Analysis of the relationship between microsatellite instability and thymic lymphoma induced by N-methyl-N-nitrosourea in C57BL/6J mice

Abstract

Microsatellite instability (MSI) has been found to be closely associated with many types of human tumors and often shows strong correlations with specific tumor features. However, the relationship between MSI and tumors are still unclear. The aim of the present study is to explore the relationships between MSI, tumor formation under the mutagenic effects of N-methyl-N-nitrosourea (MNU). Mice were administered with either MNU (90mg/kg) or PBS and DMSO (control) at the beginning of the 1st week of the experiment. Of the 31 mice that survived the entire experimental time course, 19 (61.3%) mice developed thymic lymphomas. In addition, 52.6% (10/19) of the tumors had metastasized to the liver. We detected MSI in MNU-treated mice using a panel of 42 mutation-sensitive loci. Nineteen loci (45.2%) in six organs showed 70 MSI events. Locus D8Mit14 showed enhanced MSI compared with the other examined loci. MSI frequency in thymus was higher than in other organs. Interestingly, there was no significant difference observed between the metastatic and non-metastatic livers. The MSI frequency (4.6%, 23/(42×12)) in the MNU-treated thymus that had never developed tumor was significantly higher than this in the thymus that had developed lymphoma (0.5%, 4/(42×19)) (p<0.0001). These results indicate that, although thymic tumorigenesis is associated with MSI, it occurs with higher frequency in these that have not developed tumors upon the MNU-treatment. Our study provides additional insights into the relationship between MSI occurrence and tumorigenesis.