International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

A17. Genetic Analysis of Modifier Genes which Influence the Tumor Multiplicity in FAP Model Mice

Masaki Itoh1,2, Akiteru Maeno1,3, Ayumi Tari1,3, Shihoko Itoh1,3, Akiko Kawakami1,3, Masayoshi Sawada1,3, Tsuneya Ohno2, and Tetsuo Noda1,3,4
1Dept. Cell Biol., Cancer Institute., 2Divi. Oncology, Jikei Univ., 3CREST, Japan Science and Technology, 4RIKEN. GSC

As a model for familial adenomatous polyposis coli (FAP), we generated Apc 1309/+ mutant mice that carry frameshift mutation at codon 1309 of Apc, a most common germline mutation for FAP families. On the C57BL/6J background, Apc 1309/+ mice developed about 60 polyps in the entire gastrointestinal tract including stomach, mainly in the upper region of small intestine. Since Apc Min/+ mice, another model for FAP, developed about 140 polyps mainly in the lower region of small intestine with few tumors in the stomach, this result clearly suggested that Apc 1309/+ shows different pattern of tumor formation from Apc Min/+ mice.

To study the influence of the genetic background on the tumor multiplicity of Apc 1309/+ mice, we intercrossed Apc 1309/+ (C57BL6/J background) with 5 different inbred strains: 129/SvJ, AKR/J, C3H/J, CAST/Ei and MSM/Ms. The number of tumors were reduced on all F1 hybrid background except for the (B6x129) F1. On the (B6x129) F1 background where tumor multiplicity of Apc Min/+ mice was not influenced, that of Apc 1309/+ was increased about 50%, suggesting that the reactivity for the genetic background is different between Apc 1309/+ and Apc Min/+ mice. Genetic studies on Apc Min/+ mice resulted to the identification of Mom1 (modifier of Min-1), a modifier locus of intestinal tumorigenesis. Therefore, to identify novel modifier genes, we initiated genetic analysis using Apc 1309/+ .

Since tumor formation was completely suppressed on F1 background with CAST/Ei mice, F1 mice were backcrossed to C57BL6/J and N2 mice heterozygous for Apc 1309/+ were used for linkage analysis. Suggestive effects (p<0.05) with the suppression of tumor multiplicity was found at least four regions by QTL analysis (Map Maneger QT Verb28). Congenic line carrying these effctive loci were generated and phenotypic analysis confirmed the presence of modifier within the locus on CAST/Ei chromosome 10 and localized the effect within approximately a 10cM genetic interval. We also determined that three additional regions on Ch1, Ch11 and Ch12 are associated with the decrease of tumor multiplicity. We are currently in the process of fine mapping of the choromosomal regions of these modifiers.

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