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

Issue

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 – MGI References
8674041 – National Library of Medicine/PubMed

Strain Notes

Strain	Note
B6;129P2-Apc^Min/+	Average age of death 163 days, primarily due to anemia and bowel obstruction. Mice were generated by mating C57BL/6J-Apc^Min/+ males with Msh2^tm1Mak/+ females, then intercrossing offspring.
B6;129P2-Apc^Min/+ Msh2^tm1Mak	Average age of death 82 days, primarily due to anemia and bowel obstruction. Mice were generated by mating C57BL/6J-Apc^Min/+ males with Msh2^tm1Mak/+ females, then intercrossing offspring.
B6;129P2-Apc^Min/+ Msh2^tm1Mak/+	Average age of death 159 days, primarily due to anemia and bowel obstruction. Mice were generated by mating C57BL/6J-Apc^Min/+ males with Msh2^tm1Mak/+ females, then intercrossing offspring.
C57BL/6J-Apc^Min/+	Mice were generated in house using breeding pairs originally obtained from The Jackson Laboratory.

Models
Strain	Model Name	Organ Affected	Frequency
B6;129P2-Apc^Min/+	Intestine - Large Intestine - Colon adenoma	Intestine - Large Intestine - Colon	observed
B6;129P2-Apc^Min/+ Msh2^tm1Mak/+	Intestine - Large Intestine - Colon adenoma	Intestine - Large Intestine - Colon	observed
B6;129P2-Apc^Min/+ Msh2^tm1Mak	Intestine - Large Intestine - Colon adenoma	Intestine - Large Intestine - Colon	observed - 67
B6;129P2-Apc^Min/+	Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)	Intestine - Large Intestine - Colon	observed
B6;129P2-Apc^Min/+ Msh2^tm1Mak/+	Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)	Intestine - Large Intestine - Colon	observed
B6;129P2-Apc^Min/+ Msh2^tm1Mak	Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)	Intestine - Large Intestine - Colon	very high
C57BL/6J-Apc^Min/+	Intestine - Large Intestine adenoma	Intestine - Large Intestine	observed
B6;129P2-Apc^Min/+	Intestine - Small Intestine adenoma	Intestine - Small Intestine	observed
B6;129P2-Apc^Min/+ Msh2^tm1Mak/+	Intestine - Small Intestine adenoma	Intestine - Small Intestine	observed
B6;129P2-Apc^Min/+ Msh2^tm1Mak	Intestine - Small Intestine adenoma	Intestine - Small Intestine	observed
C57BL/6J-Apc^Min/+	Intestine - Small Intestine adenoma	Intestine - Small Intestine	observed
B6;129P2-Apc^Min/+	Intestine carcinoma	Intestine	0
B6;129P2-Apc^Min/+ Msh2^tm1Mak/+	Intestine carcinoma	Intestine	0
B6;129P2-Apc^Min/+ Msh2^tm1Mak	Intestine carcinoma	Intestine	0
B6;129P2-Apc^Min/+ Msh2^tm1Mak	Leukocyte lymphoma	Thymus	29