Radiation-induced DNA damage cooperates with heterozygosity of TP53 and PTEN to generate high-grade gliomas

Pavlina K. Todorova, Eliot Fletcher-Sananikone, Bipasha Mukherjee, Rahul Kollipara, Vamsidhara Vemireddy, Xian Jin Xie, Peter M. Guida, Michael D. Story, Kimmo Hatanpaa, Amyn A. Habib, Ralf Kittler, Robert Bachoo, Robert Hromas, John R. Floyd, Sandeep Burma

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3749-3761
Number of pages13
JournalCancer Research
Volume79
Issue number14
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Todorova, P. K., Fletcher-Sananikone, E., Mukherjee, B., Kollipara, R., Vemireddy, V., Xie, X. J., Guida, P. M., Story, M. D., Hatanpaa, K., Habib, A. A., Kittler, R., Bachoo, R., Hromas, R., Floyd, J. R., & Burma, S. (2019). Radiation-induced DNA damage cooperates with heterozygosity of TP53 and PTEN to generate high-grade gliomas. Cancer Research, 79(14), 3749-3761. https://doi.org/10.1158/0008-5472.CAN-19-0680