Candidate mutator genes in mismatch repair-deficient thymic lymphomas: no evidence of mutations in the DNA polymerase delta gene

DNA mismatch repair (MMR) proteins recognize nucleotides that are incorrect ly paired. Deficiencies in MMR lead to increased genomic instability reflec ted in an increased mutation frequency and predisposition to tumorigenesis. Mice lacking the MMR gene, Msh2, develop thymic lymphomas that exhibit muc h higher mutational frequencies than other Msh2(-/-) tumours and Msh2(-/-) normal thymic tissue, suggesting that an additional mutator may have been a cquired in a tissue-specific manner, Clustered mutations observed exclusive ly in the thymic lymphomas suggests that a gene(s) associated with the repl ication machinery might have become altered during tumorigenesis, Based on mutation studies in Saccharomyces cerevisiae lacking Msh2 and DNA polymeras e delta (DNA pol delta), we hypothesized that the acquisition of mutations in DNA pol delta could contribute to the hypermutator phenotype and tumorig enesis in Msh2(-/-) thymic tissue, Furthermore, previous reports have sugge sted that genes containing mononucleotide repeats are non-random mutational targets in the absence of MMR, Therefore, we sequenced all 26 exons of the DNA pol delta catalytic subunit, including the six exons containing mononu cleotide repeats of >5 bp, from nine Msh2(-/-) thymic lymphomas and two wil d-type controls. No DNA pol delta pathogenic mutations were found in the th ymic lymphomas, although several DNA base differences compared with publish ed DNA pol delta sequences were observed, We conclude, therefore, that inac tivating mutations in DNA pol delta are not a contributing factor in the de velopment of the hypermutator phenotype in MMR-deficient murine thymic lymp homas.