Reference SummaryReitmair AH, Cancer Res 1996 Jul 1;56(13):2922-6

Title

MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis.

Authors

Reitmair AH; Cai JC; Bjerknes M; Redston M; Cheng H; Pind MT; Hay K; Mitri A; Bapat BV; Mak TW; Gallinger S

Journal

Cancer Res

Volume

56

Issue

13

Year

1996

Pages

2922-6

Abstract

Accelerated intestinal tumorigenesis is probable in hereditary nonpolyposis colorectal cancer, a condition associated with germ line DNA mismatch repair (MMR) gene defects, and is believed to be caused by rapid accumulation of replication errors in critical genes, such as the APC (adenomatous polyposis coli) tumor suppressor gene. To study the potential contribution of MMR genes to accelerated intestinal tumorigenesis, we crossed the Min mouse, heterozygous for a germ line mutation of Apc, with an MMR gene (Msh2)-deficient mouse. MSH2 deficiency resulted in the development of many colonic aberrant crypt foci, as well as reduced survival of the mice, secondary to both a greater number and more rapidly developing adenomas. The mechanism of inactivation of the wild-type Apc allele depended on MSH2 status. In the presence of functional MSH2, all tumors demonstrated loss of heterozygosity. In contrast, whereas all adenomas were APC negative by immunostaining, only 5 of 34 adenomas from Apc+/-/Msh2-/- mice demonstrated loss of heterozygosity of the wild-type Apc allele, suggesting that somatic Apc mutations are responsible for the additional tumors. These findings provide evidence for the important role of MMR genes in accelerated intestinal tumorigenesis, thus supporting more aggressive surveillance strategies to prevent colorectal cancer in hereditary nonpolyposis colorectal cancer.

Links

J:75393 – Mouse Genome Informatics
8674041 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
B6;129P2-ApcMin/+ Intestine - Large Intestine - Colon adenoma Intestine - Large Intestine - Colon

observed

B6;129P2-ApcMin/+ Msh2tm1Mak/+ Intestine - Large Intestine - Colon adenoma Intestine - Large Intestine - Colon

observed

B6;129P2-ApcMin/+ Msh2tm1Mak Intestine - Large Intestine - Colon adenoma Intestine - Large Intestine - Colon

observed - 67

B6;129P2-ApcMin/+ Intestine - Large Intestine - Colon foci - aberrant crypt (ACF) Intestine - Large Intestine - Colon

observed

B6;129P2-ApcMin/+ Msh2tm1Mak/+ Intestine - Large Intestine - Colon foci - aberrant crypt (ACF) Intestine - Large Intestine - Colon

observed

B6;129P2-ApcMin/+ Msh2tm1Mak Intestine - Large Intestine - Colon foci - aberrant crypt (ACF) Intestine - Large Intestine - Colon

very high

C57BL/6J-ApcMin/+ Intestine - Large Intestine adenoma Intestine - Large Intestine

observed

B6;129P2-ApcMin/+ Intestine - Small Intestine adenoma Intestine - Small Intestine

observed

B6;129P2-ApcMin/+ Msh2tm1Mak/+ Intestine - Small Intestine adenoma Intestine - Small Intestine

observed

B6;129P2-ApcMin/+ Msh2tm1Mak Intestine - Small Intestine adenoma Intestine - Small Intestine

observed

C57BL/6J-ApcMin/+ Intestine - Small Intestine adenoma Intestine - Small Intestine

observed

B6;129P2-ApcMin/+ Intestine carcinoma Intestine

0

B6;129P2-ApcMin/+ Msh2tm1Mak/+ Intestine carcinoma Intestine

0

B6;129P2-ApcMin/+ Msh2tm1Mak Intestine carcinoma Intestine

0

B6;129P2-ApcMin/+ Msh2tm1Mak Leukocyte lymphoma Thymus

29