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

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. Diwan, Zunamys I. Carrero, Claudia R. Ball, Tobias Hohl, Thomas Kindler, Patricia Rudolph-Hähnel, Dominic Helm, Martin Schneider, Anna Nilsson, Ingrid Øra, Roland Imle, Ana Banito, Robert B. Russell, Barbara C. Jones, Daniel B. Lipka, Hanno Glimm, Daniel Hübschmann, Wolfgang Hartmann, Stefan Fröhling () and Claudia Scholl ()
Additional contact information
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
Sebastian Uhrig: Computational Oncology Group, Molecular Precision Oncology Program, NCT Heidelberg, and DKFZ
Christoph E. Heilig: Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg
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
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)
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)
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
Thomas Kindler: University Cancer Center Mainz, Johannes Gutenberg University Mainz
Patricia Rudolph-Hähnel: University Cancer Center Mainz, Johannes Gutenberg University Mainz
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
Ana Banito: Soft-Tissue Sarcoma Junior Research Group, DKFZ
Robert B. Russell: Bioquant, Heidelberg University
Barbara C. Jones: German Cancer Consortium (DKTK)
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)
Daniel Hübschmann: Computational Oncology Group, Molecular Precision Oncology Program, NCT Heidelberg, and DKFZ
Wolfgang Hartmann: University Hospital Münster
Stefan Fröhling: Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg
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

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44360-2

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