Glioblastomas are lethal brain tumors that are treated with conventional 
radiation (X-rays and gamma rays) or particle radiation (protons and carbon 
ions). Paradoxically, radiation is also a risk factor for GBM development, 
raising the possibility that radiotherapy of brain tumors could promote tumor 
recurrence or trigger secondary gliomas. In this study, we determined whether 
tumor suppressor losses commonly displayed by patients with GBM confer 
susceptibility to radiation-induced glioma. Mice with Nestin-Cre-driven 
deletions of Trp53 and Pten alleles were intracranially irradiated with X-rays 
or charged particles of increasing atomic number and linear energy transfer 
(LET). Mice with loss of one allele each of Trp53 and Pten did not develop 
spontaneous gliomas, but were highly susceptible to radiation-induced 
gliomagenesis. Tumor development frequency after exposure to high-LET particle 
radiation was significantly higher compared with X-rays, in accordance with the 
irreparability of DNA double-strand breaks (DSB) induced by high-LET radiation. 
All resultant gliomas, regardless of radiation quality, presented 
histopathologic features of grade IV lesions and harbored populations of cancer 
stem-like cells with tumor-propagating properties. Furthermore, all tumors 
displayed concomitant loss of heterozygosity of Trp53 and Pten along with 
frequent amplification of the Met receptor tyrosine kinase, which conferred a 
stem cell phenotype to tumor cells. Our results demonstrate that 
radiation-induced DSBs cooperate with preexisting tumor suppressor losses to 
generate high-grade gliomas. Moreover, our mouse model can be used for studies 
on radiation-induced development of GBM and therapeutic strategies. 
SIGNIFICANCE: This study uncovers mechanisms by which ionizing radiation, 
especially particle radiation, promote GBM development or recurrence.