TY - JOUR
T1 - Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas
AU - Bayliss, Jill
AU - Mukherjee, Piali
AU - Lu, Chao
AU - Jain, Siddhant U.
AU - Chung, Chan
AU - Martinez, Daniel
AU - Sabari, Benjamin
AU - Margol, Ashley S.
AU - Panwalkar, Pooja
AU - Parolia, Abhijit
AU - Pekmezci, Melike
AU - McEachin, Richard C.
AU - Cieslik, Marcin
AU - Tamrazi, Benita
AU - Garcia, Benjamin A.
AU - La Rocca, Gaspare
AU - Santi, Mariarita
AU - Lewis, Peter W.
AU - Hawkins, Cynthia
AU - Melnick, Ari
AU - Allis, C. David
AU - Thompson, Craig B.
AU - Chinnaiyan, Arul M.
AU - Judkins, Alexander R.
AU - Venneti, Sriram
N1 - Funding Information:
We thank D. Yarilin, J. Zhang, A. Viale, N. Socci [Memorial Sloan Kettering Cancer Center (MSKCC)], C. Edwards, C. Paran (University of Michigan), A. Alonso (Weill Medical College of Cornell University), and K. Miller (CHLA) for experimental and data analysis help. We thank A. Heguy and I. Dolgalev (New York University) and the New York Genome Center for help with sequencing studies. We thank T. Lindsten and D. Pozega for critical reading of the manuscript.This work was supported by grants from the National Cancer Institute (K08 CA181475 to S.V.), Matthew Larson Foundation (to S.V.), Sidney Kimmel Foundation (to S.V.), Doris Duke Foundation (to S.V.), and RO1GM110174 and P01CA196539 (to B.A.G.). R.C.M. is supported by the University of Michigan Bioinformatics Core. C.L. is the Kandarian Family Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-2195-14). C.B.T. is supported by the Cancer Center Support Grant (MSKCC) (NIH P30 CA008748). J.B., P.M., C.L., S.U.J., C.C., G.L.R., D.M., A.P., and S.V. performed experiments and analyzed data; A.S.M., M.P., and M.S. provided clinical data; C.C. and J.B. captured images in a blinded manner; R.C.M., P.M., B.S., P.P., and M.C. performed bioinformatics; B.A.G. performed histone mass spectrometry; B.T. analyzed MRI scans in a blinded manner; S.V., A.R.J., M.S., C.H., and M.P. are neuropathologists who provided and assessed tumor samples; P.W.L., A.M., C.D.A., C.B.T., A.M.C., A.R.J., and S.V. provided critical insights; J.B., C.L., A.R.J., and S.V. wrote and edited the paper; all authors provided edits and comments. Competing interests: C.B.T. is cofounder of Agios Pharmaceuticals and has financial interest in Agios. C.B.T. is also on the board of directors of Merck and CRL. The other authors declare that they have no competing interests.The data for this study have been deposited in the National Center for Biotechnology Information database as GSE87779 and GSE89452.
Publisher Copyright:
© The Authors, some rights reserved;.
PY - 2016/11/23
Y1 - 2016/11/23
N2 - Childhood posterior fossa (PF) ependymomas cause substantial morbidity and mortality. These tumors lack recurrent genetic mutations, but a subset of these ependymomas exhibits CpG island (CpGi) hypermethylation [PF group A (PFA)], implicating epigenetic alterations in their pathogenesis. Further, histological grade does not reliably predict prognosis, highlighting the importance of developing more robust prognostic markers. We discovered global H3K27me3 reduction in a subset of these tumors (PF-ve ependymomas) analogous to H3K27M mutant gliomas. PF-ve tumors exhibited many clinical and biological similarities with PFA ependymomas. Genomic H3K27me3 distribution showed an inverse relationship with CpGi methylation, suggesting that CpGi hypermethylation drives low H3K27me3 in PF-ve ependymomas. Despite CpGi hypermethylation and global H3K27me3 reduction, these tumors showed DNA hypomethylation in the rest of the genome and exhibited increased H3K27me3 genomic enrichment at limited genomic loci similar to H3K27M mutant gliomas. Combined integrative analysis of PF-ve ependymomas with H3K27M gliomas uncovered common epigenetic deregulation of select factors that control radial glial biology, and PF radial glia in early human development exhibited reduced H3K27me3. Finally, H3K27me3 immunostaining served as a biomarker of poor prognosis and delineated radiologically invasive tumors, suggesting that reduced H3K27me3 may be a prognostic indicator in PF ependymomas.
AB - Childhood posterior fossa (PF) ependymomas cause substantial morbidity and mortality. These tumors lack recurrent genetic mutations, but a subset of these ependymomas exhibits CpG island (CpGi) hypermethylation [PF group A (PFA)], implicating epigenetic alterations in their pathogenesis. Further, histological grade does not reliably predict prognosis, highlighting the importance of developing more robust prognostic markers. We discovered global H3K27me3 reduction in a subset of these tumors (PF-ve ependymomas) analogous to H3K27M mutant gliomas. PF-ve tumors exhibited many clinical and biological similarities with PFA ependymomas. Genomic H3K27me3 distribution showed an inverse relationship with CpGi methylation, suggesting that CpGi hypermethylation drives low H3K27me3 in PF-ve ependymomas. Despite CpGi hypermethylation and global H3K27me3 reduction, these tumors showed DNA hypomethylation in the rest of the genome and exhibited increased H3K27me3 genomic enrichment at limited genomic loci similar to H3K27M mutant gliomas. Combined integrative analysis of PF-ve ependymomas with H3K27M gliomas uncovered common epigenetic deregulation of select factors that control radial glial biology, and PF radial glia in early human development exhibited reduced H3K27me3. Finally, H3K27me3 immunostaining served as a biomarker of poor prognosis and delineated radiologically invasive tumors, suggesting that reduced H3K27me3 may be a prognostic indicator in PF ependymomas.
UR - http://www.scopus.com/inward/record.url?scp=84997794993&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aah6904
DO - 10.1126/scitranslmed.aah6904
M3 - Article
C2 - 27881822
AN - SCOPUS:84997794993
SN - 1946-6234
VL - 8
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 366
M1 - 6904
ER -