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Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome.


ABSTRACT: 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.

SUBMITTER: Panwalkar P 

PROVIDER: S-EPMC5647236 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome.

Panwalkar Pooja P   Clark Jonathan J   Ramaswamy Vijay V   Hawes Debra D   Yang Fusheng F   Dunham Christopher C   Yip Stephen S   Hukin Juliette J   Sun Yilun Y   Schipper Matthew J MJ   Chavez Lukas L   Margol Ashley A   Pekmezci Melike M   Chung Chan C   Banda Adam A   Bayliss Jill M JM   Curry Sarah J SJ   Santi Mariarita M   Rodriguez Fausto J FJ   Snuderl Matija M   Karajannis Matthias A MA   Saratsis Amanda M AM   Horbinski Craig M CM   Carret Anne-Sophie AS   Wilson Beverly B   Johnston Donna D   Lafay-Cousin Lucie L   Zelcer Shayna S   Eisenstat David D   Silva Marianna M   Scheinemann Katrin K   Jabado Nada N   McNeely P Daniel PD   Kool Marcel M   Pfister Stefan M SM   Taylor Michael D MD   Hawkins Cynthia C   Korshunov Andrey A   Judkins Alexander R AR   Venneti Sriram S  

Acta neuropathologica 20170721 5


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  ...[more]

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