International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)


G24. Strain Background Significantly Influences Intestinal Adenoma Development in a Mouse Model of Colorectal Cancer

Revati Koratkar, Karen A. Silverman, Arthur M. Buchberg, and Linda D. Siracusa.
Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107.

Development of intestinal adenomas in ApcMin/+ mice is strongly influenced by genetic background. A major modifier of adenoma multiplicity has been localized to the distal arm of mouse chromosome 4, called Modifier of Min 1 (Mom1). The secretory phospholipase gene (Pla2g2a) is the candidate gene responsible for the Mom1 phenotype. Not only does Pla2g2a map to the same region as Mom1, but there is also a 100% concordance with the Pla2g2a genotype and the Mom1 phenotype. Strains of mice resistant to the development of intestinal adenomas carry a wildtype Pla2g2a allele and produce high levels of Pla2g2a protein expression in the small intestine. In contrast, strains of mice susceptible to the development of adenomas carry a null Pla2g2a allele and produce extremely low levels of mutant Pla2g2a transcripts, which encode nonfunctional truncated proteins. Our goal is to evaluate the influence of strain background on the development of adenomas in the ApcMin/+ mice and to genetically dissect the Mom1 locus. To do this, we generated reciprocal congenic lines using a breeding and selection method, such that the susceptible strain is substituted with a resistant Pla2g2a allele and the resistant strain is substituted with a susceptible Pla2g2a allele. Female mice from each congenic line were mated with B6 ApcMin/+ male mice. The F1 animals were genotyped to determine their allelic status at both the Apc and Pla2g2a loci. The progeny carrying the ApcMin/+ mutation were aged to 100 days and then screened for adenomas in the small intestine and the colon. It was observed that one copy of the resistant Pla2g2a allele reduced average polyp multiplicity by 50% in the small intestines of the reciprocal congenic lines. In the resistant congenic strain, which is null for Pla2g2a, there was a 2-3 fold reduction in small intestinal polyp multiplicity and more than a 10-fold reduction in colon polyp incidence when compared to the susceptible strain carrying the ApcMin/+ mutation. These results indicate that the resistant strain carries one or more additional modifier loci that significantly reduce tumor burden in both the small intestine and colon.

 


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