Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children with an annual incidence of five new cases per million. Alveolar rhabdomyosarcoma (ARMS) is characterized by the t(2;13) or t(1;13) chromosomal translocations, which generate the PAX3-FOXO1 or PAX7-FOXO1 fusion genes, respectively. The oncogenic activity of PAX3-FOXO1 has been demonstrated in vitro and in vivo, yet expression of the fusion protein alone in primary myoblasts or a mouse model is insufficient for tumorigenic transformation. To identify genes cooperating with PAX3-FOXO1 in ARMS tumorigenesis, we generated a retroviral complementary DNA (cDNA) expression library from the Rh30 ARMS cell line. Arf-/- myoblasts expressing PAX3-FOXO1 and the retroviral cDNA library rapidly formed tumors after subcutaneous injection into NOD-SCID mice. Tumors formed by Arf-/-/PAX3-FOXO1/MarX-library myoblasts contained an unknown cDNA, encoding the C-terminus of the Homo sapiens hypothetical protein, FLJ10404, herein named IRIZIO. Expression of full length IRIZIO cDNA also cooperated with PAX3-FOXO1 in the transformation of Arf-/- myoblasts. Given that IRIZIO is expressed at increased levels in RMS, it might contribute to rhabdomyosarcomagenesis in humans.
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PMID:IRIZIO: a novel gene cooperating with PAX3-FOXO1 in alveolar rhabdomyosarcoma (ARMS). 2117 67

"Convenience cohorts" comprise individuals thought to represent the general population, but chosen because they are readily available for evaluation, rather than at random. As such, these methods are subject to bias and may be misleading. Convenience cohorts have been used to investigate the prognostic significance of chromosomal translocations between the PAX3 or PAX7 and the FOXO1 genes in rhabdomyosarcoma, the most common pediatric sarcoma. However, retrospective studies assessing the role of PAX-FOXO1 translocations have yielded inconsistent results. This review highlights the findings from several clinical correlation studies of the PAX-FOXO1 biomarker and illustrates the challenges of using such methods to draw clinical conclusions.
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PMID:The inconvenience of convenience cohorts: rhabdomyosarcoma and the PAX-FOXO1 biomarker. 2273 87

Rhabdomyosarcoma (RMS) is the commonest soft-tissue sarcoma in childhood and is characterized by expression of myogenic proteins, including the transcription factors MyoD and myogenin. There are two main subgroups, embryonal RMS and alveolar RMS (ARMS). Most ARMS are associated with chromosomal translocations that have breakpoints in introns of either PAX3 or PAX7, and FOXO1A. These translocations create chimeric transcription factors termed PAX3/FOXO1A and PAX7/FOXO1A respectively. Upon ectopic PAX3/FOXO1A expression, together with other genetic manipulation in mice, both differentiating myoblasts and satellite cells (the resident stem cells of postnatal muscle) can give rise to tumours with ARMS characteristics. As PAX3 and PAX7 are part of transcriptional networks that regulate muscle stem cell function in utero and during early postnatal life, PAX3/FOXO1A and PAX7/FOXO1A may subvert normal PAX3 and PAX7 functions. Here we examined how PAX3/FOXO1A and PAX7/FOXO1A affect myogenesis in satellite cells. PAX3/FOXO1A or PAX7/FOXO1A inhibited myogenin expression and prevented terminal differentiation in murine satellite cells: the same effect as dominant-negative (DN) Pax3 or Pax7 constructs. The transcription of MyoD-target genes myogenin and muscle creatine kinase were suppressed by PAX3/FOXO1A or PAX7/FOXO1A in C2C12 myogenic cells again as seen with Pax3/7DN. PAX3/FOXO1A or PAX7/FOXO1A did not inhibit the transcriptional activity of MyoD by perturbing MyoD expression, localization, phosphorylation or interaction with E-proteins. Chromatin immunoprecipitation on the myogenin promoter showed that PAX3/FOXO1A or PAX7/FOXO1A did not prevent MyoD from binding. However, PAX3/FOXO1A or PAX7/FOXO1A reduced occupation of the myogenin promoter by RNA polymerase II and decreased acetylation of histone H4, but did not directly bind to the myogenin promoter. Together, these observations reveal that PAX3/FOXO1A and PAX7/FOXO1A act to prevent myogenic differentiation via suppression of the transcriptional activation of MyoD-target genes.
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PMID:Alveolar rhabdomyosarcoma-associated proteins PAX3/FOXO1A and PAX7/FOXO1A suppress the transcriptional activity of MyoD-target genes in muscle stem cells. 2271 Jul 12

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, has traditionally been classified into embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma (ARMS) for pediatric oncology practice. This review outlines the historical development of classification of childhood RMS and the challenges that have been associated with it, particularly problems with the diagnosis of "solid variant" ARMS and its distinction from ERMS. In addition to differences in clinical presentation and outcome, a number of genetic features underpin separation of ERMS from ARMS. Genetic differences associated with RMS subclassification include the presence of reciprocal translocations and their associated fusions in ARMS, amplification of genes in ARMS and its fusion subsets, chromosomal losses and gains that mostly occur in ERMS, and allelic losses and mutations usually associated with ERMS. Chimeric proteins encoded in most ARMS from the fusion of PAX3 or PAX7 with FOXO1 are expressed, result in a distinct pattern of downstream protein expression, and appear to be the proximate cause of the bad outcome associated with this subtype. A sizeable minority of ARMS lacks these fusions and shares the clinical and biological features of ERMS. A battery of immunohistochemical tests may prove useful in separating ERMS from ARMS and fusion-positive ARMS from fusion-negative ARMS. Because of limitation of predicting outcome solely based on histologic classification, treatment protocols will begin to utilize fusion testing for stratification of affected patients into low-risk, intermediate-risk, and high-risk groups.
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PMID:Classification of rhabdomyosarcoma and its molecular basis. 2411 9

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children. Although associations between ARMS tumorigenesis and PAX3, PAX7, and FKHR are well recognized, the complete genetic etiology underlying RMS pathogenesis and progression remains unclear. Chromosomal copy number variations (CNVs) and the involved genes may play important roles in the pathogenesis and progression of human malignancies. Using high-resolution array comparative genomic hybridization (aCGH), we examined 20 formalin-fixed, paraffin-embedded (FFPE) RMS tumors to explore the involvement of the relevant chromosomal regions with resident genes in RMS tumorigenesis. In RMS, frequent gains were identified on chromosome regions 12q13.3-q14.1, 12q24.31, 17q25.1, 1q21.1, and 7q11.23, whereas frequent losses were observed on chromosome regions 5q13.2, 14q32.33, and 15q11.2. Amplifications were observed on chromosome regions 9p13.3, 12q13.3-q14.1, 12q15, and 16p13.11, whereas deletions were detected on chromosome regions 1p36.33, 1p13.1, 2q11.1, 5q13.2, 8p23.1, 9p24.3, and 16p11.2. Frequent gains were detected in GLI1, GEFT, OS9, and CDK4 (12q13.3-q14.1), being 60% in embryonal rhabdomyosarcoma (ERMS) and 66.67% in alveolar rhabdomyosarcoma (ARMS), respectively. However, frequent losses were detected in IGHG1, IGHM, IGHG3, and IGHG4 (14q32.33), being 70% in ERMS and 55.56% in and ARMS, respectively. Frequent gains were detected in TYROBP, HCST, LRFN3, and ALKBH6 (19q13.12) in ERMS but not in ARMS. The frequency of TYROBP, HCST, LRFN3, and ALKBH6 gains is significantly different in ERMS versus ARMS (P=0.011). The results suggest that novel TYROBP, HCST, LRFN3, and ALKBH6 genes may play important roles in ERMS. The technique used is a feasible approach for array comparative genomic hybridization analysis in archival tumor samples.
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PMID:Chromosomal and genetic imbalances in Chinese patients with rhabdomyosarcoma detected by high-resolution array comparative genomic hybridization. 2455 Dec 91

Rhabdomyosarcoma, a cancer of skeletal muscle lineage, is the most common soft-tissue sarcoma in children. Major subtypes of rhabdomyosarcoma include alveolar (ARMS) and embryonal (ERMS) tumors. Whereas ARMS tumors typically contain translocations generating PAX3-FOXO1 or PAX7-FOXO1 fusions that block terminal myogenic differentiation, no functionally comparable genetic event has been found in ERMS tumors. Here we report the discovery, through whole-exome sequencing, of a recurrent somatic mutation encoding p.Leu122Arg in the myogenic transcription factor MYOD1 in a distinct subset of ERMS tumors with poor outcomes that also often contain mutations altering PI3K-AKT pathway components. Previous mutagenesis studies had shown that MYOD1 with a p.Leu122Arg substitution can block wild-type MYOD1 function and bind to MYC consensus sequences, suggesting a possible switch from differentiation to proliferation. Our functional data now confirm this prediction. Thus, MYOD1 p.Leu122Arg defines a subset of rhabdomyosarcomas eligible for high-risk protocols and the development of targeted therapeutics.
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PMID:A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations. 2529 32

Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malignancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called "fusion-positive" tumors) carries exclusive chromosomal translocations that join the DNA-binding domain of the PAX3 or PAX7 gene to the transactivation domain of the FOXO1 (previously known as FKHR) gene. Fusion-negative RMS represents a heterogeneous spectrum of tumors with frequent RAS pathway activation. Overtly metastatic disease at diagnosis is more frequently found in individuals with fusion-positive than in those with fusion-negative tumors. RMS is the most common pediatric soft-tissue sarcoma, and approximately 60% of all children and adolescents diagnosed with RMS are cured by currently available multimodal therapies. However, a curative outcome is achieved in <30% of high-risk individuals with RMS, including all those diagnosed as adults, those diagnosed with fusion-positive tumors during childhood (including metastatic and nonmetastatic tumors), and those diagnosed with metastatic disease during childhood (including fusion-positive and fusion-negative tumors). This white paper outlines current challenges in RMS research and their implications for developing more effective therapies. Urgent clinical problems include local control, systemic disease, need for improved risk stratification, and characterization of differences in disease course in children and adults. Biological challenges include definition of the cellular functions of PAX-FOXO1 fusion proteins, clarification of disease heterogeneity, elucidation of the cellular origins of RMS, delineation of the tumor microenvironment, and identification of means for rational selection and testing of new combination therapies. To streamline future therapeutic developments, it will be critical to improve access to fresh tumor tissue for research purposes, consider alternative trial designs to optimize early clinical testing of candidate drugs, coalesce advocacy efforts to garner public and industry support, and facilitate collaborative efforts between academia and industry.
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PMID:Rhabdomyosarcoma: current challenges and their implications for developing therapies. 2536 19

Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood and adolescence. The two major histological subtypes of RMS are alveolar RMS, driven by the fusion protein PAX3-FKHR or PAX7-FKHR, and embryonic RMS, which is usually genetically heterogeneous. The prognosis of RMS has improved in the past several decades due to multidisciplinary care. However, in recent years, the treatment of patients with metastatic or refractory RMS has reached a plateau. Thus, to improve the survival rate of RMS patients and their overall well-being, further understanding of the molecular and cellular biology of RMS and identification of novel therapeutic targets are imperative. In this review, we describe the most recent discoveries in the molecular and cellular biology of RMS, including alterations in oncogenic pathways, miRNA (miR), in vivo models, stem cells, and important signal transduction cascades implicated in the development and progression of RMS. Furthermore, we discuss novel potential targeted therapies that may improve the current treatment of RMS.
Sarcoma 2015
PMID:Rhabdomyosarcoma: Advances in Molecular and Cellular Biology. 2642 Sep 80

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. Alveolar (ARMS) and embryonal (ERMS) histologies predominate, but rare cases are classified as spindle cell/sclerosing (SRMS). For treatment stratification, RMS is further subclassified as fusion-positive (FP-RMS) or fusion-negative (FN-RMS), depending on whether a gene fusion involving PAX3 or PAX7 is present or not. We investigated 19 cases of pediatric RMS using high resolution single-nucleotide polymorphism (SNP) array. FP-ARMS displayed, on average, more structural rearrangements than ERMS; the single FN-ARMS had a genomic profile similar to ERMS. Apart from previously known amplification (e.g., MYCN, CDK4, and MIR17HG) and deletion (e.g., NF1, CDKN2A, and CDKN2B) targets, amplification of ERBB2 and homozygous loss of ASCC3 or ODZ3 were seen. Combining SNP array with cytogenetic data revealed that most cases were polyploid, with at least one case having started as a near-haploid tumor. Further bioinformatic analysis of the SNP array data disclosed genetic heterogeneity, in the form of subclonal chromosomal imbalances, in five tumors. The outcome was worse for patients with FP-ARMS than ERMS or FN-ARMS (6/8 vs. 1/9 dead of disease), and the only children with ERMS showing intratumor diversity or with MYOD1 mutation-positive SRMS also died of disease. High resolution SNP array can be useful in evaluating genomic imbalances in pediatric RMS.
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PMID:Genetic heterogeneity in rhabdomyosarcoma revealed by SNP array analysis. 2648 21

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. RMS can be parsed based on clinical outcome into two subtypes, fusion-positive RMS (FP-RMS) or fusion-negative RMS (FN-RMS) based on the presence or absence of either PAX3-FOXO1 or PAX7-FOXO1 gene fusions. In both RMS subtypes, tumor cells show histology and a gene expression pattern resembling that of developmentally arrested skeletal muscle. Differentiation therapy is an attractive approach to embryonal tumors of childhood including RMS; however, agents to drive RMS differentiation have not entered the clinic and their mechanisms remain unclear. MicroRNA-206 (miR-206) expression increases through normal muscle development and has decreased levels in RMS compared with normal skeletal muscle. Increasing miR-206 expression drives differentiation of RMS, but the target genes responsible for the relief of the development arrest are largely unknown. Using a combinatorial approach with gene and proteomic profiling coupled with genetic rescue, we identified key miR-206 targets responsible for the FN-RMS differentiation blockade, PAX7, PAX3, NOTCH3, and CCND2. Specifically, we determined that PAX7 downregulation is necessary for miR-206-induced cell cycle exit and myogenic differentiation in FN-RMS but not in FP-RMS. Gene knockdown of targets necessary for miR-206-induced differentiation alone or in combination was not sufficient to phenocopy the differentiation phenotype from miR-206, thus illustrating that miR-206 replacement offers the ability to modulate a complex network of genes responsible for the developmental arrest in FN-RMS. Genetic deletion of miR-206 in a mouse model of FN-RMS accelerated and exacerbated tumor development, indicating that both in vitro and in vivo miR-206 acts as a tumor suppressor in FN-RMS at least partially through downregulation of PAX7. Collectively, our results illustrate that miR-206 relieves the differentiation arrest in FN-RMS and suggests that miR-206 replacement could be a potential therapeutic differentiation strategy.
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PMID:PAX7 is a required target for microRNA-206-induced differentiation of fusion-negative rhabdomyosarcoma. 2727 78


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