Dataset Information

Establishment and Characterization of a Sclerosing Spindle Cell Rhabdomyosarcoma Cell Line with a Complex Genomic Profile.

ABSTRACT: Sclerosing spindle cell rhabdomyosarcoma (SSRMS) is a rare rhabdomyosarcomas (RMS) subtype. Especially cases bearing a myogenic differentiation 1 (MYOD1) mutation are characterized by a high recurrence and metastasis rate, often leading to a fatal outcome. SSRMS cell lines are valuable in vitro models for studying disease mechanisms and for the preclinical evaluation of new therapeutic approaches. In this study, a cell line established from a primary SSRMS tumor of a 24-year-old female after multimodal chemotherapeutic pretreatment has been characterized in detail, including immunohistochemistry, growth characteristics, cytogenetic analysis, mutation analysis, evaluation of stem cell marker expression, differentiation potential, and tumorigenicity in mice. The cell line which was designated SRH exhibited a complex genomic profile, including several translocations and deletions. Array-comparative genomic hybridization (CGH) revealed an overall predominating loss of gene loci. The mesenchymal tumor origin was underlined by the expression of mesenchymal markers and potential to undergo adipogenic and osteogenic differentiation. Despite myogenic marker expression, terminal myogenic differentiation was inhibited, which might be elicited by the MYOD1 hotspot mutation. In vivo tumorigenicity could be confirmed after subcutaneous injection into NOD/SCID/γcnull mice. Summarized, the SRH cell line is the first adult SSRMS cell line available for preclinical research on this rare RMS subtype.

SUBMITTER: Schleicher S

PROVIDER: S-EPMC7763666 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Establishment and Characterization of a Sclerosing Spindle Cell Rhabdomyosarcoma Cell Line with a Complex Genomic Profile.

Schleicher Sabine S Grote Stefan S Malenke Elke E Chan Kenneth Chun-Ho KC Schaller Martin M Fehrenbacher Birgit B Riester Rosa R Kluba Torsten T Frauenfeld Leonie L Boesmueller Hans H Göhring Gudrun G Schlegelberger Brigitte B Handgretinger Rupert R Kopp Hans-Georg HG Traub Frank F Boehme Karen A KA

Cells 20201211 12

Sclerosing spindle cell rhabdomyosarcoma (SSRMS) is a rare rhabdomyosarcomas (RMS) subtype. Especially cases bearing a myogenic differentiation 1 (<i>MYOD1</i>) mutation are characterized by a high recurrence and metastasis rate, often leading to a fatal outcome. SSRMS cell lines are valuable in vitro models for studying disease mechanisms and for the preclinical evaluation of new therapeutic approaches. In this study, a cell line established from a primary SSRMS tumor of a 24-year-old female af ...[more]

PMID: 33322555

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Project description:BackgroundFUS-TFCP2 gene fusion is a recently identified and highly distinct molecular subtype of spindle cell/sclerosing rhabdomyosarcoma (RMS), with fewer than 40 cases being reported to date. Due to its low incidence, clinical studies on this subtype are limited. Here, we report a new case of this rare entity to describe and summarize its unique clinical characteristics and treatment process, aiming to emphasize the importance of molecular testing for spindle cell/sclerosing RMS and increase the understanding of this subtype. By summarizing and comparing with previous reports on RMS with the EWSR1/FUS-TFCP2 fusion mutation, we hope to make some new hints for its management.Case descriptionIn this report, we describe a rare case of spindle cell/sclerosing RMS in a 13-year-old boy, who had a massive destructive lesion involving the mandible. Next-generation sequencing of tumor tissue revealing a FUS-TFCP2 fusion. The tumor was extremely aggressive and showed resistance to polychemotherapy, after 4 cycles of multi drug combined chemotherapy, the primary tumor still continued to grow, and suspicious chest metastasis occurred. Even after aggressive total resection of the primary tumor and postoperative chemotherapy, systemic metastasis to the vertebra and chest could not be prevented yet, ultimately with a fatal outcome within 6 months. We additionally summarize 37 cases of RMS with the EWSR1/FUS-TFCP2 fusion mutation reported in the literature. This subtype was found to be almost exclusively primary in bone and histologically showed a common origin of epithelium and muscle. The high aggressiveness made the conventional standard chemoradiotherapy ineffective. Because most tumors of this subtype express ALK protein, ALK inhibitors seem to be a new target for its therapy.ConclusionsSpindle cell/sclerosing RMS with FUS-TFCP2 fusion has its unique clinical characteristics and progression. It shows a marked skeletal predilection and an aggressive clinical course, typically resistant to traditional standard treatments for RMS. Therefore, molecular detection is crucial in managing this subtype. Once the diagnosis is clear, a more aggressive treatment plan is needed. In addition, almost all cases were found to have a positive expression of ALK. So ALK inhibitors can be a choice of targeted therapy.

Project description:Sclerosing and spindle cell rhabdomyosarcoma is a rare histologic subtype, designated in the latest WHO classification as a stand-alone pathologic entity. Three genomic groups have been defined: an infantile subset of spindle cell rhabdomyosarcoma harboring VGLL2-related gene fusions, a MYOD1-mutant subset commonly associated with sclerosing morphology, and a subset lacking recurrent genetic abnormalities. In this study, we focus on MYOD1-mutant rhabdomyosarcoma to further define their clinicopathologic characteristics and behavior in a larger patient cohort. We investigated 30 cases of MYOD1-mutant rhabdomyosarcoma (12 previously reported and 18 newly diagnosed) with an age range of 2-94 years, including 15 children. All cases showed morphology within the spectrum of spindle cell/sclerosing rhabdomyosarcoma (8 cases showing pure sclerosing morphology, 8 cases showing pure spindle cell morphology and 14 cases showing a hybrid phenotype of spindle, sclerosing and primitive undifferentiated areas). All tumors harbored either homozygous or heterozygous MYOD1 (p.L122R) exon 1 mutations. In 10 (33%) cases, a co-existent PIK3CA mutation was identified. Hot-spot mutations in NRAS and HRAS were each identified in a single case, respectively. Follow-up was available on 22 (73%) patients with a median duration of 28 months. Local recurrence was seen in 12 (55%) and distant recurrence in 12 (55%) cases, despite multimodality chemoradiation therapy. At last follow-up, 15 (68%) patients died of the disease, one patient was alive with disease and five had no evidence of disease. The prognosis was equally poor in pediatric and adult patients. In conclusion, MYOD1 mutation defines an aggressive rhabdomyosarcoma subset, with poor outcome and response to therapy, irrespective of age. Given that this distinct molecular subtype is characterized by an aggressive biologic behavior compared to other genetic subtypes of spindle and sclerosing rhabdomyosarcoma, the MYOD1 genotype should be used as a molecular marker in both subclassification and prognostication of rhabdomyosarcoma.

Dataset Information

Establishment and Characterization of a Sclerosing Spindle Cell Rhabdomyosarcoma Cell Line with a Complex Genomic Profile.

Publications

Establishment and Characterization of a Sclerosing Spindle Cell Rhabdomyosarcoma Cell Line with a Complex Genomic Profile.

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