Abstract B028: Epigenetic landscape and gene regulations in embryonal brain tumors with multilayered rosettes (ETMR)
Authors: Wang Shanzheng , Lambo Sander , Mauermann Monika , Autry Robert J , Jäger Natalie , Pfister Stefan M , Kool Marcel 
Published: February 2025

Abstract
Embryonal Tumors with Multilayered Rosettes (ETMRs) are relatively rare but aggressive embryonal brain tumors that mainly affect children under the age of 4 and which have a poor outcome. Around 90% of ETMRs harbor amplification of the C19MC miRNA cluster, in most cases fused to the TTHY1 gene. The second most recurrent aberration, present in about half of the C19MC negative cases, are bi-allelic mutations in DICER1. ETMRs are also characterized by overall lower DNA methylation levels and high LIN28A gene expression as compared with other embryonal brain tumors like medulloblastomas (MB) and atypical teratoid rhabdoid tumors (ATRT). However, a more detailed description of the epigenetic landscape marked by DNA methylation and histone modifications, and how this affects the ETMR transcriptome is still lacking. To decode the epi-genome, we have collected whole genome bisulfite sequencing (WGBS) data, ChIP sequencing (ChIP-seq) data of various (active and repressive) histone marks and epigenetic modifiers (EZH2, BRD4, CTCF), and RNA sequencing (RNA-seq) data from a series of ETMR patient tumors, and similar data from a series of MBs and ATRTs covering all molecular subtypes for comparison reasons. Using all these data and performing bioinformatic analyses, we have depicted chromatin states and DNA-methylation-defined genomic segments of ETMR for the first time. ETMR genomes are generally hypomethylated, with wider distributions of un-methylated regions and DNA methylation valleys (DMVs) on its genome compared with MB and ATRT. By integrating these data with all other omics data, we found that BRD4-regulated overexpression of TET demethylases may cause global hypomethylation in ETMRs. Polycomb and TETs are recruited at DMVs to ensure DMVs are longer in ETMRs than MBs and ATRTs. Furthermore, genes involved in embryo development and cell proliferation are enriched in entity-shared DMVs and are highly expressed in ETMRs and other embryonal brain tumors. We also depicted that TET family members, BRD4, and Polycomb complex (EZH2) are potential therapeutic targets for ETMR patients. In conclusion, we have partially described the epi-genome and epigenetic regulations of ETMR, and are currently working on more detailed regulation axes and performing drug test experiments for these potential therapeutic targets to understand better the underlying biology of these tumors and how this may lead to alternative and more effective therapies.
Citation Format: Shanzheng Wang, Sander Lambo, Monika Mauermann, Robert J Autry, Natalie Jäger, Stefan M Pfister, Marcel Kool. Epigenetic landscape and gene regulations in embryonal brain tumors with multilayered rosettes (ETMR) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B028.