The DOI matches its Crossref record; 34 of the 37 references it cites were found in a registry or an index.
Thymic lymphomas arising in Msh2 deficient mice display a large increase in mutation frequency and an altered mutational spectrum
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.
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“Mice lacking Msh2, the key component of both the MutSα and MutSβ complexes that mediate DNA MMR, display a genetic phenotype that closely mimics the spectrum of mutations found in aging human HSCs and in patients with myeloid leukemia (transition mutations and small insertions and deletions) 26, 27.”
From Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia (2015) · cites this paper as [26]
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Metadata
- Authors
- Zhang, S., Lloyd, R., Bowden, G., Glickman, B. W., & de Boer, J. G.
- Affiliations
- University of Victoria (CA)
- Corresponding author
- de Boer, Johan G
- Venue
- Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
- Publisher
- Elsevier BV
- Published
- 2002-03
- Volume
- 500
- Issue
- 1-2
- Pages
- 67-74
- ISSN
- 0027-5107 (ISSN-L)
- 1386-1964
- OpenAlex
- W2025891700
- Cited by
- 20
- References
- 37
- Citations by year
- 2019: 1 · 2017: 1 · 2015: 1 · 2014: 1 · 2012: 1
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Mutation research. Fundamental and molecular mechanisms of mutagenesis (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- thymic lymphoma, MSH2, DNA mismatch repair, mutator genes, mutation frequency, mutation spectrum, mutational hotspots, frameshift mutation, microsatellite instability
- MeSH terms
- Animals, Bacterial Proteins, DNA-Binding Proteins, Lymphoma, Mice, Transgenic, Mutation, Proto-Oncogene Proteins, Repressor Proteins, Thymus Neoplasms, Mice, Knockout, Base Pair Mismatch, Escherichia coli Proteins, Mice, MutS Homolog 2 Protein, Lac Repressors
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