High level MYCN amplification and distinct methylation signature define an aggressive subtype of spinal cord ependymoma

Abstract

We report a novel group of clinically aggressive spinal cord ependymomas characterized by Grade III histology, MYCN amplification, an absence of NF2 alterations or other recurrent pathogenic mutations, and a unique methylation classifier profile. Seven cases were found to have MYCN amplification in the course of routine mutational profiling of 552 patients with central nervous system tumors between December 2016 and July of 2019 and an eighth patient was identified from an unrelated set of cases. Methylation array analysis revealed that none of the 8 cases clustered with any of the nine previously described ependymoma methylation subgroups, and 7 of 8 formed their own tight unique cluster. Histologically all cases showed grade III features, and all demonstrated aggressive clinical behavior. These findings are presented in the context of data from three other studies describing similar cases. Therefore, a combined total of 27 MYCN amplified spinal cord ependymoma cases have now been reported in the literature, warranting their consideration as a distinctive subtype of spinal cord ependymoma (SP-EPN-MYCN) with their unique molecular characteristics and aggressive clinical behavior.

The BET Inhibitor OTX015 Exhibits In Vitro and In Vivo Antitumor Activity in Pediatric Ependymoma Stem Cell Models

“…Here, we provide evidence that BET proteins play a key role in regulating growth and survival in genetically diverse EPN SC models and OTX015-mediated BET inhibition exerts antitumor effects both in vitro and in vivo. Very recently, BRD3 has been identified as a therapeutic actionable marker to target neuronal lineage precursors in PF EPN [ 63 ], whereas MYCN amplification has been found to drive an aggressive form of spinal EPN [ 64 , 65 ], possibly identifying these molecular EPN subgroups as candidates for BETi therapy. However, the identification of other reliable predictive markers of sensitivity to BETi is warranted to improve target-driven therapy and guide effective combination approaches with BETi and other chemotherapeutics in EPN.…”

Pediatric ependymoma: an overview of a complex disease

“…MYCN protein overexpression can be demonstrated by immunohistochemistry [44,59]. Genetically, all cases show high-level MYCN amplification, which remains stable throughout the course of disease [44][45][46]59]. This subtype also shows a distinct methylation profile [44,59].…”

“…A rare and highly aggressive subtype of anaplastic spinal cord ependymoma with MYCN amplification predominantly affecting young adults but older children as well has been identified recently, further supporting the prognostic relevance of biological classification. Their site of predilection is the cervico-thoracic spine [44][45][46]59], and tumors are often large at diagnosis, involving multiple spinal segments and displaying an exophytic growth pattern as well as frequent dissemination [44,46,59]. Histologically, ependymomas with MYCN amplification present with characteristic ependymal features and signs of anaplasia [44,46,59].…”

“…Their site of predilection is the cervico-thoracic spine [44][45][46]59], and tumors are often large at diagnosis, involving multiple spinal segments and displaying an exophytic growth pattern as well as frequent dissemination [44,46,59]. Histologically, ependymomas with MYCN amplification present with characteristic ependymal features and signs of anaplasia [44,46,59]. MYCN protein overexpression can be demonstrated by immunohistochemistry [44,59].…”

“…Histologically, ependymomas with MYCN amplification present with characteristic ependymal features and signs of anaplasia [44,46,59]. MYCN protein overexpression can be demonstrated by immunohistochemistry [44,59]. Genetically, all cases show high-level MYCN amplification, which remains stable throughout the course of disease [44][45][46]59].…”