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

• Type of Material: Article
• Authors: Jason Fangusaro, Emory University; Pawel Buczkowicz, University of Toronto; Christine Hoeman, Duke University; Patricia Rakopoulos, Hospital for Sick Children; Sanja Pajovic, Hospital for Sick Children; Louis Letourneau, McGill University; Misko Dzamba, University of Toronto; Andrew Morrison, Hosp Sick Children; Peter Lewis, Rockefeller University; Eric Bouffet, Hospital for Sick Children; Ute Bartels, Hospital for Sick Children; Jennifer Zuccaro, Hospital for Sick Children; Sameer Agnihotri, Hospital for Sick Children; Mark Barszczyk, Hospital for Sick Children; Yevgen Chornenkyy, Hospital for Sick Children; Mathieu Bourgey, McGill University; Guillaume Bourque, McGill University; Alexandre Montpetit, McGill University; Francisco Cordero, Duke University; Pedro Castelo-Branco, Hospital for Sick Children; Joshua Mangere, Hospital for Sick Children; Uri Tabori, Hospital for Sick Children
• Language: English
• Date: 2014-05-01
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Nature America, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/ng.2936
• Title of Journal or Parent Work: Nature Genetics
• ISSN: 1061-4036
• Volume: 46
• Issue: 5
• Start Page: 451
• End Page: 456
• Grant/Funding Information: 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.; 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.
• Keywords: FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; Science & Technology; ID2 EXPRESSION; DIFFERENTIATION; CANCER; Life Sciences & Biomedicine; BRAIN-STEM GLIOMAS; HISTONE H3.3; CELL-PROLIFERATION; GENES; FEATURES; BONE MORPHOGENETIC PROTEIN; Genetics & Heredity
• Research Categories: Biology, Neuroscience; Health Sciences, Oncology

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.