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The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma

Nature Genetics volume 46, pages 444–450 (2014)Cite this article

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Abstract

Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 years after diagnosis1. 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-HGGs2,3,4,5. 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.

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Figure 1: Recurrent genetic alterations in pediatric HGG.
Figure 2: ACVR1 mutations in DIPG activate BMP signaling.
Figure 3: Structural variants generate oncogenic chimeric NTRK fusion proteins.
Figure 4: Pediatric HGG alterations in histone modifiers or chromatin regulators.
Figure 5: Circos plots showing the range of structural alterations in pediatric HGG.

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Acknowledgements

We thank the St. Jude Children's Research Hospital Tissue Resource Facility and B. Gordon, M. Johnson, S. Brown and C. Calabrese in the St. Jude Small Animal Imaging Core for expert assistance with intracranial implantations. We thank E. Shore and A. Culbert (University of Pennsylvania) for helpful advice with antibody selection. This work was supported by the St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project, by the American Lebanese and Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital, by grants from the US National Institutes of Health (P01 CA096832 to S.J.B., Jinghui Zhang and D.W.E. and R01 CA135554 to S.J.B.), by the Cure Starts Now Foundation and the Smile for Sophie Forever Foundation, and by Tyler's Treehouse and Musicians Against Childhood Cancer.

Author information

Author notes

  1. Gang Wu and Alexander K Diaz: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Gang Wu, Yongjin Li, Chunxu Qu, Xiang Chen, Michael Edmonson, Xiaotu Ma, Panduka Nagahawatte, Erin Hedlund, Michael Rusch, Robert Huether, Matthew Parker, Pankaj Gupta, Jared Becksfort & Jinghui Zhang

  2. Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Alexander K Diaz, Barbara S Paugh, Sherri L Rankin, Xiaoyan Zhu, Junyuan Zhang, Jake C Russell & Suzanne J Baker

  3. Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, Tennessee, USA

    Alexander K Diaz & Suzanne J Baker

  4. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Bensheng Ju & Michael R Taylor

  5. Pediatric Cancer Genome Project, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    John Easton, Heather L Mulder, Kristy Boggs, Bhavin Vadodaria & Donald Yergeau

  6. The Genome Institute, Washington University, St. Louis, Missouri, USA

    Charles Lu, Kerri Ochoa, Robert S Fulton, Lucinda L Fulton, Li Ding, Elaine R Mardis & Richard K Wilson

  7. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Stanley Pounds, Tong Lin & Arzu Onar-Thomas

  8. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Richard Kriwacki

  9. Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York, USA

    Lei Wei

  10. Division of Molecular Pathology, Institute for Cancer Research, London, UK

    Chris Jones

  11. Divison of Cancer Therapeutics, Institute for Cancer Research, London, UK

    Chris Jones

  12. Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Frederick A Boop

  13. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Alberto Broniscer, Cynthia Wetmore & Amar Gajjar

  14. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    James R Downing & David W Ellison

Consortia

the St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project

  • 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

Contributions

S.J.B., Jinghui Zhang, A.K.D., B.S.P., J.E., L.D., E.R.M., R.K.W., M.R.T., J.R.D. and D.W.E. designed experiments or supervised research. A.G., A.B., C.W., F.A.B. and C.J. provided samples or clinical data. G.W., A.K.D., B.S.P., S.L.R., B.J., Y.L., X.Z., C.Q., X.C., Junyuan Zhang, J.E., M.E., X.M., C.L., P.N., E.H., M.R., S.P., T.L., A.O.-T., R.H., R.K., M.P., P.G., J.B., L.W., H.L.M., K.B., B.V., D.Y., J.C.R., K.O., R.S.F., L.L.F., L.D., E.R.M., R.K.W., M.R.T., J.R.D., D.W.E., Jinghui Zhang and S.J.B. performed experiments, analyzed data or prepared tables and figures. D.W.E. completed all pathological evaluations. S.J.B., Jinghui Zhang, G.W. and A.K.D. wrote the manuscript with contributions from D.W.E., J.R.D. and M.R.T.

Corresponding authors

Correspondence to Jinghui Zhang or Suzanne J Baker.

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the St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46, 444–450 (2014). https://doi.org/10.1038/ng.2938

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