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

Author

Listed:
  • 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
    St. Jude Children’s Research Hospital)

  • Michael Arnold

    (Nationwide Children’s Hospital)

  • Smita Bhatia

    (St. Jude Children’s Research Hospital
    University of Alabama at Birmingham)

  • 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
    Children’s Hospital Colorado)

  • Kathleen Dorris

    (University of Colorado School of Medicine
    Children’s Hospital Colorado)

  • Jean M. Mulcahy Levy

    (University of Colorado School of Medicine
    Children’s Hospital Colorado)

  • Todd C. Hankinson

    (University of Colorado School of Medicine
    Children’s Hospital Colorado)

  • Michael Handler

    (University of Colorado School of Medicine
    Children’s Hospital Colorado)

  • Arthur K. Liu

    (Children’s Hospital Colorado)

  • Nicholas Foreman

    (University of Colorado School of Medicine
    Children’s Hospital Colorado)

  • Rajeev Vibhakar

    (University of Colorado School of Medicine
    Children’s Hospital Colorado)

  • 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
    Children’s Hospital Colorado)

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.

Suggested Citation

  • 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 & Patri, 2021. "Comprehensive molecular characterization of pediatric radiation-induced high-grade glioma," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25709-x
    DOI: 10.1038/s41467-021-25709-x
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    Cited by:

    1. Qilin Zhang & Ziyan Xu & Rui Han & Yunzhi Wang & Zhen Ye & Jiajun Zhu & Yixin Cai & Fan Zhang & Jiangyan Zhao & Boyuan Yao & Zhaoyu Qin & Nidan Qiao & Ruofan Huang & Jinwen Feng & Yongfei Wang & Wenti, 2024. "Proteogenomic characterization of skull-base chordoma," Nature Communications, Nature, vol. 15(1), pages 1-32, December.

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