Tumors of DNA mismatch repair-deficient hosts exhibit dramatic increases in genomic instability.
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.
Center for Molecular Medicine and Therapeutics, and Department of Medicine, University of British Columbia, Vancouver, BC Canada V5Z 4H4.
A
A
Baross-Francis
S E
SE
Andrew
J E
JE
Penney
F R
FR
Jirik
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D001483:Base Sequence; D004247:DNA; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009692:Nucleic Acid Heteroduplexes; 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; D009692:Nucleic Acid Heteroduplexes; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D004247:DNA; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein