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 lad gene mutation frequencies, ranging from 3.2- to 17.4-fold above the approximate to 15-fold elevations present within normal Msh2(-/-) thymi, In addition, lad genes hal boring 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.