Abstracts i42 NEURO-ONCOLOGY • JUNE 2022 EPEN-17. RECURRENT INFRATENTORIAL EPENDYMOMAS IN CHILDREN: A META-ANALYSIS ON MOLECULAR-BASED OUTCOMES Eric Montgomery 1 , Vineeth Thirunavu 1 , Nathan Shlobin 1 , Sandi Lam 1,2 , Michael DeCuypere 1,2 ; 1 Ann and Robert H. Lurie Children's Hospital of Chicago Division of Pediatric Neurosurgery, Chicago, IL, USA. 2 Northwestern University Feinberg School of Medicine Department of Neurological Surgery, Chicago, IL, USA The overall prognosis of infratentorial ependymoma differs based on molecular signature, however the impact of recurrence on prognosis re- mains poorly defned in the pediatric population. PubMed, Scopus, Embase, and Ovid were searched for publications on recurrent infratentorial ependymomas in patients under 25 years of age. Exclusion criteria were case series of less than 5 patients and studies that did not provide individualized patient data. Our search yielded 472 unique articles, of which 17 were in- cluded in the analysis. There was a total of 460 recurrent ependymomas re- ported, with 52.8% WHO grade II tumors and 47.2% grade III. The overall mortality for recurrent infratentorial ependymoma was 49.1% (226/460). The pooled median survival was 32.39 months after recurrence (95% CI: 23.45-41.33). Gross total resection was achieved in 237 (53.1%) patients at initial presentation. Raw mean survival post-recurrence was 32.9 months (SD: 11.2 months) for those who received GTR for their primary tumor versus 23.7 months (SD: 10.8 months) for those who received subtotal resection (STR) (p < 0.001). There was no difference in survival between those that received GTR (49.3 months, 95% CI: 32.3-66.3) versus STR (41.4 months, 95% CI: 11.6-71.2) of their recurrent tumor (p=0.610). In the studies that provided molecular classifcation, there were 169 PFA tu- mors (83.3%) and 34 PFB (16.6%), with 28 that demonstrated 1q gain. PFA-A tumors demonstrated worse post-progression survival (24.7 months, 95% CI: 15.3-34.0) compared to PF-B (48.0 months, 95% CI: 32.8-63.2) (p=0.0073). The average post-recurrence survival for tumors with 1q gain was 5.93 months (SD: 9.15). The overall mortality rate for recurrent infrantentorial ependymomas was found to be 49.8%, with a pooled me- dian survival of 32.39 months. Almost 90% of recurrent infratentorial ependymomas were of the PFA molecular subtype, and those tumors that demonstrated 1q gain had a worse survival than those that did not. EPEN-18. ONCOGENIC 3D GENOME CONFORMATIONS IDENTIFY NOVEL THERAPEUTIC TARGETS IN EPENDYMOMA Konstantin Okonechnikov 1,2 , Aylin Camgöz 1,2 , Donglim Esther Park 3 , Owen Chapman 4 , Jens-Martin Hübner 1 , Anne Jenseit 1,2 , Abhijit Chakraborty 5 , Meghana Pagadala 4 , Rosalind Bump 6 , Sahaana Chandran 6 , Katherina Kraft 7 , Rocio Acuna Hidalgo 8 , Derek Reid 9 , Edwin F. Juarez 4 , James T. Robinson 4 , Kristian W. Pajtler 1,10 , Till Milde 1,10 , Nicole Coufal 11 , Michael Levy 12 , Denise Malicki 13 , Shareef Nahas 14 , Matija Snuderl 15,16 , John Crawford 17 , Robert Wechsler-Reya 18 , Stefan Mundlos 8 , Anthony Schmitt 9 , Hannah Carter 4 , Kulandaimanuvel Antony Michealraj 19 , Sachin A. Kumar 19 , Michael D. Taylor 19 , Jeremy Rich 3 , Jill Mesirov 20 , Stefan P. Pfster 1,10 , Ferhat Ay 5 , Jesse Dixon 6 , Marcel Kool 1,21 , Lukas Chavez 4,20 ; 1 Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany. 2 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. 3 Division of Regenerative Medicine, Department of Medicine, University of California San Diego, La Jolla, USA. 4 Division of Medical Genetics, Department of Medicine, University of California San Diego (UCSD), San Diego, USA. 5 Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, USA. 6 Salk Institute for Biological Studies, La Jolla, USA. 7 Center for Personal Dynamic Regulomes, Stanford University, Stanford, USA. 8 Max Planck Institute for Molecular Genetics, Berlin, Germany. 9 Arima Genomics, Inc., San Diego, USA. 10 Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany. 11 Department of Pediatrics, University of California San Diego, San Diego, USA. 12 Neurosurgery, University of California San Diego – Rady Children's Hospital, San Diego, USA. 13 Pathology, University of California San Diego – Rady Children's Hospital, San Diego, USA. 14 Rady Children's Institute for Genomic Medicine, San Diego, USA. 15 Department of Pathology, NYU Langone Health, NYU Grossman School of Medicine, New York, USA. 16 Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, USA. 17 Department of Neurosciences, University of California San Diego – Rady Children's Hospital, San Diego, USA. 18 Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Research Discovery Institute, La Jolla, USA. 19 Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, University of Toronto, Toronto, Canada. 20 Moores Cancer Center, University of California San Diego (UCSD), La Jolla, USA. 21 Princess Máxima Center for Pediatric Oncology, Utrecth, Netherlands Ependymoma (EPN) is an aggressive pediatric tumor that occurs throughout the central nervous system. The two most aggressive mo- lecular subgroups of EPN are the supratentorial ZFTA-fusion associated group (ST-EPN-ZFTA) and the posterior fossa group A (PF-EPN-A). Although the molecular characteristics underlying the tumorigenesis of these subgroups have been extensively studied, these tumors remain diffcult to treat. Hence, innovative therapeutic approaches are urgently needed. Here, we used genome-wide chromosome conformation cap- ture (Hi-C), complemented with CTCF (insulators) and H3K27ac (ac- tive enhancers) ChIP-seq, as well as gene expression and whole-genome DNA methylation profling in primary and relapsed EPN tumors and cell lines, to identify chromosomal rearrangements and regulatory mech- anisms underlying aberrant expression of genes that are essential for EPN tumorigenesis. By integrating these heterogenous data types, we have observed the formation of new topologically associated domains (‘neo-TADs’) caused by intra- and inter-chromosomal structural variants in both tumors. In addition, we observed 3D chromatin complexes of regulatory elements, and the replacement of CTCF insulators by DNA hyper-methylation in PF-EPN-A tumors. These tumor-specifc 3D genome conformations can be associated with the transcriptional upregulation of nearby genes. Through inhibition experiments we validated that these newly identifed genes, including RCOR2, ITGA6, LAMC1, and ARL4C, are highly essential for the survival of patient-derived EPN cell lines in a disease subgroup-specifc manner. Thus, our study identifes novel poten- tial therapeutic vulnerabilities in EPN and extends our ability to reveal tumor-dependency genes and pathways by oncogenic 3D genome con- formations even in tumors that lack known genetic alterations. EPEN-19. IMPACT OF MOLECULAR CLASSIFICATION ON PROGNOSIS IN CHILDREN AND ADOLESCENTS WITH SPINAL EPENDYMOMA: RESULTS FROM THE HIT-MED DATABASE Lara Engertsberger 1 , Martin Benesch 1 , Martin Mynarek 2,3 , Svenja Tonn 2 , Martina Stickan-Verfürth 4 , Angela Funk 4 , Kristian W. Pajtler 5,6 , Beate Timmermann 7 , Rolf-Dieter Kortmann 8 , Torsten Pietsch 9 , Brigitte Bison 10 , Monika Warmuth-Metz 10 , Stefan Rutkowski 2 , Ulrich Schüller 2,11 ; 1 Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria. 2 Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 3 Mildred Scheel Cancer Career Center HaTriCS 4 , University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 4 Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), West German Cancer Center (WTZ), Essen, Germany. 5 Hopp Children’s Cancer Center Heidelberg (KiTZ), Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 6 Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany. 7 Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), West German Cancer Center (WTZ), German Cancer Consortium (DKTK), Essen, Germany. 8 Department of Radiation Oncology, University of Leipzig, Leipzig, Germany. 9 Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany. 10 Institute of Diagnostic and Interventional Neuroradiology, University Hospital Würzburg, Würzburg, Germany. 11 Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany PURPOSE: Ependymomas of the spinal cord are rare among children, and individual risks of disease progression are diffcult to predict. This study aims at evaluating the prognostic impact of DNA methylation-based classifcation in children with spinal ependymoma. METHODS: Eighty-two patients with spinal ependymoma <22 years registered in the HIT-MED database between 1992 and 2021 were included. Clinical, radiological, and histopathological data were col- lected retrospectively. DNA methylation profles of 46 tumors were classifed ac- cording to the Heidelberg Brain Tumor Classifer. RESULTS: Spinal myxopapillary ependymoma (SP-MPE, n=27) was the most common methylation group fol- lowed by spinal ependymoma (SP-EPN, n=15). Two cases belonged to MYCN- amplifed subgroup, one had no match, and one was re-classifed as anaplastic pilocytic astrocytoma (the latter excluded from fnal analysis). WHO grade I and III ependymomas (according to the WHO 2016 classifcation) classifed predom- inantly as SP-MPE, whereas grade II ependymomas clustered into SP-MPE and SP-EPN. 6/15 patients with SP-EPN (40%) suffered from Neurofbromatosis type 2. Among patients with SP-MPE, 23 underwent gross-total and four a subtotal resection (GTR/STR). Relapses of SP-MPE were more common following STR (5-year progression-free survival (5y-PFS) [STR] 25.0% [95% confdence interval: 0.0-68.4], [GTR] 75.0% [53.4-96.6], p=0.003). In the SP-EPN group, 2/8 pa- tients relapsed after STR (5y-PFS 64.3% [22,3-100]) and 0/7 after GTR (n.s.). WHO I° ependymoma had signifcantly inferior PFS than II° and III° ependymoma (5y-PFS [I°] 39.0% [5.8-62.2], [II°] 82.4% [67.8-97.0], [III°] 50.5% [18.9-82.1], p=0.009). However, PFS did not signifcantly differ between SP-MPE and SP-EPN (5y-PFS 65.9% [44.9-86.9], 76.9% [46.3-100], respectively). CONCLUSION: Spinal ependymomas of WHO grade I go along with relatively poor PFS in our cohort, while DNA methylation profling does not segregate patients into distinct risk groups. Still, larger cohorts and further investigations of methylation class het- erogeneity in pediatric spinal ependymomas are needed to complete the basis for future clinical decision-making. Downloaded from https://academic.oup.com/neuro-oncology/article/24/Supplement_1/i42/6600761 by guest on 13 June 2023