Abstract
Radiation carcinogenesis in human is results from combined exposure to numerous environment factors. However, little is known about its molecular mechanisms. In order to determine if the combined exposure activates the specific carcinogenic pathway or enhances each one, we scrutinized extensively the frequency and spectrum of mutations of the genes, which are critically important for T-cell lymphomagenesis, i.e., Ikaros and p53 as tumor suppressor gene, Notch1 and K-ras as oncogene, in mice thymic lymphomas (TL) induced synergistically by simultaneous combined exposure to X-rays and N-ethyl-N-nitrosourea (ENU).
Molecular analyses identified that Ikaros alteration frequency, especially point mutation frequency, was increased significantly in combined exposure (47.2%) compared with X-ray- (12.9%) or ENU-exposure (0%)(P<0.01). Our previous study demonstrated that point mutations of Ikaros are characterized by accompanying LOH in X-ray-induced TL, but not in ENU-induced TL. Here, a half of point mutations in combined exposure were associated with LOH, and remaining without LOH. Interestingly, some were accompanied by concomitant frameshift mutation or altered splicing in another allele. Thus, Ikaros inactivation was stimulated by mutation induction from both X-rays and ENU in combined exposure. The frequency of Notch1 abnormality was high in all treatments (over 58%), suggesting a mandatory step in T-cell lymphomagenesis. In contrast, mutation frequencies of p53 and Kras were low in all treatments (<23%).
In conclusion, Ikaros is a critical mutational target for enhancement and acceleration of lymphomagenesis after combined exposure to X rays and ENU.
