The Genomic Landscape of Diffuse Intrinsic Pontine Glioma and Pediatric Non-brainstem High-grade Glioma

Overview

Journal Nat Genet

Specialty Genetics

Date 2014 Apr 8

PMID 24705251

Citations 568

Authors

Gang Wu

Alexander K Diaz

Barbara S Paugh

Sherri L Rankin

Bensheng Ju

Yongjin Li

Xiaoyan Zhu

Chunxu Qu

Xiang Chen

Junyuan Zhang

John Easton

Michael Edmonson

Xiaotu Ma

Charles Lu

Panduka Nagahawatte

Erin Hedlund

Michael Rusch

Stanley Pounds

Tong Lin

Arzu Onar-Thomas

Robert Huether

Richard Kriwacki

Matthew Parker

Pankaj Gupta

Jared Becksfort

Lei Wei

Heather L Mulder

Kristy Boggs

Bhavin Vadodaria

Donald Yergeau

Jake C Russell

Kerri Ochoa

Robert S Fulton

Lucinda L Fulton

Chris Jones

Frederick A Boop

Alberto Broniscer

Cynthia Wetmore

Amar Gajjar

Li Ding

Elaine R Mardis

Richard K Wilson

Michael R Taylor

James R Downing

David W Ellison

Jinghui Zhang

Suzanne J Baker

Affiliations

Soon will be listed here.

Abstract

Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 years after diagnosis. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPGs (32%), in addition to previously reported frequent somatic mutations in histone H3 genes, TP53 and ATRX, in both DIPGs and NBS-HGGs. Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, NTRK2 and NTRK3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase-RAS-PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59% of pediatric HGGs, respectively, including in DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.

Citing Articles

Role of epigenetics in paediatric cancer pathogenesis & drug resistance.

Leung J, Chiu H, Taneja R Br J Cancer. 2025; .

PMID: 40055485 DOI: 10.1038/s41416-025-02961-2.

Fusion oncoproteins and cooperating mutations define disease phenotypes in -rearranged leukemia.

Umeda M, Hiltenbrand R, Michmerhuizen N, Barajas J, Thomas M, Arthur B medRxiv. 2025; .

PMID: 39974131 PMC: 11838931. DOI: 10.1101/2025.01.21.25320683.

Establishment of xenografts and methods to evaluate tumor burden for the three most frequent subclasses of pediatric-type diffuse high grade gliomas.

Balaguer-Lluna L, Olaciregui N, Aschero R, Resa-Pares C, Paco S, Cuadrado-Vilanova M J Neurooncol. 2025; .

PMID: 39961939 DOI: 10.1007/s11060-025-04954-w.

Opportunities in the translational pipeline for pediatric brain cancer therapies.

Rumberger Rivera L, Springer N, Bailey K, Patel J, Brett C, Barker E Pediatr Res. 2025; .

PMID: 39893288 DOI: 10.1038/s41390-025-03847-y.

Identification of the clinical and genetic characteristics of gliomas with gene fusions by integrated genomic and transcriptomic analysis.

Yi G, Zhang H, Que T, Qu S, Li Z, Qi S Eur J Med Res. 2025; 30(1):49.

PMID: 39849652 PMC: 11755825. DOI: 10.1186/s40001-025-02306-y.

References

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

Lannon C, Sorensen P . ETV6-NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages. Semin Cancer Biol. 2005; 15(3):215-23. DOI: 10.1016/j.semcancer.2005.01.003. View

Wang J, Mullighan C, Easton J, Roberts S, Heatley S, Ma J . CREST maps somatic structural variation in cancer genomes with base-pair resolution. Nat Methods. 2011; 8(8):652-4. PMC: 3527068. DOI: 10.1038/nmeth.1628. View

Jones D, Hutter B, Jager N, Korshunov A, Kool M, Warnatz H . Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet. 2013; 45(8):927-32. PMC: 3951336. DOI: 10.1038/ng.2682. View

Lee J, Son M, Woolard K, Donin N, Li A, Cheng C . Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell. 2008; 13(1):69-80. PMC: 2835498. DOI: 10.1016/j.ccr.2007.12.005. View

Schiffman J, Hodgson J, VandenBerg S, Flaherty P, Polley M, Yu M . Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res. 2010; 70(2):512-9. PMC: 2851233. DOI: 10.1158/0008-5472.CAN-09-1851. View

Butti M, Bongarzone I, Ferraresi G, Mondellini P, Borrello M, Pierotti M . A sequence analysis of the genomic regions involved in the rearrangements between TPM3 and NTRK1 genes producing TRK oncogenes in papillary thyroid carcinomas. Genomics. 1995; 28(1):15-24. DOI: 10.1006/geno.1995.1100. View

Puget S, Philippe C, Bax D, Job B, Varlet P, Junier M . Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas. PLoS One. 2012; 7(2):e30313. PMC: 3289615. DOI: 10.1371/journal.pone.0030313. View

Venneti S, Garimella M, Sullivan L, Martinez D, Huse J, Heguy A . Evaluation of histone 3 lysine 27 trimethylation (H3K27me3) and enhancer of Zest 2 (EZH2) in pediatric glial and glioneuronal tumors shows decreased H3K27me3 in H3F3A K27M mutant glioblastomas. Brain Pathol. 2013; 23(5):558-64. PMC: 3701028. DOI: 10.1111/bpa.12042. View

10.

Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W . c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell. 2012; 151(1):68-79. PMC: 3471363. DOI: 10.1016/j.cell.2012.08.033. View

11.

Dubuc A, Remke M, Korshunov A, Northcott P, Zhan S, Mendez-Lago M . Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma. Acta Neuropathol. 2012; 125(3):373-84. PMC: 3580007. DOI: 10.1007/s00401-012-1070-9. View

12.

Szymczak A, Workman C, Wang Y, Vignali K, Dilioglou S, Vanin E . Correction of multi-gene deficiency in vivo using a single 'self-cleaving' 2A peptide-based retroviral vector. Nat Biotechnol. 2004; 22(5):589-94. DOI: 10.1038/nbt957. View

13.

Chan K, Fang D, Gan H, Hashizume R, Yu C, Schroeder M . The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 2013; 27(9):985-90. PMC: 3656328. DOI: 10.1101/gad.217778.113. View

14.

Chaikuad A, Alfano I, Kerr G, Sanvitale C, Boergermann J, Triffitt J . Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva. J Biol Chem. 2012; 287(44):36990-8. PMC: 3481300. DOI: 10.1074/jbc.M112.365932. View

15.

Zhao H, Ayrault O, Zindy F, Kim J, Roussel M . Post-transcriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development. Genes Dev. 2008; 22(6):722-7. PMC: 2275424. DOI: 10.1101/gad.1636408. View

16.

Lewis P, Muller M, Koletsky M, Cordero F, Lin S, Banaszynski L . Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science. 2013; 340(6134):857-61. PMC: 3951439. DOI: 10.1126/science.1232245. View

17.

Jonkers J, Meuwissen R, van der Gulden H, Peterse H, van der Valk M, Berns A . Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet. 2001; 29(4):418-25. DOI: 10.1038/ng747. View

18.

Zhang J, Wu G, Miller C, Tatevossian R, Dalton J, Tang B . Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet. 2013; 45(6):602-12. PMC: 3727232. DOI: 10.1038/ng.2611. View

19.

Bax D, Mackay A, Little S, Carvalho D, Viana-Pereira M, Tamber N . A distinct spectrum of copy number aberrations in pediatric high-grade gliomas. Clin Cancer Res. 2010; 16(13):3368-77. PMC: 2896553. DOI: 10.1158/1078-0432.CCR-10-0438. View

20.

Piccirillo S, Reynolds B, Zanetti N, Lamorte G, Binda E, Broggi G . Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 2006; 444(7120):761-5. DOI: 10.1038/nature05349. View