Tumors arising in DNA mismatch repair-deficient mice show a wide variationin mutation frequency as assessed by a transgenic reporter gene

We reported previously that thymic lymphomas arising in mice lacking the DN A mismatch repair (MMR) gene, Msh2(-/-), exhibited striking elevations in t he mutation frequency of a transgenic lacI reporter gene when compared with normal Msh2(-/-) tissues. To investigate whether hypermutation was a featu re of all tumors arising in MMR-deficient mice, lacI transgene mutation fre quencies were obtained from several different mouse tumors deficient for PM S2 and/or MSH2, While lacI gene hypermutation was again clearly evident in Msh2(+/-)Pms2(-/-) and Msh2(-/-)Pms2(-/-) thymic lymphomas, three non-thymi c MSH2-deficient tumors failed to show lacI gene mutation frequency elevati ons when compared with a normal tissue of MMR-deficient mice. The elevated mutation frequencies in the lymphoid tumors, and the finding of multiple cl ustered mutations in lacI genes rescued from these tumors, suggest that the y are possibly generated by a lymphoma-specific hypermutational mechanism.