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MSH2 deficient mice are viable and susceptible to lymphoid tumours
A H Reitmair1, R Schmits, A Ewel
1Amgen Institute, Department of Medical Biophysics, University of Toronto, Canada.
Abstract:
Alterations of the human MSH2 gene, a homologue of the bacterial MutS mismatch repair gene, co-segregate with the majority of hereditary non-polyposis colon cancer (HNPCC) cases. We have generated homozygous MSH2-/- mice. Surprisingly, these mice were found to be viable, produced offspring in a mendelian ratio and bred through at least two generations. Starting at two months of age homozygous-/- mice began, with high frequency, to develop lymphoid tumours that contained microsatellite instabilities. These data establish a direct link between MSH2 deficiency and the pathogenesis of cancer. These mutant mice should be good models to study the progression of tumours and also to screen carcinogenic and anti-cancer agents.
Insights
MSH2 gene alterations are linked to hereditary non-polyposis colon cancer. MSH2-deficient mice developed tumors, establishing a direct link between MSH2 deficiency and cancer pathogenesis.
Area of Science:
- Genetics
- Cancer Biology
- Molecular Biology
Background:
- The MSH2 gene, a homolog of the bacterial MutS mismatch repair gene, is implicated in hereditary non-polyposis colon cancer (HNPCC).
- Understanding the precise role of MSH2 in cancer development is crucial for therapeutic strategies.
Purpose of the Study:
- To investigate the in vivo function of the MSH2 gene in mammals.
- To establish a mouse model for studying MSH2 deficiency and its link to cancer.
Main Methods:
- Generation of homozygous MSH2 knockout (MSH2-/-) mice.
- Observation of mouse viability, reproductive capacity, and tumor development.
- Analysis of microsatellite instability in tumors.
Main Results:
- MSH2-/- mice were viable, fertile, and produced offspring in Mendelian ratios.
- Homozygous MSH2-/- mice developed lymphoid tumors with high frequency starting at two months of age.
- These tumors exhibited microsatellite instabilities, indicating a defect in DNA mismatch repair.
Conclusions:
- MSH2 deficiency directly contributes to cancer pathogenesis.
- These MSH2-/- mice serve as a valuable model for studying tumor progression.
- The model can be utilized for screening carcinogenic and anti-cancer agents.