DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification

• Published in: Oncogene 2015-02, Vol.34 (8), p.1064-1072
• Main Authors: Camacho, C V, Todorova, P K, Hardebeck, M C, Tomimatsu, N, Gil del Alcazar, C R, Ilcheva, M, Mukherjee, B, McEllin, B, Vemireddy, V, Hatanpaa, K, Story, M D, Habib, A A, Murty, V V, Bachoo, R, Burma, S
• Format: Article
• Language: English
• Subjects: 631/337/1427/2122; 631/67/1922; 692/420/755; Animal models; Animals; Apoptosis; Brain cancer; Brain Neoplasms - genetics; Brain tumors; Care and treatment; Cell Biology; Copy number; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-dependent kinase inhibitors; Deoxyribonucleic acid; Development and progression; DNA; DNA Breaks, Double-Stranded - radiation effects; DNA damage; Energy transformation; Gene Amplification; Gene Deletion; Genetic aspects; Glioblastoma - genetics; Glioblastoma multiforme; Glioma; Human Genetics; INK4 protein; Internal Medicine; Ionizing radiation; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Oncology; Physiological aspects; Proto-Oncogene Proteins c-met - genetics; PTEN protein; Radiation; Radiation, Ionizing; Risk factors; short-communication; Stem cells; Stochasticity; Studies; Transgenic mice; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.29

Glioblastomas (GBM) are highly radioresistant and lethal brain tumors. Ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) are a risk factor for the development of GBM. In this study, we systematically examined the contribution of IR-induced DSBs to GBM development using transgenic mouse models harboring brain-targeted deletions of key tumor suppressors frequently lost in GBM, namely Ink4a , Ink4b , Arf and/or PTEN . Using low linear energy transfer (LET) X-rays to generate simple breaks or high LET HZE particles (Fe ions) to generate complex breaks, we found that DSBs induce high-grade gliomas in these mice which, otherwise, do not develop gliomas spontaneously. Loss of Ink4a and Arf was sufficient to trigger IR-induced glioma development but additional loss of Ink4b significantly increased tumor incidence. We analyzed IR-induced tumors for copy number alterations to identify oncogenic changes that were generated and selected for as a consequence of stochastic DSB events. We found Met amplification to be the most significant oncogenic event in these radiation-induced gliomas. Importantly, Met activation resulted in the expression of Sox2, a GBM cancer stem cell marker, and was obligatory for tumor formation. In sum, these results indicate that radiation-induced DSBs cooperate with loss of Ink4 and Arf tumor suppressors to generate high-grade gliomas that are commonly driven by Met amplification and activation.