Ependymoma relapse goes along with a relatively stable epigenome, but a severely altered tumor morphology

Abstract

The molecular biology of ependymomas is not well understood and this is particularly true for ependymoma relapses. We aimed at finding out if and to which extent, relapses differ from their corresponding primary tumors on the morphological, chromosomal and epigenetic level. We investigated 24 matched ependymoma primary and relapsed tumor samples and, as a first step, compared cell density, necrosis, vessel proliferation, Ki67 proliferative index, trimethylation at H3K27 and expression of CXorf67. For the investigation of global methylation profiles, we used public data in order to analyze copy number variation profiles, differential methylation, methylation status and fractions of hypo‐ and hypermethylated CpGs in different epigenomic substructures. Morphologically, we found a significant increase with relapse in cell density and proliferation. H3K27 trimethylation and CXorf67 expression remained stable between primary and relapse tumor samples, and the analysis of DNA methylation profiles neither revealed significant differences in copy number variations nor differentially methylated regions. Significant differences in the methylation status were found for CpG islands, but also in N Shelves or S Shelves, depending on the molecular subgroup. The fraction of probes changing their methylation in the epigenomic substructures appeared subgroup‐specific. Most changes occur in CpG islands, for which relapsed tumors demonstrate higher methylation values than primary tumors. The morphological differences reflect increased aggressiveness upon ependymoma relapse, but, despite slight changes, this observation does not appear to be sufficiently explained by epigenetic changes.

Recurrent posterior fossa group A (PFA) ependymoma in a young child with constitutional mismatch repair deficiency (CMMRD)

“…The genomic instability and high TMB, in combination with the high tumour genomic MSI, plausibly led to neoantigen expression and the relative abundance of immune infiltrates [ 34 ]. The biopsy at recurrence, though demonstrating higher cell density and proliferation with higher mutation accumulation, still retained the PFA ependymoma subgroup affiliation on methylation, as previously reported in other relapsed ependymoma tumours [ 35 , 36 , 37 ]. This higher TMB at recurrence, in combination with a higher proliferative index, suggests that mutation accumulation in CMMRD is a continuous process that can increase with each cell division, and over time [ 38 ].…”

Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology

“…In addition, we integrated data of the subtype SP-EPN-MYCN from Ghasemi et al 2019 (6 cases, EPIC) and Raffeld et al 2020 (9 cases, 450 K) [ 11 , 40 ]. Concerning the pairs of primary and first relapse tumors evaluated, we included patients of the University Hospital Hamburg-Eppendorf, cases from the Capper et al cohort [ 7 ], and two primary relapse pairs (R13 and R14) originally published by Wenger et al in 2022 (GEO accession GSE247880) [ 46 ]. Detailed information on the analysed primary relapse pairs is presented in Suppl.…”

Recurrent pediatric infratentorial ependymomas: a systematic review and meta-analysis on outcomes and molecular classification

“…1). 8,10,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] The basic demographic data including risk bias of each study are highlighted in Table 1. There were 479 patients with recurrent infratentorial ependymoma with a pooled mean age of 5.2 years (range 3.5-12.3 years; Table 1).…”