MPTH-26MOLECULAR REFINEMENT OF PEDIATRIC POSTERIOR FOSSA EPENDYMOMA

Abstract

We have recently identified nine distinct molecular subgroups of ependymoma across all age groups, three in each major anatomical compartment of the CNS: spinal (SP), posterior fossa (PF), and supratentorial (ST). These nine molecular subgroups are genetically, epigenetically, transcriptionally, demographically, and clinically distinct. Pediatric intracranial ependymomas were either affiliated with one of two supratentorial subgroups characterized by RELA (ST-EPN-RELA) or YAP1 (ST-EPN-YAP1) fusion genes, or with the PF-EPN-A subgroup in the hindbrain. Observing distinct outcomes among children with PF-EPN-A tumors, the largest molecular subgroup, we tested the hypothesis that further molecular diversity exists among these tumors. The genome-wide DNA methylation profiles of 575 pediatric PF ependymomas were analyzed by unsupervised consensus hierarchical clustering and principal component analysis, which identified three distinct molecular subtypes of PF-EPN-A tumors: PFA-1, PFA-2, and PFA-3. PFA-1 and PFA-2 showed different chromosomal copy number alterations and comprised tumors almost exclusively from infants, while PFA-3 ependymomas were generally from older children. The PFA-3 subtype was significantly enriched for gain of 1q. Distinct developmental gene expression profiles and radiological characteristics on pre-operative MR imaging suggested separate anatomic origins for the infant subtypes, PFA-1 and PFA-2. Survival analyses identified PFA-3 as having the poorest outcome. Multivariate analysis revealed molecular subgroup, grade of resection and gain of 1q as independent prognostic markers among PF-EPN-A tumors. We conclude that further molecular refinement of pediatric PF-EPN-A tumors, with their division into three distinct molecular subtypes, has clinical utility and the potential for enhanced risk assessment or therapeutic stratification.