2. Academic Validation
  3. Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions

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

  • Nat Commun. 2024 Jan 2;15(1):51. doi: 10.1038/s41467-023-44360-2.
Julia Schöpf # 1 2 3,  Sebastian Uhrig # 4 5,  Christoph E Heilig # 2 5,  Kwang-Seok Lee # 2,  Tatjana Walther 2,  Alexander Carazzato 2,  Anna Maria Dobberkau 6,  Dieter Weichenhan 7,  Christoph Plass 7,  Mark Hartmann 6,  Gaurav D Diwan 8 9,  Zunamys I Carrero 10 11,  Claudia R Ball 10 11 12 13,  Tobias Hohl 1 3,  Thomas Kindler 14 15 16,  Patricia Rudolph-Hähnel 14 15 16,  Dominic Helm 17,  Martin Schneider 17,  Anna Nilsson 18,  Ingrid Øra 19,  Roland Imle 20 21 22,  Ana Banito 20 21,  Robert B Russell 8 9,  Barbara C Jones 5 21 22,  Daniel B Lipka 6,  Hanno Glimm 10 11 12 23,  Daniel Hübschmann 4 5 24,  Wolfgang Hartmann 25,  Stefan Fröhling 26 27 28,  Claudia Scholl 29
Affiliations

Affiliations

  • 1 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, Germany.
  • 2 Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg, Heidelberg, Germany.
  • 3 Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
  • 4 Computational Oncology Group, Molecular Precision Oncology Program, NCT Heidelberg, and DKFZ, Heidelberg, Germany.
  • 5 German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 6 Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg, Heidelberg, Germany.
  • 7 Division of Cancer Epigenomics, DKFZ, Heidelberg, Germany.
  • 8 Bioquant, Heidelberg University, Heidelberg, Germany.
  • 9 Heidelberg University Biochemistry Center (BZH), Heidelberg, Germany.
  • 10 Department for Translational Medical Oncology, 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), Dresden, Germany.
  • 11 German Cancer Consortium (DKTK), Dresden, Germany.
  • 12 Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD, Dresden, Germany.
  • 13 Faculty of Biology, TUD Dresden University of Technology, Dresden, Germany.
  • 14 University Cancer Center Mainz, Johannes Gutenberg University Mainz, Mainz, Germany.
  • 15 Department of Hematology, Medical Oncology and Pneumology, University Medical Center, Mainz, Germany.
  • 16 German Cancer Consortium (DKTK), Mainz, Germany.
  • 17 Proteomics Core Facility, DKFZ, Heidelberg, Germany.
  • 18 Pediatric Oncology and Coagulation, Karolinska University Hospital, Stockholm, Sweden.
  • 19 Pediatric Oncology and Hematology, Skåne University Hospital, Lund University, Lund, Sweden.
  • 20 Soft-Tissue Sarcoma Junior Research Group, DKFZ, Heidelberg, Germany.
  • 21 Hopp Children's Cancer Center (KiTZ) and NCT Heidelberg, Heidelberg, Germany.
  • 22 Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
  • 23 Translational Functional Cancer Genomics, DKFZ, Heidelberg, Germany.
  • 24 Pattern Recognition and Digital Medicine Group, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.
  • 25 Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany.
  • 26 Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg, Heidelberg, Germany. stefan.froehling@nct-heidelberg.de.
  • 27 German Cancer Consortium (DKTK), Heidelberg, Germany. stefan.froehling@nct-heidelberg.de.
  • 28 Institute of Human Genetics, Heidelberg University, Heidelberg, Germany. stefan.froehling@nct-heidelberg.de.
  • 29 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, Germany. claudia.scholl@nct-heidelberg.de.
  • # Contributed equally.
PMID: 38168093 DOI: 10.1038/s41467-023-44360-2
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.

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