TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma

Abstract

Subependymomas are benign tumors characteristically encountered in the posterior fossa of adults that show distinct epigenetic profiles assigned to the molecular group “subependymoma, posterior fossa” (PFSE) of the recently established DNA methylation-based classification of central nervous system tumors. In contrast, most posterior fossa ependymomas exhibit a more aggressive biological behavior and are allocated to the molecular subgroups PFA or PFB. A subset of ependymomas shows epigenetic similarities with subependymomas, but the precise biology of these tumors and their potential relationships remain unknown. We therefore set out to characterize epigenetic traits, mutational profiles, and clinical outcomes of 50 posterior fossa ependymal tumors of the PFSE group. On histo-morphology, these tumors comprised 12 ependymomas, 14 subependymomas and 24 tumors with mixed ependymoma–subependymoma morphology. Mixed ependymoma–subependymoma tumors varied in their extent of ependymoma differentiation (2–95%) but consistently exhibited global epigenetic profiles of the PFSE group. Selective methylome analysis of microdissected tumor components revealed CpG signatures in mixed tumors that coalesce with their pure counterparts. Loss of chr6 (20/50 cases), as well as TERT mutations (21/50 cases), were frequent events enriched in tumors with pure ependymoma morphology (p < 0.001) and confined to areas with ependymoma differentiation in mixed tumors. Clinically, pure ependymoma phenotype, chr6 loss, and TERT mutations were associated with shorter progression-free survival (each p < 0.001). In conclusion, our results suggest that subependymomas may acquire genetic and epigenetic changes throughout tumor evolution giving rise to subclones with ependymoma morphology (resulting in mixed tumors) that eventually overpopulate the subependymoma component (pure PFSE ependymomas).

Updates in the classification of ependymal neoplasms: The 2021 WHO Classification and beyond

“…However, SE located in the posterior fossa seem to behave slightly more aggressive with a 5‐year PFS of only 83% compared to 100% in supratentorial and spinal SE [3]. In this context, a subgroup of subependymoma in the posterior fossa harboring TERT promoter mutations and/or loss of chromosome 6 were identified as biologically more aggressive with a significantly shorter progression‐free survival [38]. Therefore, even though not intended in the current WHO classification, localization and molecular characteristics may be important to consider.…”

An Insight into Pathophysiological Features and Therapeutic Advances on Ependymoma

“…In addition, the partial loss of chromosome 6 was frequently observed in SP-SE and PF-SE. In particular, TERT-promoter mutations/loss of chromosome 6 were frequently found in PF-SE tumors, and these phenotypes have been suggested as useful markers for the use of intended therapy with respect to an increased risk of recurrence [53]. The WHO group II ependymoma or III anaplastic ependymoma has multiple cases that are often difficult to distinguish [54].…”

Molecular Stratification of Childhood Ependymomas as a Basis for Personalized Diagnostics and Treatment

“…Retrospective evaluation of outcomes for the patients receiving treatment under HIT-2000 protocol implicated residual tumors, 1q gains, and high mitotic activity of tumor cells (>10 mitotic figures per 10 fields of view) as independent adverse predictors for PF-EPNs in general and PF-EPN-A tumors in particular [ 2 ]. Cytogenetic prognostic factors for PF-EPNs include 1q gains and 6q losses [ 43 , 44 ]. These cytogenetic abnormalities are detected in 18.9% and 8.6% of PF-EPNs, respectively.…”

“…Recent findings suggest that the process of clonal evolution in subependymomas may give rise to more aggressive tumor clones enriched with pure EPN phenotypes, chromosome 6 losses, and TERT mutations. These markers, associated with increased risks of recurrence, should be considered as an indication for more intensive therapies, especially under conditions of subtotal tumor resection [ 44 ].…”