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Thymic lymphomas arising in Msh2 deficient mice display a large increase in mutation frequency and an altered
Shulin Zhang1, Ruth Lloyd, Gregory Bowden
1Department of Biology, Centre for Environmental Health, University of Victoria, Victoria, BC, Canada V8W 3N5.
Abstract:
Mismatch repair (MMR) genes, such as Msh2, are classified as "mutator" genes, responsible for the microsatellite instability identified in many tumors. In the current study, the mutation frequency and mutational spectrum in thymic lymphoma arising in Msh2 deficient mice are investigated. Thymic lymphoma developed in Msh2-/- background displayed an eight to nine-fold increase in mutation frequency compared to the normal thymi in Msh2 deficient animals. Sequencing demonstrated significantly different mutational spectra between normal thymus tissue and thymic lymphomas in Msh2-/- mice (P=0.02). The tumor mutational spectrum is characterized by an increase in base substitutions occurring at A:T sites, and multiple mutations, as well as a minor increase in -1 frameshifts. We analyzed mutations in different parts of the tumors, and different regional hotspots could be identified. Several hotspot mutations that are a rare event in normal tissues were identified in the tumor tissues. We conclude that thymic lymphomas arising in Msh2 deficient genetic background are hypermutable and the altered mutational spectrum might be an indication of infidelity of DNA replication during tumorigenesis.
Insights
Mice lacking mismatch repair (MMR) gene Msh2 developed hypermutable thymic lymphomas with significantly altered mutation patterns. These findings suggest DNA replication errors drive tumor development in Msh2-deficient backgrounds.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Mismatch repair (MMR) genes, like Msh2, are crucial for genomic stability and are often implicated in cancer development.
- Microsatellite instability, a hallmark of many tumors, is frequently associated with defects in MMR genes.
- Understanding the mutational consequences of MMR deficiency is key to unraveling tumorigenesis.
Purpose of the Study:
- To investigate the mutation frequency and spectrum in thymic lymphomas that develop in Msh2-deficient mice.
- To compare the mutational landscape of Msh2-deficient thymic lymphomas with normal thymus tissue from Msh2-deficient mice.
- To identify potential mutational hotspots and characterize the types of mutations occurring during tumorigenesis.
Main Methods:
- Induction and observation of thymic lymphoma development in Msh2 knockout (Msh2-/-) mice.
- Quantification of mutation frequency in tumor and normal thymus tissues.
- DNA sequencing to determine the mutational spectrum, including base substitutions and frameshifts.
- Analysis of mutation distribution and identification of regional hotspots within tumor tissues.
Main Results:
- Thymic lymphomas in Msh2-/- mice exhibited an 8-9 fold increase in mutation frequency compared to normal Msh2-deficient thymus.
- Significant differences in mutational spectra were observed between normal thymus and thymic lymphomas (P=0.02).
- The tumor mutational spectrum was characterized by increased base substitutions at A:T sites, multiple mutations, and a minor increase in -1 frameshifts, with identifiable regional hotspots.
Conclusions:
- Thymic lymphomas arising in Msh2-deficient mice are hypermutable.
- The altered mutational spectrum in these tumors suggests infidelity of DNA replication during tumorigenesis.
- Specific mutational hotspots identified in tumors, rare in normal tissues, may hold significance for understanding Msh2-driven cancer progression.