| First Author | Camacho CV | Year | 2015 |
| Journal | Oncogene | Volume | 34 |
| Issue | 8 | Pages | 1064-72 |
| PubMed ID | 24632607 | Mgi Jnum | J:218621 |
| Mgi Id | MGI:5618053 | Doi | 10.1038/onc.2014.29 |
| Citation | Camacho CV, et al. (2015) DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification. Oncogene 34(8):1064-72 |
| abstractText | 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. |
