Abstract Posterior fossa group A ependymoma (PFA) recur in more than 50% of cases. At recurrence a significant number of cases acquire high-risk chromosomal copy number variants (CNV), specifically gain of chromosome 1q (1q+) and/or loss of 6q (6q-). Analysis of DNA methylation profiles at presentation showed a correlation between open sea hypomethylation and island hypermethylation with acquisition of 1q+ and/or 6q- at recurrence. We hypothesize that hypomethylation of open sea DNA methylation sites results in chromosomal instability in PFA, and subsequent acquisition of 1q+ and/or 6q-. Identification of 1q+/6q- predisposed cases at presentation would provide a tool for stratification into a high-risk arm for upcoming clinical trials. Using a training set of 1q+ and/or 6q- predisposed (n = 24) and non-predisposed (“stable”, n = 29) we developed a DNA methylation-based predictive classifier, predominantly based on the ratio of island to open sea methylation sites, that correctly classified 96% (51/53) of training set cases. The performance of this classifier was tested in an independent multi-institutional dataset of approximately 500 PFA for which DNA methylation from presentation samples and survival data were available. Although this dataset did not contain information regarding the CNV status of recurrences thus preventing our ability to test prediction of high-risk CNV acquisition, we could infer acquisition of a high-risk CNV phenotype by outcome analysis. Multivariate analysis of outcome from presentation showed that samples classed as “predisposed” had a significantly shorter overall survival than those classed as “stable”. This result suggests the PFA high-risk DNA methylation classifier will be of utility in identification of those cases that are predisposed to high-risk CNV acquisition. We hope to definitively test the classifier in correlative studies of both the COG ependymoma clinical trial ACNS0831and the European BIOMECA study (SIOP EPN II trial related) for which recurrence CNV status is pending.
Donson et al. (Fri,) studied this question.