Abstract 2491: Molecular and clinical characterization of the new WHO entity ‘Astroblastoma, MN1 altered’ and its molecular subgroups
Authors: Schmitt-Hoffner Felix , Gojo Johannes , Mauermann Monika , von Hoff Katja , Sill Martin , Korshunov Andrey , Stichel Damian , Sahm Felix , Jäger Natalie , Pfister Stefan , Kool Marcel 
Published: June 2022

Abstract
Using DNA methylation profiling, already in 2016 we had identified novel molecularly defined CNS tumor entities, including CNS high grade neuroepithelial tumors with MN1 alteration (HGNET-MN1), which have in the recently updated WHO classification of CNS tumors been renamed into Astroblastoma, MN1 altered. However, little is still known about the molecular and clinical characteristics of these tumors. To further molecularly and clinically characterize this unique entity, we collected patient material, clinical information and molecular data from 176 Astroblastoma, MN1 altered tumors, which were all identified based on their characteristic DNA methylation pattern. T-SNE clustering analyses of the DNA methylation data together with our large database of almost 100,000 reference cases showed that this entity forms one main cluster defined by interchromosomal gene fusions of mainly MN1 and BEND2 and a smaller, distinct, but adjacent cluster that mainly showed tumors with MN1:CXXC5 fusions. Comparing molecular data of the BEND2- and CXXC5-fused groups we found that chromosomal copy numbers show distinct patterns, such as 16q loss in one third of cases from the BEND2-fused group, and a gain of chromosome 5 in one third of CXXC5-fused cases. Patients of the BEND2-fused group showed a strong enrichment of female patients (85%), whereas the CXXC5-fused group showed the contrary trend and consisted of 75% male patients. Original histological diagnoses of 110 BEND2-fused cases revealed that most tumors were diagnosed as an Astroblastoma (39%), followed by Ependymoma (20%) and PNET histologies (15%), which is in line with previous findings on Astroblasotma, MN1 altered cases. The CXXC5-fused subset, however, showed a distinct histological distribution and only 1 out of 13 cases (8%) had an Astroblastoma histology in the original report, whereas the other cases were diagnosed as PNET (38%), Ependymoma (23%), HGG (23%), or unknown (8%). Investigations of clinical data revealed that BEND2-fused cases (n=65) show a 5/10 year OS of 97% and 89% and a 5/10 year PFS of 48% and 35%, respectively, which is in line with previous studies in smaller series indicating a favorable overall but unfavorable progression-free survival. The smaller subset of CXXC5-fused patients (n=8) indicated a 5/10 year OS of 83% and a 5/10 year PFS of 60% each. First analyses of BEND2-fused cases indicate that an Astroblastoma histology might be associated with a favorable OS, however further analyses, including a central pathology review, are needed to validate this observation.
Citation Format: Felix Schmitt-Hoffner, Johannes Gojo, Monika Mauermann, Katja von Hoff, Martin Sill, Andrey Korshunov, Damian Stichel, Felix Sahm, Natalie Jäger, Stefan Pfister, Marcel Kool. Molecular and clinical characterization of the new WHO entity ‘Astroblastoma, MN1 altered’ and its molecular subgroups [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2491.