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         headline:Super enhancers define regulatory subtypes and cell identity in neuroblastoma
         description:Half of the children diagnosed with neuroblastoma (NB) have high-risk disease, disproportionately contributing to overall childhood cancer-related deaths. In addition to recurrent gene mutations, there is increasing evidence supporting the role of epigenetic deregulation in disease pathogenesis. Yet, comprehensive cis-regulatory network descriptions from NB are lacking. Here, using genome-wide H3K27ac profiles across 60 NBs, covering the different clinical and molecular subtypes, we identified four major super-enhancer-driven epigenetic subtypes and their underlying master regulatory networks. Three of these subtypes recapitulated known clinical groups; namely, MYCN-amplified, MYCN non-amplified high-risk and MYCN non-amplified low-risk NBs. The fourth subtype, exhibiting mesenchymal characteristics, shared cellular identity with multipotent Schwann cell precursors, was induced by RAS activation and was enriched in relapsed disease. Notably, CCND1, an essential gene in NB, was regulated by both mesenchymal and adrenergic regulatory networks converging on distinct super-enhancer modules. Overall, this study reveals subtype-specific super-enhancer regulation in NBs. Westermann and colleagues define four subtypes of neuroblastoma based on super-enhancer profiles in primary patient samples, which could be linked to distinct clinical outcomes and cell identity characteristics.
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      headline:Super enhancers define regulatory subtypes and cell identity in neuroblastoma
      description:Half of the children diagnosed with neuroblastoma (NB) have high-risk disease, disproportionately contributing to overall childhood cancer-related deaths. In addition to recurrent gene mutations, there is increasing evidence supporting the role of epigenetic deregulation in disease pathogenesis. Yet, comprehensive cis-regulatory network descriptions from NB are lacking. Here, using genome-wide H3K27ac profiles across 60 NBs, covering the different clinical and molecular subtypes, we identified four major super-enhancer-driven epigenetic subtypes and their underlying master regulatory networks. Three of these subtypes recapitulated known clinical groups; namely, MYCN-amplified, MYCN non-amplified high-risk and MYCN non-amplified low-risk NBs. The fourth subtype, exhibiting mesenchymal characteristics, shared cellular identity with multipotent Schwann cell precursors, was induced by RAS activation and was enriched in relapsed disease. Notably, CCND1, an essential gene in NB, was regulated by both mesenchymal and adrenergic regulatory networks converging on distinct super-enhancer modules. Overall, this study reveals subtype-specific super-enhancer regulation in NBs. Westermann and colleagues define four subtypes of neuroblastoma based on super-enhancer profiles in primary patient samples, which could be linked to distinct clinical outcomes and cell identity characteristics.
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         Cancer genomics
         Paediatric cancer
         Life Sciences
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      name:Kai-Oliver Henrich
      affiliation:
            name:Hopp Children’s Cancer Center Heidelberg (KiTZ)
            address:
               name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
               type:PostalAddress
            type:Organization
            name:German Cancer Research Center
            address:
               name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
               type:PostalAddress
            type:Organization
      name:Johan van Nes
      url:http://orcid.org/0000-0001-7691-1431
      affiliation:
            name:University of Amsterdam
            address:
               name:Department of Oncogenomics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
               type:PostalAddress
            type:Organization
      name:Carl Herrmann
      url:http://orcid.org/0000-0003-4989-4722
      affiliation:
            name:Medical Faculty Heidelberg and BioQuant
            address:
               name:Health Data Science Unit, Medical Faculty Heidelberg and BioQuant, Heidelberg, Germany
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Frank Westermann
      url:http://orcid.org/0000-0003-1584-3636
      affiliation:
            name:Hopp Children’s Cancer Center Heidelberg (KiTZ)
            address:
               name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
               type:PostalAddress
            type:Organization
            name:German Cancer Research Center
            address:
               name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
      name:Health Data Science Unit, Medical Faculty Heidelberg and BioQuant, Heidelberg, Germany
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
      name:Health Data Science Unit, Medical Faculty Heidelberg and BioQuant, Heidelberg, Germany
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
      name:Health Data Science Unit, Medical Faculty Heidelberg and BioQuant, Heidelberg, Germany
      name:Health Data Science Unit, Medical Faculty Heidelberg and BioQuant, Heidelberg, Germany
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
      name:Center for Digital Health, Berlin Institute of Health and Charité Universitätsmedizin Berlin, Berlin, Germany
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
      name:Department of Oncogenomics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
      name:Department of Oncogenomics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Translational Pediatric Sarcoma Research, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
      name:Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Pediatric Glioma Research Group, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
      name:Department of Pediatric Hematology and Oncology, Heidelberg University Hospital and Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
      name:Department of Oncogenomics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
      name:Health Data Science Unit, Medical Faculty Heidelberg and BioQuant, Heidelberg, Germany
      name:Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
      name:Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany
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