Comprehensive molecular characterization of pediatric radiation-induced high-grade glioma

John DeSisto, John T. Lucas, Ke Xu, Andrew Donson, Tong Lin, Bridget Sanford, Gang Wu, Quynh T. Tran, Dale Hedges, Chih-Yang Hsu, Gregory T. Armstrong, Michael Arnold (), Smita Bhatia, Patrick Flannery, Rakeb Lemma, Lakotah Hardie, Ulrich Schüller, Sujatha Venkataraman, Lindsey M. Hoffman, Kathleen Dorris, Jean M. Mulcahy Levy, Todd C. Hankinson, Michael Handler, Arthur K. Liu, Nicholas Foreman, Rajeev Vibhakar, Kenneth Jones, Sariah Allen, Jinghui Zhang, Suzanne J. Baker, Thomas E. Merchant, Brent A. Orr () and Adam L. Green ()
Additional contact information
John DeSisto: University of Colorado School of Medicine
John T. Lucas: St. Jude Children’s Research Hospital
Ke Xu: St. Jude Children’s Research Hospital
Andrew Donson: University of Colorado School of Medicine
Tong Lin: St. Jude Children’s Research Hospital
Bridget Sanford: University of Colorado School of Medicine
Gang Wu: St. Jude Children’s Research Hospital
Quynh T. Tran: St. Jude Children’s Research Hospital
Dale Hedges: St. Jude Children’s Research Hospital
Chih-Yang Hsu: St. Jude Children’s Research Hospital
Gregory T. Armstrong: St. Jude Children’s Research Hospital
Smita Bhatia: St. Jude Children’s Research Hospital
Patrick Flannery: University of Colorado School of Medicine
Rakeb Lemma: University of Colorado School of Medicine
Lakotah Hardie: Children’s Hospital Colorado
Ulrich Schüller: University Medical Center, Children’s Cancer Center
Sujatha Venkataraman: University of Colorado School of Medicine
Lindsey M. Hoffman: University of Colorado School of Medicine
Kathleen Dorris: University of Colorado School of Medicine
Jean M. Mulcahy Levy: University of Colorado School of Medicine
Todd C. Hankinson: University of Colorado School of Medicine
Michael Handler: University of Colorado School of Medicine
Arthur K. Liu: Children’s Hospital Colorado
Nicholas Foreman: University of Colorado School of Medicine
Rajeev Vibhakar: University of Colorado School of Medicine
Kenneth Jones: University of Colorado School of Medicine
Sariah Allen: St. Jude Children’s Research Hospital
Jinghui Zhang: St. Jude Children’s Research Hospital
Suzanne J. Baker: St. Jude Children’s Research Hospital
Thomas E. Merchant: St. Jude Children’s Research Hospital
Brent A. Orr: St. Jude Children’s Research Hospital
Adam L. Green: University of Colorado School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25709-x

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