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

Abstract

The Apc1638N mouse carries a targeted mutant allele at the endogenous adenomatous polyposis coli (Apc) gene and represents a unique in vivo model to study intestinal tumor formation and progression. Heterozygous Apc+/Apc1638N mice progressively develop 5-6 adenomas and adenocarcinomas of the small intestine within the first 6 months of life following a histologic sequence similar to that observed in human intestinal tumors. Here, we present the somatic mutation analysis of a total of 57 tumors. The results indicate that in > or = 75% of the lesions tested the wild type copy of the Apc gene is lost and that this LOH event extends to the entire mouse chromosome 18. Unexpectedly, mutations at the K-, N- and H-ras genes have not been found in these tumors. Immunohistochemical analysis of the Apc1638N tumors failed 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 that, although the genetic inactivation of Apc is involved in the initiating event of the human as well as murine intestinal tumorigenesis, tumor growth and progression follow different mutational pathways in these two species.

Heterogeneity of Jagged1 expression in human and mouse intestinal tumors: implications for targeting Notch signaling

“…In each case, it is well documented that loss or inactivation of the wild-type allele elevates Wnt signaling and initiates intestinal adenoma formation (Levy et al, 1994;Smits et al, 1997). As assayed by replicate quantitative real-time PCR (qRT-PCR) for each tumor for each marker, there was great heterogeneity in Jagged1 expression in the tumors relative to the low levels in the flat mucosa.…”

Mouse models for colorectal cancer

“…One approach was to examine the tumors from Apc mutant mice for mutations in these genes and the second is the generation of mice with mutations in some of these genes and mate them with the Apc mutant mice and ascertain their in¯uence on tumor susceptibility. When the GI tumors from Apc mutant mice were examined, the only consistent alteration that was observed is the loss of the wild-type copy of the Apc allele through nondisjunction (Figure 1) (Smits et al, 1997;Luongo et al, 1994). These results indicated that the earliest genetic change during tumor progression is the loss of the wild-type Apc allele and this loss is su cient for progression of the tumor to the adenoma stage.…”

“…These results indicated that the earliest genetic change during tumor progression is the loss of the wild-type Apc allele and this loss is su cient for progression of the tumor to the adenoma stage. GI tumors of Apc were also examined for K-ras mutations, but no mutations were found (Smits et al, 1997;Shoemaker et al, 1997).…”

Tumor-associated Apc mutations in Mlh1−/−Apc1638N mice reveal a mutational signature of Mlh1 deficiency

“…To create a model system to study the e ects of Mlh1 de®ciency in intestinal tumorigenesis, we previously crossed Mlh1 7/7 mice with the Apc 1638N strain which carries a heterozygous germline mutation in Apc. Apc 1638N mice typically develop three to ®ve intestinal tumors per animal within 9 months, and 475% of these display allelic loss of the wild-type Apc allele (Yang et al, 1997;Smits et al, 1997). Compared to other Apc mutant strains, such as Apc Min and Apc D716 (Moser et al, 1990;Su et al, 1992;Oshima et al, 1995), Apc 1638N displays a relatively mild phenotype and is longer lived.…”