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Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions

Author

Listed:
  • Julia Schöpf

    (Division of Applied Functional Genomics, German Cancer Research Center (DKFZ), and National Center for Tumor Diseases (NCT), NCT Heidelberg, a Partnership Between DKFZ and Heidelberg University Hospital
    Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg
    Heidelberg University)

  • Sebastian Uhrig

    (Computational Oncology Group, Molecular Precision Oncology Program, NCT Heidelberg, and DKFZ
    German Cancer Consortium (DKTK))

  • Christoph E. Heilig

    (Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg
    German Cancer Consortium (DKTK))

  • Kwang-Seok Lee

    (Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg)

  • Tatjana Walther

    (Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg)

  • Alexander Carazzato

    (Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg)

  • Anna Maria Dobberkau

    (Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg)

  • Dieter Weichenhan

    (Division of Cancer Epigenomics, DKFZ)

  • Christoph Plass

    (Division of Cancer Epigenomics, DKFZ)

  • Mark Hartmann

    (Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg)

  • Gaurav D. Diwan

    (Bioquant, Heidelberg University
    Heidelberg University Biochemistry Center (BZH))

  • Zunamys I. Carrero

    (NCT, NCT/UCC Dresden, a Partnership Between DKFZ, Heidelberg Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR)
    German Cancer Consortium (DKTK))

  • Claudia R. Ball

    (NCT, NCT/UCC Dresden, a Partnership Between DKFZ, Heidelberg Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR)
    German Cancer Consortium (DKTK)
    Faculty of Medicine and University Hospital Carl Gustav Carus, TUD
    TUD Dresden University of Technology)

  • Tobias Hohl

    (Division of Applied Functional Genomics, German Cancer Research Center (DKFZ), and National Center for Tumor Diseases (NCT), NCT Heidelberg, a Partnership Between DKFZ and Heidelberg University Hospital
    Heidelberg University)

  • Thomas Kindler

    (University Cancer Center Mainz, Johannes Gutenberg University Mainz
    University Medical Center
    German Cancer Consortium (DKTK))

  • Patricia Rudolph-Hähnel

    (University Cancer Center Mainz, Johannes Gutenberg University Mainz
    University Medical Center
    German Cancer Consortium (DKTK))

  • Dominic Helm

    (Proteomics Core Facility, DKFZ)

  • Martin Schneider

    (Proteomics Core Facility, DKFZ)

  • Anna Nilsson

    (Karolinska University Hospital)

  • Ingrid Øra

    (Skåne University Hospital, Lund University)

  • Roland Imle

    (Soft-Tissue Sarcoma Junior Research Group, DKFZ
    Hopp Children’s Cancer Center (KiTZ) and NCT Heidelberg
    Hematology and Immunology, Heidelberg University Hospital)

  • Ana Banito

    (Soft-Tissue Sarcoma Junior Research Group, DKFZ
    Hopp Children’s Cancer Center (KiTZ) and NCT Heidelberg)

  • Robert B. Russell

    (Bioquant, Heidelberg University
    Heidelberg University Biochemistry Center (BZH))

  • Barbara C. Jones

    (German Cancer Consortium (DKTK)
    Hopp Children’s Cancer Center (KiTZ) and NCT Heidelberg
    Hematology and Immunology, Heidelberg University Hospital)

  • Daniel B. Lipka

    (Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg)

  • Hanno Glimm

    (NCT, NCT/UCC Dresden, a Partnership Between DKFZ, Heidelberg Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR)
    German Cancer Consortium (DKTK)
    Faculty of Medicine and University Hospital Carl Gustav Carus, TUD
    Translational Functional Cancer Genomics, DKFZ)

  • Daniel Hübschmann

    (Computational Oncology Group, Molecular Precision Oncology Program, NCT Heidelberg, and DKFZ
    German Cancer Consortium (DKTK)
    Pattern Recognition and Digital Medicine Group, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM))

  • Wolfgang Hartmann

    (University Hospital Münster)

  • Stefan Fröhling

    (Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg
    German Cancer Consortium (DKTK)
    Heidelberg University)

  • Claudia Scholl

    (Division of Applied Functional Genomics, German Cancer Research Center (DKFZ), and National Center for Tumor Diseases (NCT), NCT Heidelberg, a Partnership Between DKFZ and Heidelberg University Hospital)

Abstract

Linking clinical multi-omics with mechanistic studies may improve the understanding of rare cancers. We leverage two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective therapies. All tumors exhibit outlier ALK expression, partly accompanied by intragenic deletions and aberrant splicing resulting in ALK variants that are oncogenic and sensitive to ALK inhibitors. Additionally, recurrent CKDN2A/MTAP co-deletions provide a rationale for PRMT5-targeted therapies. Functional studies show that FUS-TFCP2 blocks myogenic differentiation, induces transcription of ALK and truncated TERT, and inhibits DNA repair. Unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibit genomic instability and signs of defective homologous recombination. DNA methylation profiling demonstrates a close relationship with undifferentiated sarcomas. In two patients, sarcoma was preceded by benign lesions carrying FUS-TFCP2, indicating stepwise sarcomagenesis. This study illustrates the potential of linking precision oncology with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers.

Suggested Citation

  • Julia Schöpf & Sebastian Uhrig & Christoph E. Heilig & Kwang-Seok Lee & Tatjana Walther & Alexander Carazzato & Anna Maria Dobberkau & Dieter Weichenhan & Christoph Plass & Mark Hartmann & Gaurav D. D, 2024. "Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44360-2
    DOI: 10.1038/s41467-023-44360-2
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    as
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