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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Julia Schöpf - , Nationales Zentrum für Tumorerkrankungen (NCT) Dresden (Autor:in)
  • Sebastian Uhrig - , Computational Oncology Group (Autor:in)
  • Christoph E Heilig - , Division of Translational Medical Oncology (Autor:in)
  • Kwang-Seok Lee - , Division of Translational Medical Oncology (Autor:in)
  • Tatjana Walther - , Division of Translational Medical Oncology (Autor:in)
  • Alexander Carazzato - , Division of Translational Medical Oncology (Autor:in)
  • Anna Maria Dobberkau - , Section of Translational Cancer Epigenomics (Autor:in)
  • Dieter Weichenhan - , Division of Cancer Epigenomics (Autor:in)
  • Christoph Plass - , Division of Cancer Epigenomics (Autor:in)
  • Mark Hartmann - , Section of Translational Cancer Epigenomics (Autor:in)
  • Gaurav D Diwan - , Nationales Zentrum für Tumorerkrankungen (NCT) Heidelberg (Autor:in)
  • Zunamys I Carrero - , Nationales Centrum für Tumorerkrankungen (Partner: UKD, MFD, HZDR, DKFZ), Deutsches Konsortium für Translationale Krebsforschung (Partner: DKTK, DKFZ) (Autor:in)
  • Claudia R Ball - , Nationales Centrum für Tumorerkrankungen (Partner: UKD, MFD, HZDR, DKFZ), Deutsches Konsortium für Translationale Krebsforschung (Partner: DKTK, DKFZ), Fakultät Biologie, Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Tobias Hohl - , Nationales Zentrum für Tumorerkrankungen (NCT) Dresden (Autor:in)
  • Thomas Kindler - , University Cancer Center Mainz (Autor:in)
  • Patricia Rudolph-Hähnel - , University Cancer Center Mainz (Autor:in)
  • Dominic Helm - , Proteomics Core Facility (Autor:in)
  • Martin Schneider - , Deutsches Krebsforschungszentrum (DKFZ) (Autor:in)
  • Anna Nilsson - , Karolinska-Universitätskrankenhaus (Autor:in)
  • Ingrid Øra - , Lund University (Autor:in)
  • Roland Imle - , Soft-Tissue Sarcoma Junior Research Group (Autor:in)
  • Ana Banito - , Soft-Tissue Sarcoma Junior Research Group (Autor:in)
  • Robert B Russell - , Nationales Zentrum für Tumorerkrankungen (NCT) Heidelberg (Autor:in)
  • Barbara C Jones - , Deutsches Konsortium für Translationale Krebsforschung (DKTK) - Frankfurt/Mainz (Autor:in)
  • Daniel B Lipka - , Section of Translational Cancer Epigenomics (Autor:in)
  • Hanno Glimm - , Nationales Centrum für Tumorerkrankungen (Partner: UKD, MFD, HZDR, DKFZ), Deutsches Konsortium für Translationale Krebsforschung (Partner: DKTK, DKFZ), Universitätsklinikum Carl Gustav Carus Dresden, Deutsches Krebsforschungszentrum (DKFZ) (Autor:in)
  • Daniel Hübschmann - , Computational Oncology Group (Autor:in)
  • Wolfgang Hartmann - , Universitätsklinikum Münster (Autor:in)
  • Stefan Fröhling - , Division of Translational Medical Oncology (Autor:in)
  • Claudia Scholl - , Nationales Zentrum für Tumorerkrankungen (NCT) Dresden (Autor:in)

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.

Details

OriginalspracheEnglisch
Aufsatznummer51
FachzeitschriftNature communications
Jahrgang15
Ausgabenummer1
PublikationsstatusVeröffentlicht - 2 Jan. 2024
Peer-Review-StatusJa

Externe IDs

PubMedCentral PMC10761971
Scopus 85181239468
ORCID /0000-0001-5164-316X/work/150883466
ORCID /0000-0001-8501-1566/work/150883654

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Humans, Multiomics, Precision Medicine, Transcription Factors/genetics, Sarcoma/genetics, RNA-Binding Protein EWS/genetics, Soft Tissue Neoplasms/genetics, Receptor Protein-Tyrosine Kinases, Biomarkers, Tumor/genetics, Oncogene Proteins, Fusion/genetics, Protein-Arginine N-Methyltransferases, DNA-Binding Proteins/genetics