Recurrent MEIS1-NCOA2/1 fusions in a subset of low-grade spindle cell sarcomas frequently involving the genitourinary and gynecologic tracts

Kao, Yu Chien; Bennett, Jennifer A.; Suurmeijer, Albert; Dickson, Brendan C.; Swanson, David; Wanjari, Pankhuri; Zhang, Lei; Lee, Jen‐Chieh; Antonescu, Cristina R.

doi:10.1038/s41379-021-00744-7

Cited by 33 publications

(54 citation statements)

References 19 publications

(24 reference statements)

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“…Eight unusual sarcomas have been reported harboring the same MEIS1‐NCOA2/1 gene fusion involving the urinary and gynecologic tract. These tumors were composed of monomorphic plump spindle cells arranged in vague fascicles with a whorling pattern, a primitive round cell component, and aggressive histological features 24,25 . Immunohistochemically, a minority of these tumors were very focally positive for desmin and all were negative for myogenin.…”

Section: Discussionmentioning

confidence: 99%

“…These tumors were composed of monomorphic plump spindle cells arranged in vague fascicles with a whorling pattern, a primitive round cell component, and aggressive histological features. 24,25 Immunohistochemically, a minority of these tumors were very focally positive for desmin and all were negative for myogenin. The relationship of these undifferentiated tumors to SpRMS with MEIS1-NCOA2 gene fusions is unclear.…”

Section: Agaram Et Al Recently Characterized Seven Primary Intraosseousmentioning

confidence: 99%

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Novel fusion genes in spindle cell rhabdomyosarcoma: The spectrum broadens

Montoya-Cerrillo

Díaz-Pérez

Torres

et al. 2021

Genes Chromosomes & Cancer

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Rhabdomyosarcoma (RMS) encompasses a heterogeneous group of tumors with striated muscle differentiation. RMSs are classified as alveolar, embryonal, spindle cell/sclerosing, and pleomorphic types and molecular analysis of these tumors has identified aberrations that are useful in their further subclassification. Spindle cell rhabdomyosarcoma (SpRMS) is uncommon and has been described with VGLL2 fusions, EWSR1/FUS-TFCP2 rearrangements, and myoD1 mutations-the mutations are associated with significantly different prognoses. In addition, the NCOA2-MEIS1 fusion gene was recently described in two primary intraosseous RMS that contained spindle cell components. Herein, we report three cases of SpRMS harboring different novel fusion genes, one possessing EP300-VGLL3, a second with NCOA2-MEIS1 and CAV1-MET, and the third case had HMGA2-NEGR1 and multiple amplified genes.

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Section: Discussionmentioning

confidence: 99%

Section: Agaram Et Al Recently Characterized Seven Primary Intraosseousmentioning

confidence: 99%

Novel fusion genes in spindle cell rhabdomyosarcoma: The spectrum broadens

Montoya-Cerrillo

Díaz-Pérez

Torres

et al. 2021

Genes Chromosomes & Cancer

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Section: Current Understanding Of the Molecular Basis Of Rmsmentioning

confidence: 99%

“…MEIS1-NCOA2 fusion-positive low grade spindle cell tumors also occur in the genitourinary and gynecological tracts and again mostly affect adults; both RMS and non-RMS cases are described. 66 A single paper describes a distinct type of welldifferentiated SCRMS with SRF-FOXO1 or SRF-NCOA1 fusions. 67 The authors describe only three cases were reported, all deep paraspinal tumors in young children.…”

Section: Introductionmentioning

confidence: 99%

Rhabdomyosarcoma: How Advanced Molecular Methods Are Shaping the Diagnostic and Therapeutic Paradigm

Giannikopoulos

Parham

2021

Pediatr Dev Pathol

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For the past 40 years, progress in rhabdomyosarcoma (RMS) has been focused on understanding its molecular basis and characterizing the mutations that drive its tumorigenesis and progression. Genetic predisposition to RMS has allowed discovery of key genetic pathways and driver mutations. Subclassification of RMS into embryonal (ERMS) and alveolar (ARMS) subtypes has shifted from histology to PAX-FOXO1 fusion status, and new driver mutations have been found in spindle cell RMS. Comprehensive molecular profiling leveraging genome-scale next-generation sequencing (NGS) indicates that the RAS/RAF/PI3K axis is mutated in the majority of ERMS and modulated by downstream effects of PAX-FOXO1 fusions in ARMS. Because of the continued poor outcome of high-risk RMS, a variety of molecular targets have been or are now being tested in current or recent therapy trials. New techniques such as single cell sequencing, spatial multi-omics, and CRISPR/Cas9 genome editing offer potential for further discovery, but a need for clinically annotated specimens persists.

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“…Additionally, in zebrafish models, vgll2a is required for neural crest cell survival and craniofacial development 12 . NCOA2 is a common 3' fusion partner in non-spindle cell sarcoma contexts; examples including HEY1-NCOA2 in mesenchymal chondrosarcoma, MEIS1-NCOA2 in genitourinary and gynecologic tract spindle cell sarcomas and intraosseous rhabdomyosarcomas, and PAX3-NCOA2 in alveolar rhabdomyosarcoma [13][14][15][16][17] . Suggestively, TEAD1-NCOA2 fusions have also been identified in infantile rhabdomyosarcoma, indicating converging developmental processes for this subtype 18,19 .…”

Section: Introductionmentioning

confidence: 99%

VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis

Watson

LaVigne

et al. 2021

Preprint

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Clinical sequencing efforts are uncovering numerous fusion genes in childhood solid tumors, yet few methods exist to delineate fusion-oncogenes from structural changes of unknown significance. One such novel fusion gene is VGLL2-NCOA2, which was described by us and others in patients with congenital sarcomas but has lacked functional validation. To determine if this fusion is an oncogene, and how it is driving disease, we developed a vertebrate zebrafish model and mouse allograft model of human VGLL2-NCOA2 driven sarcomagenesis. We found that VGLL2-NCOA2 is indeed an oncogene and is sufficient to generate mesenchymal tumors that recapitulate the human disease at the histological and transcriptional level. Zebrafish VGLL2-NCOA2 tumors display features of arrested skeletal muscle development, and a subset transcriptionally cluster with somitogenesis in developing embryos. By comparing tumor and embryonic gene expression signatures, we identified developmentally regulated targets that VGLL2-NCOA2 potentially leverages for tumorigenesis. These targets highlight the core biology of the disease and could represent therapeutic opportunities. Specifically, a RAS family GTPase, arf6/ARF6, involved in actin remodeling and rapid cycling of endocytic vesicles at the plasma membrane, is highly expressed during zebrafish somitogenesis and in VGLL2-NCOA2 tumors. In zebrafish tumors, arf6 protein is highly expressed and is absent from mature skeletal muscle. In VGLL2-NCOA2 mouse allograft models and patient tumors, ARF6 mRNA is overexpressed as compared to skeletal muscle or normal controls. More broadly, ARF6 is overexpressed in adult and pediatric sarcoma subtypes as compared to mature skeletal muscle. Overall, our cross-species comparative oncology approach provides evidence that VGLL2-NCOA2 is an oncogene which leverages developmental programs for tumorigenesis, and that one of these programs, the reactivation or persistence of arf6/ARF6, could represent a therapeutic opportunity.

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Recurrent MEIS1-NCOA2/1 fusions in a subset of low-grade spindle cell sarcomas frequently involving the genitourinary and gynecologic tracts

Abstract: C. R. (2021). Recurrent MEIS1-NCOA2/1 fusions in a subset of low-grade spindle cell sarcomas frequently involving the genitourinary and gynecologic tracts. Modern Pathology.

Cited by 33 publications

References 19 publications

Novel fusion genes in spindle cell rhabdomyosarcoma: The spectrum broadens

Novel fusion genes in spindle cell rhabdomyosarcoma: The spectrum broadens

Rhabdomyosarcoma: How Advanced Molecular Methods Are Shaping the Diagnostic and Therapeutic Paradigm

VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis

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