title: DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: C V
authors.initials: CV
authors.lastname: Camacho
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Todorova
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Hardebeck
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Tomimatsu
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Gil del Alcazar
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ilcheva
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Mukherjee
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: McEllin
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: V
authors.initials: V
authors.lastname: Vemireddy
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Hatanpaa
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Story
authors.affiliation: 1] Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] VA North Texas Health Care System, Dallas, TX, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Habib
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
authors.forename: V V
authors.initials: VV
authors.lastname: Murty
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bachoo
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Burma
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D005784:Gene Amplification; D017353:Gene Deletion; D005909:Glioblastoma / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D011839:Radiation, Ionizing
chemical_list: C417743:Cdkn2a protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019859:Proto-Oncogene Proteins c-met