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

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

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298 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)451 - 456
Number of pages6
JournalNature Genetics
Volume46
Issue number5
DOIs
Publication statusPublished - 2014

Cite this

Buczkowicz, P., Hoeman, C., Rakopoulos, P., Pajovic, S., Letourneau, L., Dzamba, M., Morrison, A., Lewis, P. W., Bouffet, E., Bartels, U., Zuccaro, J., Agnihotri, S., Ryall, S., Barszczyk, M., Chornenkyy, Y., Bourgey, M., Bourque, G., Montpetit, A., Cordero, F., ... Hawkins, C. (2014). Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nature Genetics, 46(5), 451 - 456. https://doi.org/10.1038/ng.2936