Synovial Sarcoma Chromatin Dynamics Reveal a Continuum in SS18:SSX Reprograming.
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- Hofvander J; Department of Microbiology and Immunology, Michael Smith Laboratories, UBC, Vancouver, Canada.; Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, Canada.; Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.; Qiu A; Department of Microbiology and Immunology, Michael Smith Laboratories, UBC, Vancouver, Canada.; Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, Canada.; Department of Pathology and Laboratory Medicine, UBC, Vancouver, Canada.; Lee K; Department of Microbiology and Immunology, Michael Smith Laboratories, UBC, Vancouver, Canada.; Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, Canada.; Department of Pathology and Laboratory Medicine, UBC, Vancouver, Canada.; Bilenky M; Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, Canada.; Carles A; Department of Microbiology and Immunology, Michael Smith Laboratories, UBC, Vancouver, Canada.; Cao Q; Department of Microbiology and Immunology, Michael Smith Laboratories, UBC, Vancouver, Canada.; Moksa M; Department of Microbiology and Immunology, Michael Smith Laboratories, UBC, Vancouver, Canada.; Steif J; Department of Microbiology and Immunology, Michael Smith Laboratories, UBC, Vancouver, Canada.; Su E; Department of Microbiology and Immunology, Michael Smith Laboratories, UBC, Vancouver, Canada.; Sotiriou A; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.; National Center for Tumor Diseases (NCT), NCT Heidelberg, Germany.; Soft-Tissue Sarcoma Junior Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Faculty of Biosciences, University of Heidelberg, Germany.; Goytain A; Department of Pathology and Laboratory Medicine, UBC, Vancouver, Canada.; Hill LA; Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.; Singer S; Sarcoma Biology Laboratory, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.; Andrulis IL; University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, Canada.; Wunder JS; Lunefeld-Tanenbaum Research Institute, Sinai Health System and Department of Molecular Genetics, University of Toronto, Toronto, Canada.; Mertens F; Division of Clinical Genetics, Lund University and Skåne University Hospital, Lund, Sweden.; Banito A; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.; National Center for Tumor Diseases (NCT), NCT Heidelberg, Germany.; Soft-Tissue Sarcoma Junior Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Jones KB; Department of Orthopaedics, University of Utah, Salt Lake City, Utah, United States of America.; Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, United States of America.; Underhill TM; Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.; Nielsen TO; Department of Pathology and Laboratory Medicine, UBC, Vancouver, Canada.; Hirst M; Department of Microbiology and Immunology, Michael Smith Laboratories, UBC, Vancouver, Canada.; Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, Canada.
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- Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
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- English
Synovial sarcoma (SyS) is an aggressive soft-tissue malignancy characterized by a pathognomonic chromosomal translocation leading to the formation of the SS18::SSX fusion oncoprotein. SS18::SSX associates with mammalian BAF complexes suggesting deregulation of chromatin architecture as the oncogenic driver in this tumour type. To examine the epigenomic state of SyS we performed comprehensive multi-omics analysis on 52 primary pre-treatment human SyS tumours. Our analysis revealed a continuum of epigenomic states across the cohort at fusion target genes independent of rare somatic genetic lesions. We identify cell-of-origin signatures defined by enhancer states and reveal unexpected relationships between H2AK119Ub1 and active marks. The number of bivalent promoters, dually marked by the repressive H3K27me3 and activating H3K4me3 marks, has strong prognostic value and outperforms tumor grade in predicting patient outcome. Finally, we identify SyS defining epigenomic features including H3K4me3 expansion associated with striking promoter DNA hypomethylation in which SyS displays the lowest mean methylation level of any sarcoma subtype. We explore these distinctive features as potential vulnerabilities in SyS and identify H3K4me3 inhibition as a promising therapeutic strategy.