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Updated: Jul 6, 2025
Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions
Julia Schöpf1,2,3, Sebastian Uhrig4,5, Christoph E Heilig2,5
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.
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.
Insights
This study reveals that FUS/EWSR1-TFCP2 fusions in rhabdomyosarcoma drive outlier ALK expression and genomic instability, suggesting targeted therapies. These findings offer new insights into rare cancer pathogenesis and treatment vulnerabilities.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions is a rare cancer lacking effective treatments.
- Understanding its molecular drivers is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the molecular mechanisms and therapeutic vulnerabilities of FUS/EWSR1-TFCP2-driven rhabdomyosarcoma.
- To link multi-omics data with mechanistic studies for rare cancer insights.
Main Methods:
- Leveraged two precision oncology programs and multi-omics data.
- Conducted functional studies on FUS-TFCP2 fusion proteins.
- Performed DNA methylation profiling.
Main Results:
- Identified outlier ALK expression and oncogenic ALK variants sensitive to ALK inhibitors.
- Discovered recurrent CDKN2A/MTAP co-deletions suggesting PRMT5-targeted therapy potential.
- Demonstrated FUS-TFCP2 blocks differentiation, induces ALK/TERT transcription, and impairs DNA repair, leading to genomic instability.
- Linked these tumors to undifferentiated sarcomas and observed stepwise sarcomagenesis from benign lesions.
Conclusions:
- FUS/EWSR1-TFCP2 rhabdomyosarcoma exhibits unique molecular features, including ALK alterations and defective DNA repair.
- Targeting ALK and PRMT5 presents potential therapeutic strategies.
- Linking precision oncology with preclinical research is vital for understanding and treating rare cancers.
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