EPN-31: MOLECULAR REFINEMENT OF PEDIATRIC POSTERIOR FOSSA EPENDYMOMA

Recently, we identified nine distinct molecular groups of ependymoma across all age groups, three in each major anatomical compartment of the CNS: spinal, posterior fossa, and supratentorial. These nine molecular groups are genetically, epigenetically, transcriptionally, demographically, and clinically distinct. Pediatric intracranial ependymomas were either affiliated with one of two supratentorial groups characterized by RELA or YAP1 fusion genes, or with the PFA group in the hindbrain. Observing distinct outcomes among children with PFA ependymomas, the largest molecular group, we tested the hypothesis that further molecular diversity exists among these tumors. The genome-wide DNA methylation profiles of 432 pediatric PFA ependymomas with a complete set of clinical data were analyzed by unsupervised consensus hierarchical clustering and principal component analysis, which identified three distinct molecular subgroups of PFA ependymoma: 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 subgroup 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 subgroups 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 indicators among PFA tumors. We conclude that further molecular refinement of pediatric PFA ependymomas, with their division into three distinct molecular subtypes, has clinical utility and the potential for enhanced risk assessment or therapeutic stratification.