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Oncogene Mar 2022Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar...
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar subtype (ARMS) has the poorest prognosis and represents the greatest unmet medical need for RMS. Emerging evidence supports the role of epigenetic dysregulation in RMS. Here we show that SMARCA4/BRG1, an ATP-dependent chromatin remodeling enzyme of the SWI/SNF complex, is prominently expressed in primary tumors from ARMS patients and cell cultures. Our validation studies for a CRISPR screen of 400 epigenetic targets identified SMARCA4 as a unique factor for long-term (but not short-term) tumor cell survival in ARMS. A SMARCA4/SMARCA2 protein degrader (ACBI-1) demonstrated similar long-term tumor cell dependence in vitro and in vivo. These results credential SMARCA4 as a tumor cell dependency factor and a therapeutic target in ARMS.
Topics: Biology; Child; DNA Helicases; Humans; Neoplasms; Nuclear Proteins; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal; Transcription Factors
PubMed: 35094009
DOI: 10.1038/s41388-022-02205-0 -
PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors.Nature Communications Nov 2023Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma....
Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.
Topics: Animals; Child; Humans; Mice; Cell Line, Tumor; Endothelial Cells; Forkhead Box Protein O1; Gene Expression Regulation, Neoplastic; Muscle, Skeletal; Oncogene Proteins, Fusion; Paired Box Transcription Factors; PAX3 Transcription Factor; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar
PubMed: 37968277
DOI: 10.1038/s41467-023-43044-1 -
F1000Research 2020Urothelial pediatric neoplasms are relatively rare. Papillary urothelial neoplasms of low malignant potential (PUNLMPs) and rhabdomyosarcoma (RMS) are the most common... (Review)
Review
Urothelial pediatric neoplasms are relatively rare. Papillary urothelial neoplasms of low malignant potential (PUNLMPs) and rhabdomyosarcoma (RMS) are the most common bladder malignancies in the pediatric population. Clinical presentation encompasses macroscopic hematuria or lower urinary tract symptoms (or both) or is detected incidentally at imaging. Tumors arising from the bladder can originate from any of its four histological layers (urothelium, lamina propria, detrusor, and adventitia) and are divided into tumors that have an epithelial origin (arising from the urothelium) and those that have a non-epithelial origin (mesenchymal neoplasms). RMS is the most common malignant tumor of the urinary bladder in children younger than 10 years. Deriving from the embryonic mesenchymal cell, the histopathologic subtypes of RMS are embryonal RMS (>90%) and alveolar histology (<10%). Pre-treatment imaging should be carried out by computed tomography (CT) or at present is more likely with magnetic resonance imaging of the pelvis. Chest CT and bone scintigraphy are used to screen for metastases. In selected cases, a positron emission tomography scan may be recommended to evaluate suspicious lesions. The current prognostic classification considers age, histologic subtype, tumor site, size, and extent (nodal or distant metastases). Staging is based on pre-operative findings, group is based on intra-operative findings and pathology, and risk stratification is derived from both stage and group data. Pre-operative chemotherapy is the most common first-line intervention for bladder/prostate RMS, before surgery or radiation therapy. Collaborative groups such as the Soft Tissue Sarcoma Committee of the Children's Oncology Group and the European Pediatric Soft Tissue Sarcoma Study Group endorse this therapy. PUNLMPs are generally solitary, small (1-2 cm), non-invasive lesions that do not metastasize. Therapy is usually limited to a transurethral resection of the bladder tumor. About 35% are recurrent and around 10% of them increase in size if they are not treated.
Topics: Child; Humans; Male; Prognosis; Prostatic Neoplasms; Rhabdomyosarcoma; Urinary Bladder Neoplasms
PubMed: 32148770
DOI: 10.12688/f1000research.19396.1 -
Modern Pathology : An Official Journal... Sep 2022Correctly diagnosing a rare childhood cancer such as sarcoma can be critical to assigning the correct treatment regimen. With a finite number of pathologists worldwide...
Correctly diagnosing a rare childhood cancer such as sarcoma can be critical to assigning the correct treatment regimen. With a finite number of pathologists worldwide specializing in pediatric/young adult sarcoma histopathology, access to expert differential diagnosis early in case assessment is limited for many global regions. The lack of highly-trained sarcoma pathologists is especially pronounced in low to middle-income countries, where pathology expertise may be limited despite a similar rate of sarcoma incidence. To address this issue in part, we developed a deep learning convolutional neural network (CNN)-based differential diagnosis system to act as a pre-pathologist screening tool that quantifies diagnosis likelihood amongst trained soft-tissue sarcoma subtypes based on whole histopathology tissue slides. The CNN model is trained on a cohort of 424 centrally-reviewed histopathology tissue slides of alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma and clear-cell sarcoma tumors, all initially diagnosed at the originating institution and subsequently validated by central review. This CNN model was able to accurately classify the withheld testing cohort with resulting receiver operating characteristic (ROC) area under curve (AUC) values above 0.889 for all tested sarcoma subtypes. We subsequently used the CNN model to classify an externally-sourced cohort of human alveolar and embryonal rhabdomyosarcoma samples and a cohort of 318 histopathology tissue sections from genetically engineered mouse models of rhabdomyosarcoma. Finally, we investigated the overall robustness of the trained CNN model with respect to histopathological variations such as anaplasia, and classification outcomes on histopathology slides from untrained disease models. Overall positive results from our validation studies coupled with the limited worldwide availability of sarcoma pathology expertise suggests the potential of machine learning to assist local pathologists in quickly narrowing the differential diagnosis of sarcoma subtype in children, adolescents, and young adults.
Topics: Adolescent; Animals; Child; Humans; Machine Learning; Mice; Neural Networks, Computer; Pathologists; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Young Adult
PubMed: 35449398
DOI: 10.1038/s41379-022-01075-x -
Archives of Pathology & Laboratory... Aug 2022Rhabdomyosarcoma, the most common soft tissue sarcoma of children, is currently classified into the following 4 subtypes: embryonal rhabdomyosarcoma, alveolar... (Review)
Review
CONTEXT.—
Rhabdomyosarcoma, the most common soft tissue sarcoma of children, is currently classified into the following 4 subtypes: embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, spindle cell/sclerosing rhabdomyosarcoma, and pleomorphic rhabdomyosarcoma, based on recent molecular genetic knowledge and morphologic features.
OBJECTIVE.—
To highlight the most recent advances of molecular genetic alterations, and to familiarize pathologists with most recent genotype and phenotype correlation in rhabdomyosarcoma.
DATA SOURCES.—
Data were derived from the World Health Organization Classification of Soft Tissue and Bone Tumors, fifth edition, recently published literature (PubMed), and clinical practice experience.
CONCLUSIONS.—
Current classification has been significantly impacted by genotype and phenotype correlation, especially with PAX-FOXO1 fusion-positive rhabdomyosarcoma versus fusion-negative rhabdomyosarcoma, and with the emergence of 3 distinct new subtypes of spindle cell/sclerosing rhabdomyosarcoma. Although all rhabdomyosarcomas were considered a single diagnostic entity in the past, they are now considered to be a group of histologically similar but biologically diverse entities because their clinical behavior and underlying molecular alterations dramatically differ. This review outlines recent molecular genetic developments, corresponding morphologic features, and current challenges faced by pathologists in daily practice.
Topics: Humans; Mutation; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Soft Tissue Neoplasms; World Health Organization
PubMed: 35051261
DOI: 10.5858/arpa.2021-0183-RA -
JCO Precision Oncology Jun 2023Extremity rhabdomyosarcoma (RMS) is associated with a very poor outcome compared with other sites, mainly because of its high incidence of alveolar histology and...
PURPOSE
Extremity rhabdomyosarcoma (RMS) is associated with a very poor outcome compared with other sites, mainly because of its high incidence of alveolar histology and regional lymph node involvement. To better define prognostic markers in this clinical subset, we investigated our experience of 61 patients with extremity RMS treated at our tertiary cancer center for the past 2 decades.
PATIENTS AND METHODS
The patients had a median age of 8 years at diagnosis, equal gender distribution, and two-thirds occurred in the lower extremity. Most (85%) patients had fusion-positive alveolar RMS (ARMS), with 70% having a transcript. Remaining were seven patients with fusion-negative embryonal RMS (ERMS) and two with mutant spindle cell/sclerosing RMS (SRMS). In 40% of the patients, material was available for DNA-based targeted sequencing using MSK-IMPACT cancer gene panel.
RESULTS
One-third of patients presented with localized disease at diagnosis while the remaining had regional nodal (18%) or distant metastases (51%). Metastatic disease, high-risk group, and age 10 years or older significantly affected the overall survival (OS; hazard ratio [HR], 2.68 [ = .004], 2.78 [ = .010] and 2.26 [ .034], respectively). Although the presence of metastatic disease had a dismal impact on 5-year EFS and OS (19% and 29%, respectively), nodal involvement had a comparatively lower impact on 5-year EFS and 5-year OS (43% and 66%, respectively). ARMS had worse prognosis and afflicted older children compared with (HR = 3.45, .016). The most common events in the ARMS group included alterations, amplifications, and deletions (8%-17%). The latter two abnormalities were mutually exclusive, enriched for acral and high-risk lesions, and correlated with poor outcome on OS ( = .02).
CONCLUSION
Our data provide rationale for considering the integration of molecular abnormalities to refine risk stratification in extremity RMS.
Topics: Child; Humans; Adolescent; Genomics; Rhabdomyosarcoma; Extremities; Oncogenes; Risk Assessment
PubMed: 37315267
DOI: 10.1200/PO.22.00705 -
Cold Spring Harbor Molecular Case... Feb 2021Rhabdomyosarcoma (RMS) is a mesenchymal malignancy phenocopying muscle and is among the leading causes of death from childhood cancer. Metastatic alveolar...
Rhabdomyosarcoma (RMS) is a mesenchymal malignancy phenocopying muscle and is among the leading causes of death from childhood cancer. Metastatic alveolar rhabdomyosarcoma is the most aggressive subtype with an 8% 5-yr disease-free survival rate when a chromosomal fusion is present and a 29% 5-yr disease-free survival rate when negative for a fusion event. The underlying biology of -fusion-negative alveolar rhabdomyosarcoma remains largely unexplored and is exceedingly rare in Li-Fraumeni syndrome patients. Here, we present the case of an 11-yr-old male with fusion-negative alveolar rhabdomyosarcoma studied at end of life with a comprehensive functional genomics characterization, resulting in identification of potential therapeutic targets for broader investigation.
Topics: Antineoplastic Agents; Child; Drug Screening Assays, Antitumor; Germ Cells; Humans; Male; Rhabdomyosarcoma, Alveolar; Tumor Suppressor Protein p53; Exome Sequencing
PubMed: 33436392
DOI: 10.1101/mcs.a005983 -
Histopathology May 2021Mucin 4 (MUC4) is a transmembrane glycoprotein normally expressed by several human epithelial surfaces, including those of the colon, vagina, and respiratory tract....
AIMS
Mucin 4 (MUC4) is a transmembrane glycoprotein normally expressed by several human epithelial surfaces, including those of the colon, vagina, and respiratory tract. Although MUC4 overexpression is seen in various carcinomas, its expression among mesenchymal neoplasms is fairly specific to low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma. Having observed unanticipated anti-MUC4 immunoreactivity in rhabdomyosarcoma, we aimed to further characterise its expression.
METHODS AND RESULTS
Expression of MUC4 was assessed by immunohistochemistry in a total of 97 rhabdomyosarcomas using formalin-fixed paraffin-embedded tissue sections. MUC4 was expressed by 21 of 26 PAX3/7-FOXO1 fusion-positive cases, wherein immunoreactivity, varying from weak to strong, was present in 20-100% of neoplastic cells. With the exception of one sclerosing rhabdomyosarcoma showing immunoreactivity in 20% of cells, MUC4 was not expressed by embryonal (n = 28), sclerosing (n = 20), or pleomorphic (n = 23) rhabdomyosarcomas. Analysing published gene expression microarray data from a separate cohort of 33 fusion-positive and 25 fusion-negative rhabdomyosarcomas, we found on average a 11.4-fold increased expression in fusion-positive tumours (P = 0.0004).
CONCLUSIONS
MUC4 is expressed to a variable extent in the majority of PAX3/7-FOXO1 fusion-positive (alveolar) rhabdomyosarcomas, while expression in other rhabdomyosarcoma subtypes is rare.
Topics: Adult; Female; Head and Neck Neoplasms; Humans; Mucin-4; Rhabdomyosarcoma, Alveolar; Soft Tissue Neoplasms
PubMed: 33368602
DOI: 10.1111/his.14321 -
Nature Communications Nov 2021Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations...
Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations encoding for PAX3- or PAX7-FOXO1 chimeric transcription factors, respectively, and are referred to as fusion positive RMS (FP-RMS). The fusion gene alters the myogenic program and maintains the proliferative state while blocking terminal differentiation. Here, we investigated the contributions of chromatin regulatory complexes to FP-RMS tumor maintenance. We define the mSWI/SNF functional repertoire in FP-RMS. We find that SMARCA4 (encoding BRG1) is overexpressed in this malignancy compared to skeletal muscle and is essential for cell proliferation. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which is further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with core regulatory transcription factors. Further, mSWI/SNF complexes localize to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes, which is recapitulated by BRG1 targeting compounds. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for this lethal childhood tumor.
Topics: Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Child; Chromatin; DNA Helicases; Epigenomics; Gene Expression Regulation, Neoplastic; Humans; Muscle Development; Muscle, Skeletal; Nuclear Proteins; Oncogene Proteins, Fusion; PAX7 Transcription Factor; Paired Box Transcription Factors; Proteomics; Rhabdomyosarcoma; Transcription Factors; Transcriptional Activation
PubMed: 34836971
DOI: 10.1038/s41467-021-27176-w -
Journal of the Korean Association of... Apr 2023This systematic review aimed to analyze the clinicopathological profile and relevant prognostic factors of head and neck rhabdomyosarcoma in pediatric patients. The... (Review)
Review
This systematic review aimed to analyze the clinicopathological profile and relevant prognostic factors of head and neck rhabdomyosarcoma in pediatric patients. The search was carried out in the electronic search portals PubMed, Lilacs, Embase, Scopus, and Web of Science. The search yielded studies that were then analyzed regarding study topic, data extraction, and risk of bias using the STROBE (Strengthening the Reporting of Observational Studies) guidelines. Finally, three studies were included for qualitative analysis. Most of the cases involved embryonic and alveolar rhabdomyosarcoma. Expression of MYOD1 was highly correlated with diagnosis of spindle cell/sclerosing rhabdomyosarcoma, which appears to have a poor prognosis in children. Furthermore, tumor size <5 cm and absence of metastasis accompanied by complete resection and administration of adjuvant therapies such as chemotherapy and radiotherapy favored a better prognosis.
PubMed: 37114443
DOI: 10.5125/jkaoms.2023.49.2.61