The expanding morphological and genetic spectrum of <i>MYOD1</i>‐mutant spindle cell/sclerosing rhabdomyosarcomas: a clinicopathological and molecular comparison of mutated and non‐mutated cases

Tsai, Jen‐Wei; Changchien, Yi-Che; Lee, Jen‐Chieh; Kao, Yu-Chien; Li, Wan-Shan; Liang, Cher‐Wei; Liao, I‐Chuang; Chang, Yi-Ming; Wang, Jui-Chu; Tsao, Cheng-Feng; Yu, Shih-Chen; Huang, Hsuan‐Ying

doi:10.1111/his.13819

Cited by 18 publications

(16 citation statements)

References 25 publications

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“…Including our six cases, the MYOD1 p.L122R hotspot mutation has been reported in 30 pediatric patients (Table 2) [26]. Notably, tumors with the MYOD1 mutation were more likely to arise in the head or neck (40%; 12/30) and more commonly diagnosed in adolescence (63%; 19/30).…”

Section: Resultsmentioning

confidence: 86%

Genomic analysis and preclinical xenograft model development identify potential therapeutic targets for MYOD1‐mutant soft‐tissue sarcoma of childhood

Ting

Reuther

Chandramohan

et al. 2021

The Journal of Pathology

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The myogenic differentiation 1 gene (MYOD1) p.L122R somatic mutation was first discovered in a subset of clinically aggressive embryonal rhabdomyosarcomas and has since been described in both pediatric and adult spindle cell/sclerosing rhabdomyosarcomas. Relatively little is known about the clinical, molecular, and histopathological features of these tumors in children. In order to further characterize the genomic and clinical features of pediatric MYOD1‐mutant sarcomas, we evaluated a cohort of soft‐tissue sarcoma patients treated at Texas Children's Hospital. Tumor DNA was subjected to next‐generation panel sequencing and/or Sanger sequencing of the MYOD1 hotspot mutation. The MYOD1 p.L122R mutation was identified in six tumors, with a variant allele fraction greater than 0.8 in three cases, suggestive of loss of heterozygosity. One sclerosing rhabdomyosarcoma lacking the MYOD1 hotspot mutation was observed to have a MYOD1 copy number gain, also with evidence of loss of heterozygosity. Cancer gene panel sequencing revealed potentially targetable alterations in six of seven (86%) patients with MYOD1 alterations, including four patients with an alteration in the PI3K‐AKT pathway: two hotspot PIK3CA mutations and deletions in PTEN and TSC2. On histopathologic review, MYOD1‐altered tumors exhibited spindle and/or round cells and varying degrees of hyaline sclerosis. At last follow‐up, six patients had died of disease and the seventh progressed early and was subsequently lost to follow‐up. Both pre‐ and post‐therapy patient‐derived xenograft models were generated from one patient's tumor. These models were confirmed to harbor the MYOD1 and PIK3CA mutations seen in the primary tumor and were shown to be sensitive to PI3K/mTOR inhibition in vitro and in vivo. In conclusion, this study adds to recent reports describing the clinicopathologic and genomic features of MYOD1‐altered soft‐tissue sarcomas in children, including dismal prognosis and potential molecular targets for therapy. The novel preclinical models developed will facilitate further biological and preclinical study of this rare and aggressive tumor. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Resultsmentioning

confidence: 86%

Genomic analysis and preclinical xenograft model development identify potential therapeutic targets for MYOD1‐mutant soft‐tissue sarcoma of childhood

Ting

Reuther

Chandramohan

et al. 2021

The Journal of Pathology

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“…While several ERMS and ARMS cell lines are available for research [39], the establishment of the first SSRMS cell line from an adolescent was only recently reported [29]. Indeed, SSRMS is a rare RMS subtype that is often characterized by aggressive progress, especially when exhibiting a MYOD1 mutation [16][17][18][19].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, desmin is frequently expressed by SSRMS and a focal positivity for myogenin (MYOG), combined with a high proliferative index (marker of proliferation Ki-67), has been reported, while the ARMS typic paired box (PAX)-forkhead box protein O1 (FOXO1) fusion proteins are absent in SSRMS [14][15][16]. Though expressing myogenic marker proteins, the completion of myogenic differentiation is inhibited in SSRMS, due to frequently observed recurrent MYOD1 mutations [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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

Schleicher

Grote

Malenke

et al. 2020

Cells

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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.

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“… 7 TIAL1 protein intracellularly binds with its target mRNA, which generally decreases their stability or inhibits its translation and participates in various cellular functions. 7 - 9 …”

Section: Introductionmentioning

confidence: 99%

“… 8 MyoD1 and myogenin are myogenic regulatory protein that is expressed in the early stage of skeletal muscle differentiation, which is only expressed in embryonic skeletal muscle. 8 , 10 Zhu et al 5 reported that Long non-coding RNA MBNL1-AS1 regulates proliferation, migration, and invasion of cancer stem cells in colon cancer. The present study aimed to investigate the function and mechanism of MBNL1 in skin squamous cell carcinoma.…”

Section: Introductionmentioning

confidence: 99%

MBNL1 Suppressed Cancer Metastatic of Skin Squamous Cell Carcinoma Via by TIAL1/MYOD1/Caspase-9/3 Signaling Pathways

Chen

Wang

Qian

et al. 2021

Technol Cancer Res Treat

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Objective: The incidence of skin squamous cell carcinoma (SSCC) has recently been increasing, with diverse clinical manifestations.SSCC could metastasize to lymph nodes or other organs, posing a great threat to life. The present study was designed to investigate the function and underlying mechanism of muscleblind-like protein 1 (MBNL1) in skin squamous cell carcinoma. Methods: SCL-1 cell was used for vitro model and transfected with MBNL1 or siMBNL1 plasmids. MTT Assays, LDH activity ELISA, and Transwell chamber migration experiment were used to confirm the effects of MBNL1 on cell growth of SCL-1 cell. Western blot analysis was used to analyze the mechanism of MBNL1 in SCL-1 cell. Results: Down-regulation of MBNL1 promoted cell metastasis of SSCC, while up-regulation of MBNL1 reduced cell metastasis of SSCC in vitro. Down-regulation of MBNL1 suppressed the protein expression of T cell intracellular antigen (TIAL1), myogenic determinant 1 (MyoD1) and Caspase-3 in vitro. Consistent with these observations, inhibition of TIAL1 or MYOD1 expression attenuated the effects of MBNL1 in SSCC. Conclusion: The present study revealed that MBNL1 suppressed thecancer metastatic capacity of SSCC via by TIAL1/MYOD1/Caspase-3 signaling pathways.

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The expanding morphological and genetic spectrum of MYOD1‐mutant spindle cell/sclerosing rhabdomyosarcomas: a clinicopathological and molecular comparison of mutated and non‐mutated cases

Cited by 18 publications

References 25 publications

Genomic analysis and preclinical xenograft model development identify potential therapeutic targets for MYOD1‐mutant soft‐tissue sarcoma of childhood

Genomic analysis and preclinical xenograft model development identify potential therapeutic targets for MYOD1‐mutant soft‐tissue sarcoma of childhood

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

MBNL1 Suppressed Cancer Metastatic of Skin Squamous Cell Carcinoma Via by TIAL1/MYOD1/Caspase-9/3 Signaling Pathways

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