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

Schöpf, Julia ; Uhrig, Sebastian ; Heilig, Christoph E. ; Lee, Kwang Seok ; Walther, Tatjana ; Carazzato, Alexander ; Dobberkau, Anna Maria ; Weichenhan, Dieter ; Plass, Christoph and Hartmann, Mark , et al. (2024) In Nature Communications 15. p.1-17
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
15
article number
51
pages
1 - 17
publisher
Nature Publishing Group
external identifiers
  • pmid:38168093
  • scopus:85181239468
ISSN
2041-1723
DOI
10.1038/s41467-023-44360-2
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2024, The Author(s).
id
0aab4783-323c-4552-83ce-ac638a8962ab
date added to LUP
2024-01-12 04:33:30
date last changed
2024-04-27 00:17:28
@article{0aab4783-323c-4552-83ce-ac638a8962ab,
  abstract     = {{<p>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.</p>}},
  author       = {{Schöpf, Julia and Uhrig, Sebastian and Heilig, Christoph E. and Lee, Kwang Seok and Walther, Tatjana and Carazzato, Alexander and Dobberkau, Anna Maria and Weichenhan, Dieter and Plass, Christoph and Hartmann, Mark and Diwan, Gaurav D. and Carrero, Zunamys I. and Ball, Claudia R. and Hohl, Tobias and Kindler, Thomas and Rudolph-Hähnel, Patricia and Helm, Dominic and Schneider, Martin and Nilsson, Anna and Øra, Ingrid and Imle, Roland and Banito, Ana and Russell, Robert B. and Jones, Barbara C. and Lipka, Daniel B. and Glimm, Hanno and Hübschmann, Daniel and Hartmann, Wolfgang and Fröhling, Stefan and Scholl, Claudia}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  pages        = {{1--17}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions}},
  url          = {{http://dx.doi.org/10.1038/s41467-023-44360-2}},
  doi          = {{10.1038/s41467-023-44360-2}},
  volume       = {{15}},
  year         = {{2024}},
}