Characteristic Genetic Alterations Associated with the Partial Deletion of Chromosome 11 in Mouse Thymic Lymphomas Induced by High-Linear Energy Transfer Irradiation with Carbon Ions.

High-linear energy transfer (LET) radiation is thought to induce highly complex DNA damage compared with photon radiation such as X-rays, suggesting a characteristic mechanism for the development of cancers associated with high-LET radiation exposure. However, few studies have investigated the carcinogenic mechanisms that are dependent on radiation quality or LET. This study analyzed mutations and gene expression in thymic lymphomas (TL) induced by high-LET carbon-ion irradiation to identify characteristic genetic alterations. The results revealed that TL arising after four-fractionated high-LET carbon-ion irradiation frequently exhibited loss of heterozygosity (LOH) in the region containing the TL-associated gene Ikzf1 on chromosome 11 owing to extensive genomic deletions in the paternal allele. Nevertheless, for carbon ion-induced TL, those with only LOH without Ikzf1 alterations were observed at a relatively high frequency (16/39, 41.0%). Comprehensive RNA sequencing and reverse-transcription PCR analysis of neighboring genes of Ikzf1 revealed highly upregulated expression of Grb10 (17/39, 43.6%), an imprinted gene that is barely expressed in the normal thymus. In TL expressing Grb10, enhanced interferon signaling and Pten mutations, along with activation of the PI3K-AKT-mTOR signaling pathway, were suggested to promote cell proliferation and survival. These results suggest that extensive genomic deletions caused by high-LET carbon-ion irradiation may contribute to carcinogenesis by altering the expression of multiple genes located in the deleted region.