Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-25709-x
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Funding
- Cancer Center support grant [P30CA046934]
- Rocky Mountain Neurological Disorders Core Grant [P30 NS048154]
- Diabetes Research Center [P30 DK116073]
- National Cancer Institute [CA55727]
- Fordergemeinschaft Kinderkrebs-Zentrum Hamburg
- St. Jude Children's Research Hospital Cancer Center Support (CORE) grant [CA21765]
- ALSAC
- Morgan Adams Foundation
- St. Baldrick's Foundation Scholarship
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Radiation-induced high-grade gliomas (RIGs) are an incurable late complication of cranial radiation therapy. Genomic analysis revealed common copy-number alterations and different subgroups based on DNA methylation and transcriptome profiles, suggesting potential therapeutic targets such as microtubule inhibitors and MEK inhibitors. These findings provide insights into the molecular mechanisms of RIGs and potential treatment strategies.
Radiation-induced high-grade gliomas (RIGs) are an incurable late complication of cranial radiation therapy. We performed DNA methylation profiling, RNA-seq, and DNA sequencing on 32 RIG tumors and an in vitro drug screen in two RIG cell lines. We report that based on DNA methylation, RIGs cluster primarily with the pediatric receptor tyrosine kinase I high-grade glioma subtype. Common copy-number alterations include Chromosome (Ch.) 1p loss/1q gain, and Ch. 13q and Ch. 14q loss; focal alterations include PDGFRA and CDK4 gain and CDKN2A and BCOR loss. Transcriptomically, RIGs comprise a stem-like subgroup with lesser mutation burden and Ch. 1p loss and a pro-inflammatory subgroup with greater mutation burden and depleted DNA repair gene expression. Chromothripsis in several RIG samples is associated with extrachromosomal circular DNA-mediated amplification of PDGFRA and CDK4. Drug screening suggests microtubule inhibitors/stabilizers, DNA-damaging agents, MEK inhibition, and, in the inflammatory subgroup, proteasome inhibitors, as potentially effective therapies.
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