Reference SummaryKuraguchi M, Cancer Res 2001 Nov 1;61(21):7934-42

Title

The Distinct Spectra of Tumor-associated Apc Mutations in Mismatch Repair-deficient Apc(1638N) Mice Define the Roles of MSH3 and MSH6 in DNA Repair and Intestinal Tumorigenesis.

Authors

Kuraguchi M; Yang K; Wong E; Avdievich E; Fan K; Kolodner RD; Lipkin M; Brown AM; Kucherlapati R; Edelmann W

Journal

Cancer Res

Volume

61

Issue

21

Year

2001

Pages

7934-42

Abstract

In mammalian cells, mismatch recognition has been attributed to two partially redundant heterodimeric protein complexes of MutS homologues, MSH2-MSH3 and MSH2-MSH6. We have conducted a comparative analysis of Msh3 and Msh6 deficiency in mouse intestinal tumorigenesis by generating Apc(1638N) mice deficient in Msh3, Msh6 or both. We have found that Apc(1638N) mice defective in Msh6 show reduced survival and a 6-7-fold increase in intestinal tumor multiplicity. In contrast, Msh3-deficient Apc(1638N) mice showed no difference in survival and intestinal tumor multiplicity as compared with Apc(1638N) mice. However, when Msh3 deficiency is combined with Msh6 deficiency (Msh3(-/-)Msh6(-/-)Apc(1638N)), the survival rate of the mice was further reduced compared to Msh6(-/-)Apc(1638N) mice because of a high multiplicity of intestinal tumors at a younger age. Almost 90% of the intestinal tumors from both Msh6(-/-)Apc(1638N) and Msh3(-/-)Msh6(-/-)Apc(1638N) mice contained truncation mutations in the wild-type Apc allele. Apc mutations in Msh6(-/-)Apc(1638N) mice consisted predominantly of base substitutions (93%) creating stop codons, consistent with a major role for Msh6 in the repair of base-base mismatches. However, in Msh3(-/-)Msh6(-/-)Apc(1638N) tumors, we observed a mixture of base substitutions (46%) and frameshifts (54%), indicating that in Msh6(-/-)Apc(1638N) mice frameshift mutations in the Apc gene were suppressed by Msh3. Interestingly, all except one of the Apc mutations detected in mismatch repair-deficient intestinal tumors were located upstream of the third 20-amino acid beta-catenin binding repeat and before all of the Ser-Ala-Met-Pro repeats, suggesting that there is selection for loss of multiple domains involved in beta-catenin regulation. Our analysis therefore has revealed distinct mutational spectra and clarified the roles of Msh3 and Msh6 in DNA repair and intestinal tumorigenesis.

Links

J:73030 – Mouse Genome Informatics
11691815 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6-Apctm1Rak/+ Msh3tm1Rak Msh6tm1Rak Gastrointestinal tract adenocarcinoma Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Msh6tm1Rak Gastrointestinal tract adenocarcinoma Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Gastrointestinal tract adenocarcinoma Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Gastrointestinal tract adenocarcinoma Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Msh6tm1Rak Gastrointestinal tract adenoma - microadenoma Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Msh6tm1Rak Gastrointestinal tract adenoma - microadenoma Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Gastrointestinal tract adenoma - microadenoma Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Msh6tm1Rak Gastrointestinal tract adenoma - tubular Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Msh6tm1Rak Gastrointestinal tract adenoma - tubular Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Gastrointestinal tract adenoma - tubular Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Gastrointestinal tract adenoma - tubular Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Msh6tm1Rak Gastrointestinal tract adenoma - villous Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Msh6tm1Rak Gastrointestinal tract adenoma - villous Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Gastrointestinal tract adenoma - villous Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Gastrointestinal tract adenoma - villous Gastrointestinal tract

observed

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Msh6tm1Rak Gastrointestinal tract tumor Gastrointestinal tract

100

C57BL/6-Apctm1Rak/+ Msh6tm1Rak Gastrointestinal tract tumor Gastrointestinal tract

100

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Gastrointestinal tract tumor Gastrointestinal tract

100

C57BL/6-Apctm1Rak/+ Gastrointestinal tract tumor Gastrointestinal tract

89

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Msh6tm1Rak Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

observed

C57BL/6-Apctm1Rak/+ Msh6tm1Rak Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

observed

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

observed

C57BL/6-Apctm1Rak/+ Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

observed

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Msh6tm1Rak Intestine - Small Intestine tumor Intestine - Small Intestine

observed

C57BL/6-Apctm1Rak/+ Msh6tm1Rak Intestine - Small Intestine tumor Intestine - Small Intestine

observed

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Intestine - Small Intestine tumor Intestine - Small Intestine

observed

C57BL/6-Apctm1Rak/+ Intestine - Small Intestine tumor Intestine - Small Intestine

observed

C57BL/6-Apctm1Rak/+ Msh6tm1Rak Skin gland - Sweat gland carcinoma Skin gland - Sweat gland

7.7

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Skin squamous cell carcinoma Skin

8.3

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Msh6tm1Rak Stomach tumor Stomach

0

C57BL/6-Apctm1Rak/+ Msh6tm1Rak Stomach tumor Stomach

observed

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Stomach tumor Stomach

observed

C57BL/6-Apctm1Rak/+ Stomach tumor Stomach

observed

C57BL/6-Apctm1Rak/+ Msh3tm1Rak Msh6tm1Rak (Unspecified organ) tumor (Unspecified organ)

0

C57BL/6-Apctm1Rak/+ (Unspecified organ) tumor (Unspecified organ)

0