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Tumors of DNA mismatch repair-deficient hosts exhibit dramatic increases in genomic instability
A Baross-Francis1, S E Andrew, J E Penney
1Center for Molecular Medicine and Therapeutics, and Department of Medicine, University of British Columbia, Vancouver, BC Canada V5Z 4H4.
Abstract:
DNA mismatch repair (MMR) deficiency is associated with an increased mutational burden and predisposition to certain malignancies. Relatively little is known, however, about gene-specific mutation frequencies within MMR-deficient primary tumors. Thymic lymphomas from Msh2(-/-) mice were thus analyzed by using a lacI-based transgenic shuttle-phage mutation detection system. All tumors exhibited greatly elevated lacI gene mutation frequencies, ranging from 3.2- to 17.4-fold above the approximately 15-fold elevations present within normal Msh2(-/-) thymi. In addition, lacI genes harboring multiple changes, including clusters of mutations, were found in thymic tumor DNA. The results suggest that an additional mutator activity, such as an error-prone DNA polymerase, leads to increased genomic instability in these MMR-deficient tumors.
Insights
DNA mismatch repair (MMR) deficiency in thymic lymphomas shows significantly higher mutation rates. This suggests an additional mutator activity contributes to genomic instability in these tumors.
Area of Science:
- Genetics
- Cancer Biology
- Molecular Oncology
Background:
- DNA mismatch repair (MMR) deficiency is linked to increased mutation rates and cancer predisposition.
- Gene-specific mutation frequencies in MMR-deficient primary tumors remain largely uncharacterized.
Purpose of the Study:
- To investigate gene-specific mutation frequencies in Msh2-deficient thymic lymphomas.
- To explore the mechanisms underlying genomic instability in these tumors.
Main Methods:
- Utilized a lacI-based transgenic shuttle-phage mutation detection system.
- Analyzed thymic lymphoma samples from Msh2(-/-) mice.
Main Results:
- All analyzed tumors displayed substantially elevated lacI gene mutation frequencies (3.2- to 17.4-fold increases).
- Mutation frequencies exceeded those found in normal Msh2(-/-) thymi.
- Identified lacI genes with multiple mutations, including mutation clusters, in tumor DNA.
Conclusions:
- MMR deficiency in thymic lymphomas leads to a significant mutational burden.
- An additional mutator activity, potentially an error-prone DNA polymerase, likely contributes to increased genomic instability in these MMR-deficient tumors.