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


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.

DOI: 10.1038/ng.2936

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@inproceedings{Buczkowicz2014GenomicAO, title={Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations}, author={Pawel Buczkowicz and Christine Hoeman and Patricia Rakopoulos and Sanja Pajovic and Louis Letourneau and Misko Dzamba and Andrew Morrison and Peter Lewis and Eric Bouffet and Ute Bartels and Jennifer Zuccaro and Sameer Agnihotri and Scott Ryall and Mark Barszczyk and Yevgen Chornenkyy and Mathieu Bourgey and Guillaume Bourque and Alexandre Montpetit and Francisco Cordero and Pedro Castelo-Branco and Joshua Mangerel and Uri Tabori and King Ching Ho and Annie Huang and Kathryn R. Taylor and Alan Mackay and Anne E Bendel and Javad Nazarian and Jason R Fangusaro and Matthias A. Karajannis and David Zagzag and Nicholas K. Foreman and Andrew Donson and Julia V. Hegert and Amy Smith and Jennifer Chan and Lucy Lafay-Cousin and Sandra Dunn and Juliette Hukin and Chris Dunham and Katrin Scheinemann and Jean Michaud and Shayna Zelcer and David Ramsay and Jason Cain and Cameron Brennan and Mark M. Souweidane and Chris Jones and C. David Allis and Michael Brudno and Oren Becher and Cynthia Hawkins}, booktitle={Nature genetics}, year={2014} }