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

被引：42

作者：

DeSisto, John ^{[1
]}

Lucas, John T. ^{[2
]}

Xu, Ke ^{[3
]}

Donson, Andrew ^{[1
]}

Lin, Tong ^{[4
]}

Sanford, Bridget ^{[1
]}

Wu, Gang ^{[3
]}

Tran, Quynh T. ^{[5
]}

Hedges, Dale ^{[2
]}

Hsu, Chih-Yang ^{[2
]}

Armstrong, Gregory T. ^{[6
,7
]}

Arnold, Michael ^{[8
]}

Bhatia, Smita ^{[7
,9
]}

Flannery, Patrick ^{[1
]}

Lemma, Rakeb ^{[1
]}

Hardie, Lakotah ^{[10
]}

Schueller, Ulrich ^{[11
,12
]}

Venkataraman, Sujatha ^{[1
]}

Hoffman, Lindsey M. ^{[1
,10
]}

Dorris, Kathleen ^{[1
,10
]}

Levy, Jean M. Mulcahy ^{[1
,10
]}

Hankinson, Todd C. ^{[1
,10
]}

Handler, Michael ^{[1
,10
]}

Liu, Arthur K. ^{[10
]}

Foreman, Nicholas ^{[1
,10
]}

Vibhakar, Rajeev ^{[1
,10
]}

Jones, Kenneth ^{[1
]}

Allen, Sariah ^{[5
]}

Zhang, Jinghui ^{[3
]}

Baker, Suzanne J. ^{[13
]}

Merchant, Thomas E. ^{[2
]}

Orr, Brent A. ^{[5
]}

Green, Adam L. ^{[1
,10
]}

机构：

[1] Univ Colorado, Sch Med, Morgan Adams Fdn Pediat Brain Tumor Res Program, Aurora, CO 80045 USA

[2] St Jude Childrens Res Hosp, Dept Radiat Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA

[3] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA

[4] St Jude Childrens Res Hosp, Dept Biostat, 332 N Lauderdale St, Memphis, TN 38105 USA

[5] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA

[6] St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, 332 N Lauderdale St, Memphis, TN 38105 USA

[7] St Jude Childrens Res Hosp, Childhood Canc Survivor Study, 332 N Lauderdale St, Memphis, TN 38105 USA

[8] Nationwide Childrens Hosp, Dept Pathol, Columbus, OH USA

[9] Univ Alabama Birmingham, Div Hematol & Oncol, Birmingham, AL USA

[10] Childrens Hosp Colorado, Aurora, CO 80045 USA

[11] Univ Med Ctr, Childrens Canc Ctr, Inst Neuropathol, Hamburg, Germany

[12] Univ Med Ctr, Childrens Canc Ctr, Dept Pediat Hematol & Oncol, Hamburg, Germany

[13] St Jude Childrens Res Hosp, Dept Dev Neurobiol, 332 N Lauderdale St, Memphis, TN 38105 USA

来源：

NATURE COMMUNICATIONS | 2021年 / 12卷 / 01期

关键词：

STRUCTURAL-VARIATION; CHILDHOOD-CANCER; DNA-DAMAGE; GENE; REPAIR; RETINOBLASTOMA; AMPLIFICATION; EXPRESSION; MUTATIONS; LANDSCAPE;

D O I：

10.1038/s41467-021-25709-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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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