LOSS OF APC AND THE ENTIRE CHROMOSOME-18 BUT ABSENCE OF MUTATIONS AT THE RAS AND TP53 GENES IN INTESTINAL TUMORS FROM APC1638N, A MOUSE MODEL FOR APC-DRIVEN CARCINOGENESIS

The Apc1638N mouse carries a targeted mutant allele at the endogenous adenomatous polyposis coli (Ape) gene and represents a unique in vivo model to study intestinal tumor formation and progression. Heterozygou s Apc(+)/Apc1638N mice progressively develop 5-6 adenomas and adenocar cinomas of the small intestine within the first 6 months of life follo wing a histologic sequence similar to that observed in human intestina l tumors, Here, we present the somatic mutation analysis of a total of 57 tumors, The results indicate that in greater than or equal to 75% of the lesions tested the wild type copy of the Ape gene is lost and t hat this LOH event extends to the entire mouse chromosome 18, Unexpect edly, mutations at the K-, N- and H-ras genes have not been found in t hese tumors. Immunohistochemical analysis of the Apc1638N tumors faile d to detect accumulation of the Tp53 protein, Also, no mutations have been found in exons 7 and 8 of the Tp53 gene. These results indicate t hat, although the genetic inactivation of Ape is involved in the initi ating event of the human as well as murine intestinal tumorigenesis, t umor growth and progression follow different mutational pathways in th ese two species.