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Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas

Nature Genetics volume 45, pages 602–612 (2013)Cite this article

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Abstract

The most common pediatric brain tumors are low-grade gliomas (LGGs). We used whole-genome sequencing to identify multiple new genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24 of 39 (62%) tumors. Intragenic duplications of the portion of FGFR1 encoding the tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes expressing FGFR1 with the duplication involving the TKD into the brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. FGFR1 with the duplication induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs and LGGNTs.

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Figure 1: Clinicopathological characteristics and genetic alterations in tumors from series 1 examined by whole-genome sequencing or RNA-seq.
Figure 2: Genetic alterations in supratentorial LGGs.
Figure 3: Genetic alterations in infratentorial LGGs.
Figure 4: Genetic alterations in LGGNTs.
Figure 5: FGFR1 aberrations in LGGs and LGGNTs.
Figure 6: MYB and MYBL1 aberrations in diffusely infiltrating LGGs.
Figure 7: Activation of MAPK/ERK and PI3K pathways in LGGs and LGGNTs with FGFR1, MYB and BRAF abnormalities.
Figure 8: TKD-duplicated FGFR1 in neonatal astrocytes generates gliomas in vivo.

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Acknowledgements

We thank W. Evans for advice and support and P. Nagahawatte for submitting the genomic data to EBI. We are grateful for support from Anatomic Pathology and the Hartwell Center of Biotechnology and Bioinformatics at St. Jude Children's Research Hospital and from Beckman Coulter Genomics. We acknowledge the St. Jude Children's Research Hospital tissue resource facility, from which tissue samples were obtained in accordance with institutional review board approval for the Pediatric Cancer Genome Project. This work was supported by the St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project and the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital and by a grant from the US National Institutes of Health (NIH; CA096832).

Author information

Authors and Affiliations

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

    Jinghui Zhang, Gang Wu, Matthew Parker, Robert Huether, Xiang Chen, Erin Hedlund, Panduka Nagahawatte, Michael Rusch, Jared Becksfort, Yongjin Li, David Zhao & Chunlao Tang

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

    Claudia P Miller, Richard J Gilbertson & Suzanne J Baker

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

    Ruth G Tatevossian, James D Dalton, Bo Tang, Wilda Orisme, Chandanamali Punchihewa, Ryan Lee, Jinjun Cheng, Jing Ma, Guangchun Song, Lei Wei, Sheila Shurtleff, Charles G Mullighan, James R Downing & David W Ellison

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

    Ibrahim Qaddoumi & Amar Gajjar

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

    Fredrick A Boop

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

    Charles Lu, Cyriac Kandoth, Robert S Fulton, Lucinda L Fulton, David J Dooling, Kerri Ochoa, Elaine R Mardis & Richard K Wilson

  7. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA

    Li Ding

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

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

  9. Hartwell Center for Biotechnology & Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Jianmin Wang

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

    Richard Kriwacki

  11. Queen Mary University of London Centre for Neuroscience and Trauma, The Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK

    Denise Sheer

Consortia

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

  • Jinghui Zhang
  • , Gang Wu
  • , Claudia P Miller
  • , Ruth G Tatevossian
  • , James D Dalton
  • , Bo Tang
  • , Wilda Orisme
  • , Chandanamali Punchihewa
  • , Matthew Parker
  • , Ibrahim Qaddoumi
  • , Fredrick A Boop
  • , Charles Lu
  • , Cyriac Kandoth
  • , Li Ding
  • , Ryan Lee
  • , Robert Huether
  • , Xiang Chen
  • , Erin Hedlund
  • , Panduka Nagahawatte
  • , Michael Rusch
  • , Kristy Boggs
  • , Jinjun Cheng
  • , Jared Becksfort
  • , Jing Ma
  • , Guangchun Song
  • , Yongjin Li
  • , Lei Wei
  • , Jianmin Wang
  • , Sheila Shurtleff
  • , John Easton
  • , David Zhao
  • , Robert S Fulton
  • , Lucinda L Fulton
  • , David J Dooling
  • , Bhavin Vadodaria
  • , Heather L Mulder
  • , Chunlao Tang
  • , Kerri Ochoa
  • , Charles G Mullighan
  • , Amar Gajjar
  • , Richard Kriwacki
  • , Denise Sheer
  • , Richard J Gilbertson
  • , Elaine R Mardis
  • , Richard K Wilson
  • , James R Downing
  • , Suzanne J Baker
  •  & David W Ellison

Contributions

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

Corresponding author

Correspondence to David W Ellison.

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the St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 45, 602–612 (2013). https://doi.org/10.1038/ng.2611

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