nine adenocarcinomas exhibited microsatellite instability in at least one of the five loci examined; 1 tumor had microsatellite instability in two loci. Molecular genetics, as well as clinical features, of colon cancer in the beta(2)m(null) x IL-2(null) mice are similar to those of human UC-associated colorectal cancer. As such, this model appears to be an excellent animal model to study UC-associated colorectal carcinogenesis.