Journal Article

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

Zelcer, Shayna, Hukin, Juliette, Chornenkyy, Yevgen, Castelo-Branco, Pedro, Ramsay, David, Cain, Jason, Bouffet, Eric, Pajovic, Sanja, Morrison, Andrew, Bendel, Anne E, Mangerel, Joshua, Bartels, Ute, Bourque, Guillaume, Hawkins, Cynthia, Smith, Amy, Brudno, Michael, Chan, Jennifer, Dzamba, Misko, Michaud, Jean, Dunn, Sandra, Bourgey, Mathieu, Foreman, Nicholas K, Ryall, Scott, Rakopoulos, Patricia, Mackay, Alan, Huang, Annie, Donson, Andrew, Allis, C David, Karajannis, Matthias A, Lafay-Cousin, Lucy, Becher, Oren, Buczkowicz, Pawel, Montpetit, Alexandre, Zagzag, David, Tabori, Uri, Cordero, Francisco, Lewis, Peter, Jones, Chris, Scheinemann, Katrin, Fangusaro, Jason R, Taylor, Kathryn R, Barszczyk, Mark, Souweidane, Mark M, Zuccaro, Jennifer, Nazarian, Javad, Agnihotri, Sameer, Ho, King Ching, Brennan, Cameron, Hoeman, Christine, Letourneau, Louis, Dunham, Chris, Hegert, Julia V

2014

Overview

Cynthia Hawkins, Oren Becher and colleagues report the identification of recurrent mutations in ACVR1 in 20% of diffuse intrinsic pontine gliomas. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/105 / 13/106 / 13/109 / 13/51 / 14/63 / 38 / 45/23 / 45/61 / 49/88 / 631/337/176 / 692/699/67/1922 / Activin Receptors, Type I - genetics / Activins / Agriculture / Animal Genetics and Genomics / Animals / Biomedical research / Biomedicine / Brain cancer / Brain research / Brain Stem Neoplasms - classification / Brain Stem Neoplasms - genetics / Brain tumors / Cancer / Cancer Research / Cancer therapies / Child / DNA Copy Number Variations / DNA Methylation / Epigenetics / Gene amplification / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic - genetics / Gene Function / Gene mutations / Genetic aspects / Genetic research / Genome, Human - genetics / Genomes / Genomics / Glioma - classification / Glioma - genetics / Gliomas / Health aspects / Histology / Human Genetics / Humans / Identification and classification / Inhibitor of Differentiation Protein 1 - metabolism / Inhibitor of Differentiation Protein 2 - metabolism / Kinases / letter / Medical research / Mutation / Pediatrics / Phosphorylation / Sequence Analysis, DNA / Smad Proteins - metabolism / Tumorigenesis / Tumors / Zebrafish