한빛사논문
- 조회453
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 *
1Division 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.
2Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg, Heidelberg, Germany.
3Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
4Computational Oncology Group, Molecular Precision Oncology Program, NCT Heidelberg, and DKFZ, Heidelberg, Germany.
5German Cancer Consortium (DKTK), Heidelberg, Germany.
6Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg, Heidelberg, Germany.
7Division of Cancer Epigenomics, DKFZ, Heidelberg, Germany.
8Bioquant, Heidelberg University, Heidelberg, Germany.
9Heidelberg University Biochemistry Center (BZH), Heidelberg, Germany.
10Department 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.
11German Cancer Consortium (DKTK), Dresden, Germany.
12Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD, Dresden, Germany.
13Faculty of Biology, TUD Dresden University of Technology, Dresden, Germany.
14University Cancer Center Mainz, Johannes Gutenberg University Mainz, Mainz, Germany.
15Department of Hematology, Medical Oncology and Pneumology, University Medical Center, Mainz, Germany.
16German Cancer Consortium (DKTK), Mainz, Germany.
17Proteomics Core Facility, DKFZ, Heidelberg, Germany.
18Pediatric Oncology and Coagulation, Karolinska University Hospital, Stockholm, Sweden.
19Pediatric Oncology and Hematology, Skåne University Hospital, Lund University, Lund, Sweden.
20Soft-Tissue Sarcoma Junior Research Group, DKFZ, Heidelberg, Germany.
21Hopp Children's Cancer Center (KiTZ) and NCT Heidelberg, Heidelberg, Germany.
22Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
23Translational Functional Cancer Genomics, DKFZ, Heidelberg, Germany.
24Pattern Recognition and Digital Medicine Group, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.
25Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany.
26Division of Translational Medical Oncology, DKFZ, and NCT Heidelberg, Heidelberg, Germany.
27German Cancer Consortium (DKTK), Heidelberg, Germany.
28Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
29Division 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.
#Contributed equally.
*Corresponding authors: correspondence to Stefan Fröhling or Claudia Scholl
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.
논문정보
- Research article
- 2024년 01월 (BRIC 등록일 2024-01-08)
- 국외 연구진
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