Tumors arising in DNA mismatch repair-deficient mice show a wide variation in mutation frequency as assessed by a transgenic reporter gene.
We reported previously that thymic lymphomas arising in mice lacking the DNA mismatch repair (MMR) gene, Msh2(-/-), exhibited striking elevations in the mutation frequency of a transgenic lacI reporter gene when compared with normal Msh2(-/-) tissues. To investigate whether hypermutation was a feature of all tumors arising in MMR-deficient mice, lacI transgene mutation frequencies were obtained from several different mouse tumors deficient for PMS2 and/or MSH2. While lacI gene hypermutation was again clearly evident in Msh2 +/- ms2(-/-) and Msh2(-/-)Pms2(-/-) thymic lymphomas, three non-thymic MSH2-deficient tumors failed to show lacI gene mutation frequency elevations when compared with a normal tissue of MMR-deficient mice. The elevated mutation frequencies in the lymphoid tumors, and the finding of multiple clustered mutations in lacI genes rescued from these tumors, suggest that they are possibly generated by a lymphoma-specific hypermutational mechanism.
Baross-Francis
A
A
Centre for Molecular Medicine and Therapeutics, Department of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
Milhausen
M K
MK
Andrew
S E
SE
Jevon
G
G
Jirik
F R
FR
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D020137:Base Pair Mismatch; D004260:DNA Repair; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D017930:Genes, Reporter; D056968:Lac Repressors; D008223:Lymphoma / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D051718:MutS Homolog 2 Protein; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D013953:Thymus Neoplasms / Q000235:genetics
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