TY - JOUR
T1 - Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome
AU - Panwalkar, Pooja
AU - Clark, Jonathan
AU - Ramaswamy, Vijay
AU - Hawes, Debra
AU - Yang, Fusheng
AU - Dunham, Christopher
AU - Yip, Stephen
AU - Hukin, Juliette
AU - Sun, Yilun
AU - Schipper, Matthew J.
AU - Chavez, Lukas
AU - Margol, Ashley
AU - Pekmezci, Melike
AU - Chung, Chan
AU - Banda, Adam
AU - Bayliss, Jill M.
AU - Curry, Sarah J.
AU - Santi, Mariarita
AU - Rodriguez, Fausto J.
AU - Snuderl, Matija
AU - Karajannis, Matthias A.
AU - Saratsis, Amanda M.
AU - Horbinski, Craig M.
AU - Carret, Anne Sophie
AU - Wilson, Beverly
AU - Johnston, Donna
AU - Lafay-Cousin, Lucie
AU - Zelcer, Shayna
AU - Eisenstat, David
AU - Silva, Marianna
AU - Scheinemann, Katrin
AU - Jabado, Nada
AU - McNeely, P. Daniel
AU - Kool, Marcel
AU - Pfister, Stefan M.
AU - Taylor, Michael D.
AU - Hawkins, Cynthia
AU - Korshunov, Andrey
AU - Judkins, Alexander R.
AU - Venneti, Sriram
N1 - Funding Information:
Acknowledgements We thank Dr. Paul Mischel for insightful comments. This work was supported by grants from NCI K08 CA181475 (S.V.), Mathew Larson Foundation (SV), Sidney Kimmel Foundation (SV), Doris Duke Foundation (SV); Making Headway Foundation (M.S. and M.A.K.), the Sohn Conference Foundation (M.S. and M.A.K.), the Friedberg Charitable Foundation (M.S. and M.A.K.) and Canadian Children’s Cancer & Blood Disorders-C17 grant (JH). Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number P30CA046592 by the use of the following Cancer Center Shared Resource(s): Biostatistics. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
We thank Dr. Paul Mischel for insightful comments. This work was supported by grants from NCI K08 CA181475 (S.V.), Mathew Larson Foundation (SV), Sidney Kimmel Foundation (SV), Doris Duke Foundation (SV); Making Headway Foundation (M.S. and M.A.K.), the Sohn Conference Foundation (M.S. and M.A.K.), the Friedberg Charitable Foundation (M.S. and M.A.K.) and Canadian Children?s Cancer & Blood Disorders-C17 grant (JH). Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number P30CA046592 by the use of the following Cancer Center Shared Resource(s): Biostatistics. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2017, Springer-Verlag GmbH Germany.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de-escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available. We have previously shown that a subset of poorly prognostic childhood EPN_PF exhibits global reduction in H3K27me3. Therefore, we set out to determine whether a simple immunohistochemical assay for H3K27me3 could be used to segregate EPN_PFA from EPN_PFB tumors. We assembled a cohort of 230 childhood ependymomas and H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner. H3K27me3 staining results were compared with DNA methylation-based subgroup information available in 112 samples [EPN_PFA (n = 72) and EPN_PFB tumors (n = 40)]. H3K27me3 staining was globally reduced in EPN_PFA tumors and immunohistochemistry showed 99% sensitivity and 100% specificity in segregating EPN_PFA from EPN_PFB tumors. Moreover, H3K27me3 immunostaining was sufficient to delineate patients with worse prognosis in two independent, non-overlapping cohorts (n = 133 and n = 97). In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN_PFB tumors to inform prognosis and to enable the design of future clinical trials.
AB - Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de-escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available. We have previously shown that a subset of poorly prognostic childhood EPN_PF exhibits global reduction in H3K27me3. Therefore, we set out to determine whether a simple immunohistochemical assay for H3K27me3 could be used to segregate EPN_PFA from EPN_PFB tumors. We assembled a cohort of 230 childhood ependymomas and H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner. H3K27me3 staining results were compared with DNA methylation-based subgroup information available in 112 samples [EPN_PFA (n = 72) and EPN_PFB tumors (n = 40)]. H3K27me3 staining was globally reduced in EPN_PFA tumors and immunohistochemistry showed 99% sensitivity and 100% specificity in segregating EPN_PFA from EPN_PFB tumors. Moreover, H3K27me3 immunostaining was sufficient to delineate patients with worse prognosis in two independent, non-overlapping cohorts (n = 133 and n = 97). In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN_PFB tumors to inform prognosis and to enable the design of future clinical trials.
KW - Childhood ependymoma
KW - Epigenetics
KW - H3K27me3
KW - Molecular subgrouping
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UR - http://www.scopus.com/inward/citedby.url?scp=85025470938&partnerID=8YFLogxK
U2 - 10.1007/s00401-017-1752-4
DO - 10.1007/s00401-017-1752-4
M3 - Article
C2 - 28733933
AN - SCOPUS:85025470938
SN - 0001-6322
VL - 134
SP - 705
EP - 714
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 5
ER -