Put away your microscopes: the ependymoma molecular era has begun

Abstract

Purpose of review To synthesize, integrate, and comment on recent research developments to our understanding of the molecular basis of ependymoma, and to place this in context with current treatment and research efforts. Recent findings Our recent understanding of the histologically defined molecular entity ependymoma has rapidly advanced through genomic, transcriptomic, and epigenomic profiling studies. Summary These advancements lay the groundwork for development of future ependymoma biomarkers, models, and therapeutics. Our review discusses these discoveries and their impact on our clinical understanding of this disease. Lastly, we offer insight into clinical and research areas requiring further validation, and open questions remaining in the field.

New therapeutic target for pediatric anaplastic ependymoma control: study of anti-tumor activity by a Kunitz-type molecule, Amblyomin-X

“…Recently, EPNs were classified according to the DNA methylation profile 6 , such classification showed to be increasingly dependent on molecular biology findings 29 . We highlight the WHO revised 2016 classification of CNS tumors 4 , which incorporates, for the first time, genetic information in addition to morphology for the classification of many tumor entities 30,31 .…”

Treatment Decisions of World Health Organization Grade II and III Ependymomas in Molecular Era

“…Supratentorial EPNs are divided into two distinct molecular subgroups: oncogenic mutually exclusive gene fusions involving either RELA or YAP1 [ 25 ]. Although Illumina DNA methylation provides an indirect measure of molecular subgroup associated with a particular fusion, fluorescence in situ hybridization (FISH) can be used to identify and verify samples harboring C11orf95-RELA fusion [ 15 ]. RNA-seq also provides an approach to identify C11orf95-RELA fusion as a discovery method to identify novel or less obvious fusion event.…”

“…Interestingly, it has been reported that the level of resection does not significantly affect the outcome within the STEPN- RELA -positive subgroup in a retrospective analysis for patient samples collected over a long period of time over 20 years [ 25 ]. ST-EPN- YAP1 subgroup is associated with favorable clinical outcome [ 13 , 15 ]. Clinical trials with de-escalating therapy could be recommended for this subgroup.…”

“…RELA fusion found in most supratentorial EPNs results in constitutive activation of NF-κB, a potential therapeutic target [ 27 ]. NF-κB or YAP1 inhibitors might have potential for supratentorial EPNs [ 15 ].…”

Understanding the Deadly Silence of Posterior Fossa A Ependymoma

“…Many PFA ependymoma tumors have unremarkable whole-genome sequencing but exhibit epigenetic dysregulation, including H3K27 hypomethylation, and oncogenic gene expression (Bayliss et al, 2016;Mack et al, 2014;Pajtler et al, 2015). The lack of candidate genetic driver mutations has made modeling PFA ependymomas difficult, which has been compounded by the fact that patient-derived culture models have been particularly difficult to generate (Mack and Taylor, 2017). In a breakthrough study, Michealraj et al (2020) demonstrate that PFA ependymomas are dependent on metabolic changes driven by hypoxia, offering a compelling mechanism in which microenvironmental regulation of epigenetic state is an oncogenic driver in this disease.…”