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pubmed:abstractText |
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.
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