Thymic lymphomas arising in Msh2 deficient mice display a large increase in mutation frequency and an altered mutational spectrum.
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.
Zhang
Shulin
S
Department of Biology, Centre for Environmental Health, University of Victoria, Victoria, BC, Canada V8W 3N5.
Lloyd
Ruth
R
Bowden
Gregory
G
Glickman
Barry W
BW
de Boer
Johan G
JG
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D020137:Base Pair Mismatch / Q000235:genetics*; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051718:MutS Homolog 2 Protein; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics; D013953:Thymus Neoplasms / Q000235:genetics* / Q000473:pathology
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein