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

Panwalkar, P.; Clark, J.; Ramaswamy, V.; Hawes, D.; Yang, F.; Dunham, C.; Yip, S.; Hukin, J.; Sun, Y.; Schipper, M. J.; Chavez, L.; Margol, A.; Pekmezci, M.; Chung, C.; Banda, A.; Bayliss, J. M.; Curry, S. J.; Santi, M.; Rodriguez, F. J.; Snuderl, M.; Karajannis, M. A.; Saratsis, A. M.; Horbinski, C. M.; Carret, A. S.; Wilson, B.; Johnston, D.; Lafay-Cousin, L.; Zelcer, S.; Eisenstat, D.; Silva, M.; Scheinemann, K.; Jabado, N.; McNeely, P. D.; Kool, M.; Pfister, S. M.; Taylor, M. D.; Hawkins, C.; Korshunov, A.; Judkins, A. R.; Venneti, S.

Acta Neuropathol. 2017 Jul 25; 134(5):705-714


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.

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