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

Pooja Panwalkar, Jonathan Clark, Vijay Ramaswamy, Debra Hawes, Fusheng Yang, Christopher Dunham, Stephen Yip, Juliette Hukin, Yilun Sun, Matthew J. Schipper, Lukas Chavez, Ashley Margol, Melike Pekmezci, Chan Chung, Adam Banda, Jill M. Bayliss, Sarah J. Curry, Mariarita Santi, Fausto J. Rodriguez, Matija SnuderlMatthias A. Karajannis, Amanda M. Saratsis, Craig M. Horbinski, Anne Sophie Carret, Beverly Wilson, Donna Johnston, Lucie Lafay-Cousin, Shayna Zelcer, David Eisenstat, Marianna Silva, Katrin Scheinemann, Nada Jabado, P. Daniel McNeely, Marcel Kool, Stefan M. Pfister, Michael D. Taylor, Cynthia Hawkins, Andrey Korshunov, Alexander R. Judkins, Sriram Venneti*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)705-714
Number of pages10
JournalActa Neuropathologica
Volume134
Issue number5
DOIs
StatePublished - Nov 1 2017

Keywords

  • Childhood ependymoma
  • Epigenetics
  • H3K27me3
  • Molecular subgrouping

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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