Novel <scp><i>EWSR1::UBP1</i></scp> fusion expands the spectrum of spindle cell rhabdomyosarcomas

Djeroudi, Lounes; Reynaud, Stéphanie; Guillemot, Delphine; Masliah‐Planchon, Julien; Nicolas, Nayla; Loarer, François Le; Daniel, Catherine; Delattre, Olivier; Pierron, Gaëlle; Watson, Sarah

doi:10.1002/gcc.23019

Cited by 7 publications

(4 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The clinical course of the patient described above who responded to radiotherapy followed by ALK inhibition also suggests that these tumors have reduced DNA repair capacity 51 . Zein et al reported a patient with RMS carrying an EWSR1-UBP1 fusion, which seems to be a variant of EWSR1-TFCP2, as TFCP2 and UBP1 belong to the same transcription factor family, have high sequence homology, and share the same domain structure 59 . This patient responded to a lung cancer regimen that included carboplatin, which is not a standard in RMS, but progressed on subsequent maintenance therapy with pembrolizumab 59 .…”

Section: Discussionmentioning

confidence: 99%

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

Schöpf,

Uhrig,

Heilig

et al. 2024

Nat Commun

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Schöpf,

Uhrig,

Heilig

et al. 2024

Nat Commun

View full text Add to dashboard Cite

show abstract

“…The clinical course of the patient described above who responded to radiotherapy followed by ALK inhibition also suggests that these tumors have reduced DNA repair capacity (51). Interestingly, Zein et al reported a patient with RMS carrying an EWSR1-UBP1 fusion, which seems to be a variant of EWSR1-TFCP2, as TFCP2 and UBP1 belong to the same transcription factor family, have high sequence homology, and share the same domain structure (58). This patient responded to a lung cancer regimen that included carboplatin, which is not a standard in RMS, but progressed on subsequent maintenance therapy with pembrolizumab (58).…”

Section: Discussionmentioning

confidence: 99%

Multidimensional Characterization of Soft-Tissue Sarcomas with FUS-TFCP2 or EWSR1-TFCP2 Fusions

Schopf

Uhrig

Heilig

et al. 2023

Preprint

View full text Add to dashboard Cite

Linking clinical multi-omics analyses with mechanistic studies provides opportunities to explore the pathogenesis of rare cancers. We leveraged two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective systemic therapies. All tumors exhibited outlier expression of the ALK receptor tyrosine kinase, which was partly accompanied by intragenic deletions and aberrant splicing, resulting in truncated ALK variants that were oncogenic and sensitive to ALK inhibitors. Additional recurrent alterations included CKDN2A/MTAP co-deletions, providing a rationale for therapies targeting CDK4/6 and PRMT5. Functional studies showed that FUS-TFCP2 blocks myogenic differentiation and induces transcription of ALK and a truncated form of TERT through binding outside their regular promoters. Furthermore, FUS-TFCP2 inhibited DNA double-strand break repair. Consistent with this, and unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibited marked genomic instability and signs of defective homologous recombination. DNA methylation profiling indicated a close relationship with undifferentiated sarcomas rather than rhabdomyosarcoma. Finally, we identified patients in whom overt disease was preceded by benign lesions carrying TFCP2 fusions, providing insight into stepwise sarcomagenesis and suggesting new approaches to early detection and interception.

show abstract

“…Nevertheless, as the advance of molecular biology technique, especially next-generation sequencing applying for the pathological diagnosis, numerous novel characteristic molecules involving neoplastic diagnosis have been unearthed and thus refined many tumor entities in mesenchymal tumor, such as HEY1-NCOA2 fusion in mesenchymal chondrosarcoma [ 2 ], EWSR1-NR4A3 fusion in extraskeletal myxoid chondrosarcoma [ 3 ], WWTR1-CAMAT1 fusion and YAP1-TFE3 fusion in epithelioid hemangioendothelioma [ 4 , 5 ]. As regard to RMS, PAX3-FOXO1 and PAX7-FOX1 fusion were characteristics in alveolar RMS [ 6 ], and the MYOD1 mutation, EP300-VGLL3, NCOA2-MEIS1, CAV1-MET, YAP1-MAML2, EWSR1-UBP1 fusion in a small subset of spindle cell/sclerosing RMS (SS-RMS) [ 7 – 11 ]. Most importantly, rare cases of RMS characteristic by the profiling of epithelioid to spindle cells, namely epithelioid and spindle RMS (ES-RMS), were recently found to harbor EWSR1-TFCP2 or FUS-TFCP2 fusion and predominately arising in the bone of head and neck and pelvis, the patients with these RMS have extraordinarily adverse prognosis [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Epithelioid and spindle rhabdomyosarcoma with TFCP2 rearrangement in abdominal wall: a distinctive entity with poor prognosis

Wang

et al. 2023

Diagn Pathol

View full text Add to dashboard Cite

Background Epithelioid and spindle rhabdomyosarcoma (ES-RMS) with TFCP2 rearrangement is a recently discovered rare variant of rhabdomyosarcoma composed of epithelioid and spindle cells, because it shows extraordinarily adverse prognosis and is easily misdiagnosed as other epithelioid or spindle cell tumors. Methods A rare case of ES-RMS with TFCP2 rearrangement was presented and English literatures in Pubmed online up to 01 July 2022 were gathered by two authors for a systematic review according to the inclusion and exclusion criteria. Case presentation/results We report a case of ES-RMS in an early 30s-years-old female, the neoplastic cells are remarkably immunoreactive with CK(AE1/AE3), and partially with ALK protein. Unexpectedly, the tumor shows TFCP2 rearrangement with coexistence of increased copy numbers of EWSR1 and ROS1 gene and MET gene mutation. Besides, Next-generation sequencing for genetic mutational profiling revealed frequent MET exon14 mutations in chromosome 7, most of which are C > T nonsynonymous SNV, and exon42 of ROS1 in chromosome 6 showed frequent G > T mutation up to 57.54%. In addition, neither MyoD1 mutation nor gene fusions were detected. Moreover, the patient shows high tumor mutational burden (TMB) up to 14.11 counts/Mb. Finally, as many cases of ES-RMS including our case had local progression or metastasis, we find, similar to epithelioid rhabdomyosarcoma (median survival time is 10 month), ES-RMS shows a more aggressive behavior and adverse prognosis (median survival time is 17 month) than spindle cell/sclerosing rhabdomyosarcoma (median survival time is 65 month) according previous studies. Conclusions ES-RMS with TFCP2 rearrangement is a rare malignant tumor and easily confused with other epithelioid or spindle cell tumors, it may harbor additional gene alteration in addition to TFCP2 rearrangement, such as MET mutation, increased copy numbers of EWSR1 and ROS1 gene, high TMB. Most importantly, it may show very poor outcome with extensive metastasis.

show abstract

Novel EWSR1::UBP1 fusion expands the spectrum of spindle cell rhabdomyosarcomas

Cited by 7 publications

References 21 publications

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

Multidimensional Characterization of Soft-Tissue Sarcomas with FUS-TFCP2 or EWSR1-TFCP2 Fusions

Epithelioid and spindle rhabdomyosarcoma with TFCP2 rearrangement in abdominal wall: a distinctive entity with poor prognosis

Contact Info

Product

Resources

About