This is a preview of subscription content, log in via an institution to check access.
Data availability
The raw methylation array data (IDAT format) have been made available for download at the Gene Expression Omnibus (GEO) repository under the accession number GSE196013 (https://www.ncbi.nlm.nih.gov/geo/).
References
Buczkowicz P, Hoeman C, Rakopoulos P, Pajovic S, Letourneau L, Dzamba M et al (2014) Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet 46:451–456. https://doi.org/10.1038/ng.2936
Carvalho DM, Richardson PJ, Olaciregui N, Stankunaite R, Lavarino C, Molinari V et al (2022) Repurposing vandetanib plus everolimus for the treatment of ACVR1-mutant diffuse intrinsic pontine glioma. Cancer Discov 12:416–431. https://doi.org/10.1158/2159-8290.CD-20-1201
Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J, Nikbakht H, Gerges N, Fiset PO et al (2014) Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet 46:462–466. https://doi.org/10.1038/ng.2950
Gessi M, Capper D, Sahm F, Huang K, von Deimling A, Tippelt S et al (2016) Evidence of H3 K27M mutations in posterior fossa ependymomas. Acta Neuropathol 132:635–637. https://doi.org/10.1007/s00401-016-1608-3
Keenan C, Graham RT, Harreld JH, Lucas JT Jr, Finkelstein D, Wheeler D et al (2020) Infratentorial C11orf95-fused gliomas share histologic, immunophenotypic, and molecular characteristics of supratentorial RELA-fused ependymoma. Acta Neuropathol 140:963–965. https://doi.org/10.1007/s00401-020-02238-3
Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D et al (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol 23:1231–1251. https://doi.org/10.1093/neuonc/noab106
Mack SC, Pajtler KW, Chavez L, Okonechnikov K, Bertrand KC, Wang X et al (2018) Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature 553:101–105. https://doi.org/10.1038/nature25169
Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stutz AM et al (2014) Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506:445–450. https://doi.org/10.1038/nature13108
Pajtler KW, Wen J, Sill M, Lin T, Orisme W, Tang B et al (2018) Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol 136:211–226. https://doi.org/10.1007/s00401-018-1877-0
Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F et al (2015) Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27:728–743. https://doi.org/10.1016/j.ccell.2015.04.002
Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH et al (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38:525–527. https://doi.org/10.1038/ng1783
Taylor KR, Mackay A, Truffaux N, Butterfield Y, Morozova O, Philippe C et al (2014) Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet 46:457–461. https://doi.org/10.1038/ng.2925
Thomas C, Thierfelder F, Trager M, Soschinski P, Muther M, Edelmann D et al (2021) TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma. Acta Neuropathol 141:959–970. https://doi.org/10.1007/s00401-021-02300-8
Wu G, Diaz AK, Paugh BS, Rankin SL, Ju B, Li Y et al (2014) The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46:444–450. https://doi.org/10.1038/ng.2938
Acknowledgements
The authors gratefully acknowledge all patients and their families. This work utilized the computational resources of the NIH HPC Biowulf cluster (https://hpc.nih.gov/systems/). D.A.S. is supported by the Yuvaan Tiwari Foundation, Morgan Adams Foundation, Panattoni Family Foundation, UCSF Glioblastoma Precision Medicine Program, and UCSF Brain Tumor SPORE (P50 CA097257).
Author information
Authors and Affiliations
Contributions
All authors provided meaningful contributions to the manuscript. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
None declared.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
401_2022_2435_MOESM2_ESM.pdf
Supplementary file2 Supplemental Figure 1. Copy number profiles derived from DNA methylation data. Sample-specific profiles for PF-ACVR1 showed frequent broad chromosomal gains and losses. Proportion-based plots for other PF ependymoma types are shown on the right. Supplemental Figure 2. Age distribution of PF ependymoma types and statistical differences when compared to PF-ACVR1. ns = p > 0.05, * = p ≤ 0.05, ** = p ≤ 0.01. Supplemental Figure 3. Representative histologic and immunophenotypic (H3K27me3, EZHIP) features of PF-ACVR1 (cases 1-5, 7) and PFA-ACVR1 (cases 8 and 9) included in this series. Supplemental Figure 4. Kaplan-Meier curves of overall survival and progression-free survival stratified by PF ependymoma tumor type (the exact log rank test is a permutation test based on 100,000 random permutations). Pairwise comparison of the other groups vs. PF-ACVR1 did not reveal significant differences in survival distributions; this may be a result of unbalanced sample sizes in pairwise comparisons with PF-ACVR1. (PDF 2455 KB)
Rights and permissions
About this article
Cite this article
Pratt, D., Lucas, CH.G., Selvam, P.P. et al. Recurrent ACVR1 mutations in posterior fossa ependymoma. Acta Neuropathol 144, 373–376 (2022). https://doi.org/10.1007/s00401-022-02435-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-022-02435-2