Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Beckwith-Wiedemann syndrome (BWS) is a genetic disorder characterized by somatic overgrowth and predisposition to embryonal tumors, such as Wilm's tumor, hepatoblastoma, neuroblastoma and rhabdomyosarcoma (RMS). BWS is associated with various genetic alterations: a variety of molecular lesions are described on the chromosome 11p15, affecting gene expression for IGF2, H19, CDKN1C and KCNQ1OT1. Alveolar RMS also recognises characteristic genetic alterations: two types of translocations, t(2,13) or t(1,13), that generate the PAX3-FKHR or PAX7-FKHR fusion proteins. It has been postulated however, that in BWS this kind of tumor occurs without this characteristic chromosomal rearrangement. The authors describe case of a neonate with BWS that presented at birth with cutaneous metastasis due to alveolar RMS. Genetic analysis showed lack of the two characteristic translocations in the tumor tissue, supporting a different oncogenic pathway of alveolar RMS in children with BWS.
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PMID:Decreased CDKN1C Expression in Congenital Alveolar Rhabdomyosarcoma Associated with Beckwith-Wiedemann Syndrome. 2734 68

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of skeletal muscle origin in children and adolescents. Among RMS subtypes, alveolar rhabdomyosarcoma (ARMS), which is characterized by the presence of the PAX3-FOXO1A or PAX7-FOXO1A chimeric oncogenic transcription factor, is associated with poor prognosis and a strong risk of metastasis compared with the embryonal subtype (ERMS). To identify molecular pathways involved in ARMS aggressiveness, we first characterized the migratory behavior of cell lines derived from ARMS and ERMS biopsies using a three-dimensional spheroid cell invasion assay. ARMS cells were more invasive than ERMS cells and adopted an ellipsoidal morphology to efficiently invade the extracellular matrix. Moreover, the invasive potential of ARMS cells depended on ROCK activity, which is regulated by the GTPase RhoE. Specifically, RhoE expression was low in ARMS biopsies, and its overexpression in ARMS cells reduced their invasion potential. Conversely, ARHGAP25, a GTPase-activating protein for Rac, was up-regulated in ARMS biopsies. Moreover, we found that ARHGAP25 inhibits Rac activity downstream of ROCKII and is required for ARMS cell invasion. Our results indicate that the RhoE/ROCK/ARHGAP25 signaling pathway promotes ARMS invasive potential and identify these proteins as potential therapeutic targets for ARMS treatment.
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PMID:The RhoE/ROCK/ARHGAP25 signaling pathway controls cell invasion by inhibition of Rac activity. 2741 8

Rhabdomyosarcoma, the most common soft tissue malignancy of childhood, is a morphologically variable tumor defined by its phenotype of skeletal muscle differentiation. The diagnosis of rhabdomyosarcoma often relies in part on the identification of myogenic gene expression using immunohistochemical or molecular techniques. However, these techniques show imperfect sensitivity and specificity, particularly in scant tissue biopsies. Here, we expand the toolkit for rhabdomyosarcoma diagnosis by studying the expression of PAX7, a transcriptional regulator of mammalian muscle progenitor cells implicated in the pathogenesis of rhabdomyosarcoma. Immunohistochemical analysis of tissue microarrays using a monoclonal anti-PAX7 antibody was used to characterize PAX7 expression in 25 non-neoplastic tissues, 109 rhabdomyosarcomas, and 697 small round blue cell or other soft tissue tumors. Among non-neoplastic tissues, PAX7 was specifically expressed in adult muscle progenitor cells (satellite cells). In embryonal rhabdomyosarcoma, PAX7 expression was positive in 52 of 63 cases (83%), negative in 9 of 63 cases (14%), and focal in 2 of 63 cases (3%). PAX7-positive embryonal rhabdomyosarcoma cases included several showing focal or negative myogenin expression. PAX7 expression in alveolar rhabdomyosarcoma was positive in 6 of 31 cases (19%), negative in 14 of 31 cases (45%), and focal in 11 of 31 cases (36%). In addition, PAX7 was expressed in 5 of 7 pleomorphic rhabdomyosarcomas (71%) and 6 of 8 spindle cell rhabdomyosarcomas (75%). Among histologic mimics, only Ewing sarcoma showed PAX7 expression (7/7 cases, 100%). In contrast, expression of PAX7 was not seen in the large majority (688/690, 99.7%) of examined cases of other soft tissue tumors, small round blue cell neoplasms, and leukemias/lymphomas. In summary, immunohistochemical analysis of PAX7 expression may be a useful diagnostic tool in the assessment of skeletal muscle differentiation in human tumors.
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PMID:PAX7 Expression in Rhabdomyosarcoma, Related Soft Tissue Tumors, and Small Round Blue Cell Neoplasms. 2752 98

Rhabdomyosarcomas (RMS) are rare, heterogeneous, soft tissue sarcomas and a common type of childhood malignancy with a distinct histomorphology. At the molecular level, alveolar rhabdomyosarcoma (ARMS), a subtype of RMS, harbors a signature genetic makeup characterized by specific translocations. The type of translocation and associated genetic aberrations correlate with disease progression, hence we used multiple molecular modalities including high-resolution array comparative genomic hybridization to explore the oncogenic gene fusion and associated copy number variations in a case of metastatic ARMS. We describe a case where traditional cytogenetic and molecular methods yielded inconclusive results in detecting the FOXO1 gene rearrangement. However, microarray analysis identified the essential FOXO1-PAX7 aberration and additional submicroscopic genomic alterations, including amplification of MYCN and MDM2 and deletion of RB1.
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PMID:Genomic Characterization of a Metastatic Alveolar Rhabdomyosarcoma Case Using FISH Studies and CGH+SNP Microarray Revealing FOXO1-PAX7 Rearrangement with MYCN and MDM2 Amplification and RB1 Region Loss. 2825 4

PAX7 is a paired-box transcription factor that is required for the developmental specification of adult skeletal muscle progenitors in mice. We previously demonstrated PAX7 expression as a marker of skeletal muscle differentiation in rhabdomyosarcoma. Here, using analyses of published whole-genome gene expression microarray data, we identify PAX7 as a gene with significantly increased expression in Ewing sarcoma in comparison to CIC-DUX4 round cell sarcoma. Analysis of PAX7 in a large cohort of 103 Ewing sarcoma cases by immunohistochemistry revealed expression in 99.0% of cases (102/103). PAX7 expression was noted in cases demonstrating three distinct Ewing sarcoma EWSR1 translocations involving FLI1, ERG, and NFATc2. No PAX7 expression was observed in any of 27 cases of CIC-DUX4 sarcoma by immunohistochemistry (0%; 0/27). Exploring the mechanism of PAX7 expression in Ewing sarcoma using curated RNA- and ChIP-sequencing data, we demonstrate that the EWSR1 fusion protein is required for PAX7 expression in Ewing sarcoma and identify a candidate EWSR1-FLI1-bound PAX7 enhancer that coincides with both a consensus GGAA repeat-containing binding site and a peak of regulatory H3K27 acetylation. Taken together, our findings provide mechanistic support for the utility of PAX7 immunohistochemistry in the diagnosis of Ewing sarcoma, while linking this sarcoma of uncertain histogenesis to a key transcriptional regulator of mammalian muscle progenitor cells.
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PMID:EWSR1 fusion proteins mediate PAX7 expression in Ewing sarcoma. 2998 54

Rhabdomyosarcoma is the most common soft-tissue sarcoma in childhood and histologically resembles developing skeletal muscle. Alveolar rhabdomyosarcoma (ARMS) is an aggressive subtype with a higher rate of metastasis and poorer prognosis. The majority of ARMS tumors (80%) harbor a PAX3-FOXO1 or less commonly a PAX7-FOXO1 fusion gene. The presence of either the PAX3-FOXO1 or PAX7-FOXO1 fusion gene foretells a poorer prognosis resulting in clinical re-classification as either fusion-positive (FP-RMS) or fusion-negative RMS (FN-RMS). The PAX3/7-FOXO1 fusion genes result in the production of a rogue transcription factors that drive FP-RMS pathogenesis and block myogenic differentiation. Despite knowing the molecular driver of FP-RMS, targeted therapies have yet to make an impact for patients, highlighting the need for a greater understanding of the molecular consequences of PAX3-FOXO1 and its target genes including microRNAs. Here we show FP-RMS patient-derived xenografts and cell lines display a distinct microRNA expression pattern. We utilized both loss- and gain-of function approaches in human cell lines with knockdown of PAX3-FOXO1 in FP-RMS cell lines and expression of PAX3-FOXO1 in human myoblasts and identified microRNAs both positively and negatively regulated by the PAX3-FOXO1 fusion protein. We demonstrate PAX3-FOXO1 represses miR-221/222 that functions as a tumor suppressing microRNA through the negative regulation of CCND2, CDK6, and ERBB3. In contrast, miR-486-5p is transcriptionally activated by PAX3-FOXO1 and promotes FP-RMS proliferation, invasion, and clonogenic growth. Inhibition of miR-486-5p in FP-RMS xenografts decreased tumor growth, illustrating a proof of principle for future therapeutic intervention. Therefore, PAX3-FOXO1 regulates key microRNAs that may represent novel therapeutic vulnerabilities in FP-RMS.
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PMID:PAX3-FOXO1 drives miR-486-5p and represses miR-221 contributing to pathogenesis of alveolar rhabdomyosarcoma. 2936 56

We present the case of a 2-year-old male patient with a facial tumor partially treated with chemotherapy before his admission to our institution. The tumor involved from the frontal region to the maxillary floor, the orbit, and the maxillary and sphenoid sinuses. The histopathological diagnosis revealed a stage IV alveolar rhabdomyosarcoma with infiltration to bone marrow and cerebrospinal fluid. He was managed with four cycles of adriamycin, actinomycin, cyclophosphamide and vincristine; cisplatin and irinotecan were added to the last cycle. The tumor had a 50% size reduction, but the patient died after a neutropenia and fever episode. The aggressive behavior of alveolar rhabdomyosarcoma has been associated with the expression of oncogenic fusion proteins resulting from chromosomal translocations, particularly t(2;13) (q35;q14) PAX3/FOXO1, and t(1;13) (p36;q14) PAX7/FOXO1 which were present in this patient.
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PMID:Alveolar rhabdomyosarcoma: origin and prognostic implications of molecular findings. 2942 Dec 85

Biphenotypic sinonasal sarcoma (BSNS) is a distinctive, anatomically restricted, low-grade spindle cell sarcoma that shows considerable histologic overlap with other cellular spindle cell neoplasms. This tumor type shows both myogenic and neural differentiation, which can be demonstrated by immunohistochemistry; however, the available diagnostic markers are relatively nonspecific. BSNS is characterized by PAX3 rearrangements, with MAML3 as the most common fusion partner. Our aim was to determine whether immunohistochemistry using a monoclonal PAX3 antibody could distinguish BSNS from potential histologic mimics, as well as to evaluate a widely available polyclonal PAX8 antibody, which is known to cross-react with other paired box transcription factor family members. Immunohistochemistry for PAX3 and PAX8 was performed on whole sections of 15 BSNS (10 with confirmed PAX3 rearrangement) and 10 cases each of the following histologic mimics: malignant peripheral nerve sheath tumor, monophasic synovial sarcoma, spindle cell rhabdomyosarcoma (RMS), solitary fibrous tumor, sinonasal hemangiopericytoma, and cellular schwannoma, as well as alveolar RMS (which harbors PAX3 or PAX7 gene rearrangements). BSNS showed consistent expression of PAX3 (15/15), all multifocal-to-diffuse and most with moderate-to-strong intensity of staining. One single case of spindle cell RMS showed PAX3 expression (1/10), and all other histologic mimics were completely PAX3-negative. In contrast, nuclear staining for PAX8 was present in all 15 BSNS, 7/10 malignant peripheral nerve sheath tumor, 3/10 cellular schwannomas, 2/10 sinonasal hemangiopericytomas, 1/10 synovial sarcoma, 1 spindle cell RMS, and 1 solitary fibrous tumor. All cases of alveolar RMS were positive for PAX8, and most were also positive for PAX3 (8/10). Immunohistochemical expression of PAX3 is highly sensitive (100%) and specific (98%) for BSNS. A polyclonal PAX8 antibody also stains BSNS (likely due to cross-reactivity with PAX3) but has much lower specificity (75%), with frequent expression in numerous mimics.
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PMID:Expression of PAX3 Distinguishes Biphenotypic Sinonasal Sarcoma From Histologic Mimics. 2986 47

The RAS isoforms are frequently mutated in many types of human cancers, including PAX3/PAX7 fusion-negative rhabdomyosarcoma. Pediatric RMS arises from skeletal muscle progenitor cells that have failed to differentiate normally. The role of mutant RAS in this differentiation blockade is incompletely understood. We demonstrate that oncogenic RAS, acting through the RAF-MEK [mitogen-activated protein kinase (MAPK) kinase]-ERK (extracellular signal-regulated kinase) MAPK effector pathway, inhibits myogenic differentiation in rhabdomyosarcoma by repressing the expression of the prodifferentiation myogenic transcription factor, MYOG. This repression is mediated by ERK2-dependent promoter-proximal stalling of RNA polymerase II at the MYOG locus. Small-molecule screening with a library of mechanistically defined inhibitors showed that RAS-driven RMS is vulnerable to MEK inhibition. MEK inhibition with trametinib leads to the loss of ERK2 at the MYOG promoter and releases the transcriptional stalling of MYOG expression. MYOG subsequently opens chromatin and establishes super-enhancers at genes required for late myogenic differentiation. Furthermore, trametinib, in combination with an inhibitor of IGF1R, potently decreases rhabdomyosarcoma cell viability and slows tumor growth in xenograft models. Therefore, this combination represents a potential therapeutic for RAS-mutated rhabdomyosarcoma.
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PMID:MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma. 2997 6

PAX7 has been recently demonstrated to be a highly sensitive marker for Ewing sarcoma, and thus far has only been shown to label a relatively small set of other mesenchymal neoplasms. Because the processing of bone marrow core biopsies can often hinder the performance of immunohistochemical stains, we set out to determine if our laboratory's PAX7 staining protocol effectively detects Ewing sarcoma in Bouin's fixed, decalcified bone marrow core biopsies. We stained ten core biopsies involved by Ewing sarcoma, nine non-involved core biopsies, and 13 core biopsies involved by histologic mimics of Ewing sarcoma. Only the ten biopsies involved by Ewing sarcoma and four biopsies with rhabdomyosarcoma showed strong nuclear PAX7 staining. None of the other tumors demonstrated PAX7 expression. This study demonstrates that the PAX7 staining protocol used in our laboratory is a useful marker for Ewing sarcoma and other PAX7-positive tumors in decalcified bone marrow core biopsies.
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PMID:Immunohistochemistry for PAX7 is a useful confirmatory marker for Ewing sarcoma in decalcified bone marrow core biopsy specimens. 3001 88


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