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Spontaneous intestinal carcinomas and skin neoplasms in Msh2-deficient mice
A H Reitmair1, M Redston, J C Cai
1Department of Medical Biophysics, Ontario Cancer Institute/Amgen Institute, University of Toronto, Ontario, Canada.
Abstract:
Hereditary nonpolyposis colorectal cancer is associated with defects in DNA mismatch repair. Here, we characterize tumor susceptibility of the recently described Msh2-deficient mouse model. Within the first year of observation, all homozygous mice succumbed to disease, with lymphomas observed in at least 80% of the cases. The majority (70%) of animals 6 months or older developed intestinal neoplasms associated with APC inactivation. Microsatellite instability was more common in carcinomas than in adenomas, but uncommon in normal tissues. Some animals (7%) developed a variety of skin neoplasms analogous to the Muir-Torre syndrome. Msh2-/- mice implicate a direct role for mismatch repair in several neoplasms with striking phenotypic similarities to humans.
Insights
Mice lacking DNA mismatch repair (Msh2-/-) rapidly developed various cancers, including lymphomas and intestinal tumors. This highlights the critical role of DNA mismatch repair in preventing hereditary nonpolyposis colorectal cancer and other neoplasms.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Hereditary nonpolyposis colorectal cancer (HNPCC) is linked to DNA mismatch repair (MMR) gene defects.
- The Msh2 gene is crucial for MMR, and its deficiency is implicated in various cancers.
Purpose of the Study:
- To investigate tumor susceptibility in Msh2-deficient mice.
- To understand the role of MMR in neoplasm development and progression.
Main Methods:
- Characterization of Msh2-deficient (Msh2-/-) mouse models.
- Tumor surveillance and histopathological analysis.
- Assessment of microsatellite instability (MSI) in tumor tissues.
Main Results:
- All Msh2-/- mice died within one year, with 80% developing lymphomas.
- 70% of older Msh2-/- mice developed intestinal neoplasms, often with APC inactivation.
- MSI was prevalent in carcinomas but rare in normal tissues.
- A subset of mice developed skin neoplasms, resembling Muir-Torre syndrome.
Conclusions:
- Msh2 deficiency leads to rapid tumor development and high mortality in mice.
- MMR plays a direct role in preventing multiple types of neoplasms.
- Msh2-/- mice serve as a valuable model for HNPCC and Muir-Torre syndrome research.