Specrtum of mutations in Ikaros, K-ras and P53 genes in radiogenic thymic lymphomas in B6C3F1 mice

Accumulation of genetic changes is considered as important processes for the development of cancer. Recent progress in molecular biology has provided new markers for the approach to study the relationship between the exposure to carcinogens and development of cancers. Therefore, identification of genetic changes in radiation-induced cancers is of great concern for the risk assessment of low dose radiation. Currently, we are investigating the spectrum of molecular lesions in radiation-induced thymic lymphomas in B6C3F1 mice. In comparison with spontaneous or N-ethyl-N-nitrosourea-induced lymphomas, X-ray-induced lymphomas exhibited unique loss of heterozygosiy at a frequency of ∼50% in the centromeric region of chromosome 11, where Ikaros gene was genetically linked. Interestingly, there appeared to be a hot spot of breaking point for LOH at both sides of Ikaros locus. It is implied that the loss of heterozygosity at Ikaros locus represented radiation signature. Molecular analysis showed that Ikaros gene was inactivated by a variety of mechanisms, including null expression, expression of dominant negative short isoforms, point mutations and an insertion of dinucleotides. K-ras and P53 mutations were also identified in the lymphomas, but their frequencies were low and mutation spectrum was not specific. These results suggest loss of heterozygosity at Ikaros locus may be a possible radiation fingerprint in the thymic lymphomas induced by ionizing radiation