Genomic and transcriptomic characterization of gamma ray- and heavy-ion-induced precursor B-cell lymphomas in B6C3F1 mice: radiation-type-dependent interstitial chromosomal deletions at tumor-suppressor gene loci.

Epidemiological studies have revealed that ionizing radiation is a risk factor for acute lymphoblastic leukemia. Humans can be exposed to radiation via clinical radiotherapies or spaceflight, yet our knowledge of the potential carcinogenic effects of various types of radiation remains incomplete. To address this shortcoming, we analyzed the development of precursor B-cell lymphoma (pBL) in B6C3F1 mice after irradiation with gamma rays or heavy ions (carbon, silicon, argon, or iron ions) followed by array comparative genomic hybridization, whole-exome sequencing, and RNA-sequencing analyses. Heavy-ion irradiation predominantly induced late-onset pBLs. In addition, chromosomal deletions in late-onset pBLs depended on radiation type: gamma-ray-induced pBLs had interstitial deletions of chromosome 8 (del8) affecting the tumor-suppressor gene Cyld, whereas silicon-ion-induced pBLs had interstitial deletions of chromosome 19 (del19) affecting the tumor-suppressor genes Cd274, Pten, and Fas; notably, carbon ions induced both types of pBL and no pBLs harbored these deletions in the argon- or iron-ion-irradiated mice. Late-onset pBLs were classified into two clusters with differential mutation patterns based on their gene-expression profiles, and pBLs with del8 and del19 were classified into different gene-expression clusters. Furthermore, the mutational and transcriptomic profiles of the late-onset del8 pBLs were reminiscent of human activated B-cell-like diffuse large B-cell lymphoma (DLBCL), whereas those of the del19 pBLs resembled germinal center B-cell-like DLBCL. These results establish the molecular signatures in radiation-induced pBLs that depend on radiation type, which will help improve both targeted molecular therapies for patients and risk assessment after exposure.