Common molecular features of H3K27M DMGs and PFA ependymomas map to hindbrain developmental pathways

Acta Neuropathologica Communications

Research

Aparna Bhaduri¹  Patricia R. Nano¹  Arvind Rao²  Li Jiang³  Mariella G. Filbin⁴  Bernhard Englinger⁵  Piyush K. Joshi⁶  Stefan Pfister⁷  Matthew Pun⁸  Sriram Venneti⁹  Kenneth Aldape^1,10  Drew Pratt^1,10  Marcin Cieslik^1,11  Arul M. Chinnaiyan^1,12 

[1] Department of Biological Chemistry, University of California, Los Angeles, 90095, Los Angeles, CA, USA;Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, 48109, Ann Arbor, MI, USA;Department of Biostatistics, University of Michigan, 48109, Ann Arbor, MI, USA;Department of Radiation Oncology, University of Michigan Medical School, 48109, Ann Arbor, MI, USA;Rogel Cancer Center, University of Michigan Medical School, 48109, Ann Arbor, MI, USA;Department of Pediatric Oncology, Dana-Farber Boston Children’s Cancer and Blood Disorders Center, 02115, Boston, MA, USA;Department of Pediatric Oncology, Dana-Farber Boston Children’s Cancer and Blood Disorders Center, 02115, Boston, MA, USA;Broad Institute of Harvard and MIT, 02142, Cambridge, MA, USA;Department of Pediatric Oncology, Dana-Farber Boston Children’s Cancer and Blood Disorders Center, 02115, Boston, MA, USA;Broad Institute of Harvard and MIT, 02142, Cambridge, MA, USA;Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, 1090, Vienna, Austria;Center for Cancer Research and Comprehensive Cancer Center, Medical University Vienna, 1090, Vienna, Austria;Hopp Children’s Cancer Center (KiTZ) Heidelberg, Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany;Hopp Children’s Cancer Center (KiTZ) Heidelberg, Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany;Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120, Heidelberg, Germany;Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, 69120, Heidelberg, Germany;Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan, 3520E MSRB 1, 1150 W. Medical Center, 41804, Ann Arbor, MI, USA;Chad Carr Pediatric Tumor Center, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA;Cellular and Molecular Biology Program, University of Michigan Medical School, 48109, Ann Arbor, MI, USA;Medical Scientist Training Program, University of Michigan Medical School, 48109, Ann Arbor, MI, USA;Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan, 3520E MSRB 1, 1150 W. Medical Center, 41804, Ann Arbor, MI, USA;Chad Carr Pediatric Tumor Center, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA;Cellular and Molecular Biology Program, University of Michigan Medical School, 48109, Ann Arbor, MI, USA;Rogel Cancer Center, University of Michigan Medical School, 48109, Ann Arbor, MI, USA;Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Dr., Room 2S235, 20892, Bethesda, MD, USA;Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, 48109, Ann Arbor, MI, USA;Rogel Cancer Center, University of Michigan Medical School, 48109, Ann Arbor, MI, USA;Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, 48109, Ann Arbor, MI, USA;Rogel Cancer Center, University of Michigan Medical School, 48109, Ann Arbor, MI, USA;Department of Urology, University of Michigan Medical School, 48109, Ann Arbor, MI, USA;Howard Hughes Medical Institute, University of Michigan Medical School, 48109, Ann Arbor, MI, USA;

关键词: Cancer;    Chromatin biology;    Onco-histones;    Pediatric tumors;    Brain development;    Neuro-oncology;   

DOI  :  10.1186/s40478-023-01514-z

 received in 2022-11-14, accepted in 2023-01-11,  发布年份 2023

来源: Springer

【 摘 要 】

Globally decreased histone 3, lysine 27 tri-methylation (H3K27me3) is a hallmark of H3K27-altered diffuse midline gliomas (DMGs) and group-A posterior fossa ependymomas (PFAs). H3K27-altered DMGs are largely characterized by lysine-to-methionine mutations in histone 3 at position 27 (H3K27M). Most PFAs overexpress EZH inhibitory protein (EZHIP), which possesses a region of similarity to the mutant H3K27M. Both H3K27M and EZHIP inhibit the function of the polycomb repressive complex 2 (PRC2) responsible for H3K27me3 deposition. These tumors often arise in neighboring regions of the brainstem and posterior fossa. In rare cases PFAs harbor H3K27M mutations, and DMGs overexpress EZHIP. These findings together raise the possibility that certain cell populations in the developing hindbrain/posterior fossa are especially sensitive to modulation of H3K27me3 states. We identified shared molecular features by comparing genomic, bulk transcriptomic, chromatin-based profiles, and single-cell RNA-sequencing (scRNA-seq) data from the two tumor classes. Our approach demonstrated that 1q gain, a key biomarker in PFAs, is prognostic in H3.1K27M, but not H3.3K27M gliomas. Conversely, Activin A Receptor Type 1 (ACVR1), which is associated with mutations in H3.1K27M gliomas, is overexpressed in a subset of PFAs with poor outcome. Despite diffuse H3K27me3 reduction, previous work shows that both tumors maintain genomic H3K27me3 deposition at select sites. We demonstrate heterogeneity in shared patterns of residual H3K27me3 for both tumors that largely segregated with inferred anatomic tumor origins and progenitor populations of tumor cells. In contrast, analysis of genes linked to H3K27 acetylation (H3K27ac)-marked enhancers showed higher expression in astrocytic-like tumor cells. Finally, common H3K27me3-marked genes mapped closely to expression patterns in the human developing hindbrain. Overall, our data demonstrate developmentally relevant molecular similarities between PFAs and H3K27M DMGs and support the overall hypothesis that deregulated mechanisms of hindbrain development are central to the biology of both tumors.

【 授权许可】

CC BY   
© The Author(s) 2023

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