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Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma

Nature Genetics volume 46, pages 462–466 (2014)Cite this article

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Abstract

Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.

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Figure 1: Genomic landscape of pediatric midline HGAs.
Figure 2: Increased levels of phosphorylated SMAD1/5/8 in ACVR1-mutant mHGAs.
Figure 4: Mutations identified in ACVR1 are associated with activation of downstream SMAD signaling pathways.
Figure 3: Clustering analysis of global DNA methylation profiles for 98 high-grade astrocytomas.

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Acknowledgements

The authors would like to express their sincere gratitude toward all staff at the McGill University and Génome Québec Innovation Centre for excellent technical expertise, library preparation and sequencing. The authors are very grateful to J.-J. Lebrun (McGill University) for primer sequences and materials for SMAD signaling studies. This work was performed within the context of the I-CHANGE (International Childhood Astrocytoma Integrated Genomics and Epigenomics) Consortium and was supported by funding from Genome Canada, Génome Québec, the Institute for Cancer Research of the Canadian Institutes for Health Research (CIHR), McGill University and the Montreal Children's Hospital Foundation. This work was also supported by Hungarian Scientific Research Fund (OTKA) contract T-04639, National Research and Development Fund (NKFP) contract 1A/002/2004 (P.H. and M.G.) and TÁMOP-4.2.2A-11/1/KONV-2012-0025 (A.K. and L.B.). N.J. is a member of the Penny Cole laboratory and the recipient of a Chercheur Clinicien Senior Award. J. Majewski holds a Canada Research Chair (tier 2). L.G., K.L.L. and M.W.K. are supported by NCI P01CA142536. We acknowledge the support of the Zach Carson DIPG Fund at the Dana-Farber Cancer Institute (DFCI), the Ellie Kavalieros Fund (DFCI), the Mikey Czech Foundation, the Prayer From Maria Foundation, the Hope for Caroline Fund (DFCI), the Ryan Harvey DIPG Fund (DFCI), the Stop&Shop Pediatric Brain Tumor Program (DFCI) and the Pediatric Brain Tumor Clinical and Research Fund (DFCI). A.M.F. is supported by a studentship from CIHR, as well as by an award from the CIHR Systems Biology Training Program at McGill University. D.B. is supported by a studentship from the T.D. Trust/Montreal Children's Hospital Foundation, and N. Gerges is supported by a studentship from the Cedars Cancer Institute. N.D.J. is supported by an award from the McGill Integrated Cancer Research Training Program.

Author information

Author notes

  1. Adam M Fontebasso, Simon Papillon-Cavanagh and Jeremy Schwartzentruber: These authors contributed equally to this work.

  2. Keith L Ligon, Jacek Majewski, Nada Jabado and Mark W Kieran: These authors jointly directed this work.

Authors and Affiliations

  1. Division of Experimental Medicine, Montreal Children′s Hospital, McGill University and McGill University Health Centre, Montreal, Quebec, Canada

    Adam M Fontebasso & Nada Jabado

  2. Department of Human Genetics, McGill University, Montreal, Quebec, Canada

    Simon Papillon-Cavanagh, Hamid Nikbakht, Noha Gerges, Denise Bechet, Damien Faury, Nicolas De Jay, Jacek Majewski & Nada Jabado

  3. Wellcome Trust Sanger Institute, Hinxton, UK

    Jeremy Schwartzentruber

  4. Department of Pathology, Montreal Children′s Hospital, McGill University Health Centre, Montreal, Quebec, Canada

    Pierre-Olivier Fiset & Steffen Albrecht

  5. Department of Pediatrics, McGill University, Montreal, Quebec, Canada

    Damien Faury & Nada Jabado

  6. Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Lori A Ramkissoon, Aoife Corcoran, Azra H Ligon & Keith L Ligon

  7. Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    David T W Jones, Dominik Sturm, Pascal Johann & Stefan M Pfister

  8. Department of Neurological Surgery, Ann & Robert H. Lurie Children′s Hospital of Chicago, Northwestern University, Chicago, Illinois, USA

    Tadanori Tomita & Tord Alden

  9. Department of Pediatrics Hematology-Oncology, Ann & Robert H. Lurie Children′s Hospital of Chicago, Northwestern University, Chicago, Illinois, USA

    Stewart Goldman

  10. Department of Surgery, Clinical Pediatric Neurosurgical Oncology, Boston Children′s Hospital, Boston, Massachusetts, USA

    Mahmoud Nagib

  11. Department of Pediatric Hematology-Oncology, Children′s Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA

    Anne Bendel

  12. Department of Neurosurgery, Boston Children′s Hospital, Boston, Massachusetts, USA

    Liliana Goumnerova

  13. Harvard Medical School, Boston, Massachusetts, USA

    Liliana Goumnerova, Azra H Ligon, Keith L Ligon & Mark W Kieran

  14. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Daniel C Bowers

  15. Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA

    Jeffrey R Leonard

  16. Department of Pediatrics, Hematology-Oncology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA

    Joshua B Rubin

  17. Department of Neurosurgery, Seattle Children′s Hospital, Seattle, Washington, USA

    Samuel Browd

  18. Cancer and Blood Disorders Center, Seattle Children′s Hospital, Seattle, Washington, USA

    J Russell Geyer & Sarah Leary

  19. Department of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA

    George Jallo

  20. Department of Pediatric Hematology-Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA

    Kenneth Cohen

  21. Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA

    Nalin Gupta & Michael D Prados

  22. Department of Hematology-Oncology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada

    Anne-Sophie Carret

  23. Department of Pathology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada

    Benjamin Ellezam

  24. Department of Neurosurgery, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada

    Louis Crevier

  25. Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    Almos Klekner & Laszlo Bognar

  26. 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary

    Peter Hauser & Miklos Garami

  27. Department of Neurosurgery, Children′s National Medical Center, Washington, DC, USA

    John Myseros

  28. Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada

    Zhifeng Dong & Peter M Siegel

  29. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Hayley Malkin & Mark W Kieran

  30. Department of Pathology, Brigham and Women′s Hospital, Boston, Massachusetts, USA

    Azra H Ligon & Keith L Ligon

  31. Department of Pathology, Boston Children′s Hospital, Boston, Massachusetts, USA

    Keith L Ligon

  32. Division of Pediatric Hematology/Oncology, Boston Children′s Hospital, Boston, Massachusetts, USA

    Mark W Kieran

Authors
  1. Adam M Fontebasso
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  2. Simon Papillon-Cavanagh
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Contributions

A.M.F., N. Gerges, P.-O.F., D.B., D.F., L.A.R., A.C., A.H.L., S.A. and Z.D. performed experiments. A.M.F., S.P.-C., J.S., H.N., N.D.J., A.H.L., S.A., Z.D. and P.M.S. analyzed the data and produced figures and tables. D.T.W.J., D.S., P.J., T.T., S.G., M.N., A.B., L.G., D.C.B., J.R.L., J.B.R., T.A., S.B., J.R.G., G.J., K.C., N. Gupta, M.D.P., A.-S.C., B.E., L.C., A.K., L.B., P.H., M.G., J. Myseros, H.M., S.A. and S.M.P. provided tissue samples. K.L.L., J. Majewski, N.J. and M.W.K. provided project leadership and designed the study. All authors contributed to the final manuscript.

Corresponding authors

Correspondence to Keith L Ligon, Jacek Majewski, Nada Jabado or Mark W Kieran.

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Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Patterns of K27M-associated mutations among midline pediatric high-grade astrocytomas.

a, Neuroanatomical distribution of mutations and alterations of interest in pediatric midline high-grade astrocytomas. b, The age of patients harboring H3.3 and H3.1 mutations is significantly different (P = 0.0280; two-tailed t test). c, Mutual exclusivity and associative statistical analyses (represented as P values) of mutations in H3F3A, HIST1H3B/HIST1H3C, TP53, FGFR1, ACVR1, PDGFRA and PI3K pathway genes PIK3CA/PIK3R1/PTEN demonstrates predilection for co-occurrence of and exclusion of particular mutations as unique mutational groups within 39 midline high-grade astrocytomas profiled by whole-exome sequencing. P values were calculated utilizing Fisher's exact test (two-sided) with highlighted values indicating statistically significant (P < 0.05) preferences for co-occurrence or mutual exclusivity.

Supplementary Figure 2 PDGFRA amplification is present in a minority of cells in DIPG.

Representative images from FISH assay for PDGFRA amplification reveal substantial increase in the number of PDFRA-positive nuclei following treatment compared with samples from pretreatment biopsies. Green, PDGFRA; red, Chr4/CEN4.

Supplementary Figure 3 Copy number variant analysis using biopsy material from five different anatomical loci in a single tumor.

a, Tumor biopsies (n = 5) show highly similar CNV patterns across the genome. b, Plots depicting 20-Mb zoom-in of chromosome 4, showing significant PDGFRA, KIT and KDR amplification in only the deep tissue biopsy and not others.

Supplementary Figure 4 H3.1 and H3.3 K27M variants demonstrate similar patterns of global DNA methylation.

Heat map of hierarchical clustering analysis of DNA methylation array data from the top 10,000 most variable β values from 27 K27M-mutant high-grade gliomas demonstrates that H3.3 and H3.1 K27M mutant tumors show similar patterns of global epigenomic dysregulation.

Supplementary Figure 5 Multiscale bootstrapping of the high-grade astrocytoma methylation cluster.

Dendrogram of multiscale bootstrapping of DNA methylation profiles of patient high-grade tumors. P values, represented as the red values at the internal nodes, are the approximately unbiased (AU) P value computed by the R package pvclust.

Supplementary Figure 6 Mutation subgroup-specific overall survival of midline high-grade astrocytomas (mHGAs) and diffuse intrinsic pontine gliomas (DIPGs).

Kaplan-Meier analysis of overall survival (months) of mHGAs with available outcome data, with indicated P values from Mantel-Cox (log-rank) and Gehan-Breslow-Wilcoxon testing for comparison based on a, ACVR1 mutation status (n = 27), b, H3.3/H3.1 K27M mutation status (n = 27) and overall survival restricted to tumors of the pontine area based on c, ACVR1 mutation status (n = 23), d, H3.3/H3.1 K27M mutation status (n = 22).

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Fontebasso, A., Papillon-Cavanagh, S., Schwartzentruber, J. et al. Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet 46, 462–466 (2014). https://doi.org/10.1038/ng.2950

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