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Author Notes:

Dr. Cynthia Hawkins, MD, PhD, FRCPC, Division of Pathology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Phone: (1) 416-813-5938, Fax: (1) 416-813-5974, cynthia.hawkins@sickkids.ca. Dr. Oren Becher, MD, Departments of Pediatrics and Pathology, Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Phone: (1) 919-681-0172, oren.becher@duke.edu.

See publication for full list of authors.

We would like to thank all of the patients and families for donating tissue for this research.

PB is a recipient of CIHR Doctoral Frederick Banting and Charles Best Canada Graduate Scholarships award.

OB is a Damon Runyon Clinical Investigator, and is supported by Department of Defense and Pediatric Brain Tumor Foundation.

CJ, AM and KT acknowledge NHS funding to the Biomedical Research Centre, and support from the Stavros Niarchos Foundation.

Author contributions: E.B., U.B., P.B., O.B., and C.H. designed the study; P.B., C.H., F.C, P.R., S.P., A.M., J.Z., S.A., S.R., M.B., Y.C., P.C-B., K-C.H and J.M. performed experiments; P.B., C.H., F.C., P.R., L.L., M.D., M.B., G.B., and A.M. collected and analyzed data; O.B., C.H., C.J., K.R.T., A.M., A.E.B., J.N., J.R.F., M.A.K., D.Z., N.K.F., A.D., J.V.H., A.S., J.C., L.L-C., S.D., J.H., C.D., K.S., J.M., S.Z., D.R., J.C., M.M.S., E.B., U.T., and U.B. provided reagents, tissue and mice; P.B., P.R., S.P., M.D., O.B., and C.H. wrote the manuscript; P.L., C.B., C.D.A., M.B, A.H. and U.T. gave technical support and conceptual advice.

All authors approved the manuscript.

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Research Funding:

This work was supported by the Canadian Institutes of Health Research (CIHR, MOP 115004) and was funded in part by a Genome Canada/CIHR grant (co-funding from Genome BC, Genome Quebec, CIHR-ICR (Institute for Cancer Research) and C17, through the Genome Canada/CIHR joint ATID Competition (project title: The Canadian Paediatric Cancer Genome Consortium (CPCGC): Translating next generation sequencing technologies into improved therapies for high-risk childhood cancer.

Sample collection for M.A.K. and D.Z. was supported in part by grant UL1TR000038 from the National Center for Research Resources, National Institute of Health and grant 5P30CA016087-32 from the National Cancer Institute.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • FIBRODYSPLASIA OSSIFICANS PROGRESSIVA
  • BONE MORPHOGENETIC PROTEIN
  • BRAIN-STEM GLIOMAS
  • CELL-PROLIFERATION
  • ID2 EXPRESSION
  • HISTONE H3.3
  • CANCER
  • GENES
  • DIFFERENTIATION
  • FEATURES

Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations

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Journal Title:

Nature Genetics

Volume:

Volume 46, Number 5

Publisher:

, Pages 451-456

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

Copyright information:

© 2014 Nature America, Inc. All rights reserved.

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