Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.
Bibliographical noteFunding Information:
The authors would like to express their sincere gratitude toward all staff at the McGill University and Génome Québec Innovation Centre for excellent technical expertise, library preparation and sequencing. The authors are very grateful to J.-J. Lebrun (McGill University) for primer sequences and materials for SMAD signaling studies. This work was performed within the context of the I-CHANGE (International Childhood Astrocytoma Integrated Genomics and Epigenomics) Consortium and was supported by funding from Genome Canada, Génome Québec, the Institute for Cancer Research of the Canadian Institutes for Health Research (CIHR), McGill University and the Montreal Children’s Hospital Foundation. This work was also supported by Hungarian Scientific Research Fund (OTKA) contract T-04639, National Research and Development Fund (NKFP) contract 1A/002/2004 (P.H. and M.G.) and TÁMOP-4.2.2A-11/1/KONV-2012-0025 (A.K. and L.B.). N.J. is a member of the Penny Cole laboratory and the recipient of a Chercheur Clinicien Senior Award. J. Majewski holds a Canada Research Chair (tier 2). L.G., K.L.L. and M.W.K. are supported by NCI P01CA142536. We acknowledge the support of the Zach Carson DIPG Fund at the Dana-Farber Cancer Institute (DFCI), the Ellie Kavalieros Fund (DFCI), the Mikey Czech Foundation, the Prayer From Maria Foundation, the Hope for Caroline Fund (DFCI), the Ryan Harvey DIPG Fund (DFCI), the Stop&Shop Pediatric Brain Tumor Program (DFCI) and the Pediatric Brain Tumor Clinical and Research Fund (DFCI). A.M.F. is supported by a studentship from CIHR, as well as by an award from the CIHR Systems Biology Training Program at McGill University. D.B. is supported by a studentship from the T.D. Trust/Montreal Children’s Hospital Foundation, and N. Gerges is supported by a studentship from the Cedars Cancer Institute. N.D.J. is supported by an award from the McGill Integrated Cancer Research Training Program.