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Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas

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Abstract

To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), we performed whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). We found that 78% of DIPGs and 22% of non-BS-PGs contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, that caused a p.Lys27Met amino acid substitution in each protein. An additional 14% of non-BS-PGs had somatic mutations in H3F3A causing a p.Gly34Arg alteration.

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Figure 1: Recurrent somatic mutations in H3F3A and HIST1H3B.

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Acknowledgements

We thank X. Zhu and A. Diaz for assistance with PCR reactions, J. Partridge for helpful discussions, the Hartwell Center of Biotechnology and Bioinformatics at St. Jude Children's Research Hospital and Beckman Coulter Genomics. 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 grants from the US National Institutes of Health (NIH) (CA096832), the Sydney Schlobohm Chair of Research from the National Brain Tumor Society, the Cure Starts Now Foundation, the Smile for Sophie Forever Foundation, Tyler's Treehouse Foundation, the Musicians Against Childhood Cancer and the Noyes Brain Tumor Foundation.

Author information

Author notes

  1. Gang Wu, Alberto Broniscer and Troy A McEachron: 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, Robert Huether, Matthew Parker & Jinghui Zhang

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

    Alberto Broniscer & Amar Gajjar

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

    Troy A McEachron, Barbara S Paugh, Junyuan Zhang, Michael A Dyer, Richard J Gilbertson & Suzanne J Baker

  4. The Genome Institute, Washington University School of Medicine, Saint Louis, Missouri, USA

    Charles Lu, Li Ding, Elaine R Mardis & Richard K Wilson

  5. Hartwell Center of Biotechnology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Jared Becksfort & Chunxu Qu

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

    Charles G Mullighan, James R Downing & David W Ellison

Consortia

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

  • Gang Wu
  • , Alberto Broniscer
  • , Troy A McEachron
  • , Charles Lu
  • , Barbara S Paugh
  • , Jared Becksfort
  • , Chunxu Qu
  • , Li Ding
  • , Robert Huether
  • , Matthew Parker
  • , Junyuan Zhang
  • , Amar Gajjar
  • , Michael A Dyer
  • , Charles G Mullighan
  • , Richard J Gilbertson
  • , Elaine R Mardis
  • , Richard K Wilson
  • , James R Downing
  • , David W Ellison
  • , Jinghui Zhang
  •  & Suzanne J Baker

Contributions

S.J.B., T.A.M., B.S.P., C.Q., J.R.D., E.R.M. and R.K.W. designed the experiments. A.B. and A.G. provided samples and clinical data. D.W.E. performed histopathological analyses. D.W.E., M.A.D., C.G.M., R.J.G. and J.R.D. provided data from other tumor types. G.W. and C.L. analyzed the whole-genome sequence data. T.A.M., B.S.P. and Junyuan Zhang performed validation experiments. J.B. analyzed the Sanger sequencing data for the validation cohort. R.H. performed structural modeling for the mutations. L.D. and Jinghui Zhang supervised the data analysis. G.W., M.P., Jinghui Zhang and S.J.B. prepared the tables and figures. J.R.D., Jinghui Zhang and S.J.B. wrote the manuscript.

Corresponding authors

Correspondence to Richard K Wilson, James R Downing, Jinghui Zhang or Suzanne J Baker.

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Competing interests

The author declare no competing financial interests.

Additional information

A full list of consortium members is provided in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Methods, Supplementary Tables 1–3 and Supplementary Figure 1 (PDF 496 kb)

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St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44, 251–253 (2012). https://doi.org/10.1038/ng.1102

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  • DOI: https://doi.org/10.1038/ng.1102

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