Genetic Events Underlying Radiation-Induced Gliomagenesis

Glioblastoma multiforme (GBM) are highly lethal brain tumors for which exposure to ionizing radiation is the only known risk factor. GBM is characterized by alterations in three core signaling pathways: 1) RTK-PI3K-Akt, 2) ARF-MDM2-p53, and 3) Ink4a-RB1. We have developed in vitro and in vivo models in order to objectively evaluate the risk of developing malignant gliomas from exposure to ionizing radiation (IR). DNA double-strand breaks (DSBs) are the most deleterious lesion inflicted by IR. We hypothesize that DSBs cooperate with pre-existing tumor suppressor loss to trigger IR-induced transformation. We demonstrate that complex DSBs induced by high linear-energy transfer (LET) Fe ions are repaired slowly and incompletely, while those induced by low-LET gamma rays are repaired efficiently by mammalian cells. The incomplete repair of Fe-induced damage results in persistent DNA damage signaling and culminates in high levels of senescence and increased cell killing. // To examine long-term carcinogenic consequences, we used ‘sensitized’ Ink4a/Arf-knockout astrocytes, which are immortal but not tumorigenic. We find that Fe ions are potently tumorigenic when directed to these astrocytes, generating tumors with much higher frequency and shorter latency compared to tumors.