Abstract 3523: A systematic comparison of molecular features shared by H3K27-altered diffuse midline gliomas and posterior fossa A ependymomas

Abstract

Abstract In children, brain tumors account for the highest mortality rates of all malignancies, and in contrast to adult brain cancers, pediatric tumors often arise in infratentorial regions. Two tumors in particular, H3K27-altered diffuse midline gliomas (DMGs) and group-A posterior fossa ependymomas (PFAs) arise from structures around the fourth ventricle, and strikingly, both tumors exhibit a global decrease in the histone mark histone 3, lysine 27 tri-methylation (H3K27me3) that is associated with transcriptional repression. H3K27-altered DMGs primarily are found primarily in the pons and exhibit by lysine-to-methionine mutations at H3K27 (H3K27M). This missense mutation results in inhibition of the catalytic activity of the polycomb repressive complex 2 (PRC2) which mediates H3K27me3 deposition. PFAs are found in the lateral recess of the fourth ventricle and the cerebellum and demonstrate overexpression of EZH inhibitory protein (EZHIP). EZHIP contains a domain with striking resemblance to the mutant H3K27M histone tail and similarly blocks PRC2 activity. Although H3K27me3 levels are dramatically reduced in both areas, select genes retain H3K27me3 in both tumor types. Increasingly, data have emerged demonstrating that cases of PFAs actually harbor H3K27M mutations and cases of H3-wildtype DMGs in fact overexpress EZHIP. The neighboring origins and overlapping recurrent H3K27me3-modulating alterations observed in these two pediatric brain tumors suggest certain populations of cells in the developing hindbrain may be particularly prone to malignant transformation in the setting of PRC2 inhibition. A systematic comparison of genomic, transcriptomic, and epigenomic datasets for both tumors identified key molecular similarities between subsets of DMGs and PFAs and highlighted how developmental signatures may be preserved in tumor expression profiles. Specifically, these analyses identify shared copy-number profiles between PFAs and different subtypes of DMGs and demonstrate that the Activin A Receptor Type 1 (ACVR1), a gene with recurrent activating mutations in H3K27-altered DMGs, is overexpressed in a subset PFAs with worse survival outcomes. Additionally, interrogation of the H3K27me3 and enhancer landscapes identified critical genes with similar chromatin profiles and revealed heterogeneity in repression of H3K27me3-marked genes that correlated with patterns of inferred anatomic origins for each tumor. Moreover, one of these genes, cellular retinoic acid binding partner 1 (CRABP1) showed enrichment in progenitor cell types in single-cell transcriptomic datasets. Together, these analyses characterize the common and unique molecular features of H3K27-altered DMGs and PFAs and shed light on the cellular contexts of the developing hindbrain that lead to development of each tumor. Citation Format: Matthew Pun, Drew Pratt, Patricia R. Nano, Piyush K. Joshi, Li Jiang, Bernhard Englinger, Arvind Rao, Marcin Cieslik, Arul M. Chinnaiyan, Kenneth Aldape, Stefan Pfister, Mariella G. Filbin, Aparna Bhaduri, Sriram Venneti. A systematic comparison of molecular features shared by H3K27-altered diffuse midline gliomas and posterior fossa A ependymomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3523.