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)

Rhabdomyosarcomas are a heterogeneous group of malignant tumors and are the most common soft-tissue sarcoma of childhood. Rhabdomyosarcomas resemble developing skeletal muscle, notably in their expression of the MRF family of transcription factors and the PAX3 and PAX7 genes. These PAX genes are also involved through specific translocations, t(2;13)(q35;q14) and variant t(1;13)(p36;q14) in the alveolar subtype, which result in PAX3-FKHR and PAX7-FKHR fusion genes, respectively. The fusion genes are thought critically to affect downstream targets of PAX3 and PAX7 or possibly have novel targets. Similar downstream changes may also be involved in embryonal and fusion gene negative cases. Genomic amplification of such genes as MYCN, MDM2, CDK4, and PAX7-FKHR is a feature mainly of the alveolar subtype, while specific chromosomal gains, including chromosomes 2, 8, 12, and 13, are associated with the embryonal subtype. Loss of alleles and imprinting at 11p15.5 and disruption of genes such as IGF2, ATR, PTC, P16, and TP53 have also been implicated in rhabdomyosarcoma development. Whereas there is now a realistic possibility of cure in the majority of cases, there remains a subset that is resistant to multimodality therapy, including high-dose chemotherapy. Characterization of the defining molecular features of tumors that are likely to behave aggressively represents a particular challenge. Current research is leading toward a better understanding of rhabdomyosarcoma tumorigenesis, which may ultimately result in novel therapeutic strategies that increase the overall cure. Genes Chromosomes Cancer 26:275-285, 1999.
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PMID:Genes, chromosomes, and rhabdomyosarcoma. 1053 62

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood. Histologically, it is subdivided histologically into two main subtypes: alveolar (ARMS) and embryonal (ERMS). ARMS is characterized by t(2;13)(q35;q14) or its variant t(1;13)(p36;q14), which fuse PAX3 and PAX7, respectively, with FKHR to produce chimeric genes. ERMS is frequently associated with loss of heterozygosity of 11p15.5. We investigated seven RMS (three ARMS and four ERMS) by means of cytogenetic, fluorescence in situ hybridization, and molecular analyses, including the study of the main genes implicated in the G1- to S-phase cell cycle transition, and correlated these studies with pathologic findings and clinical outcome. All tumors showed clonal, numerical, and structural chromosomal abnormalities. Two ARMS had the t(2;13)(q35;q14) and the third a PAX7/FKHR fusion, a cryptic t(1;13)(p36;q14), undetected by cytogenetic techniques, but revealed by reverse transcriptase polymerase chain reaction. One ERMS showed a der(11)t(3;11)(p21;p15) as a sole structural anomaly. Gene amplification was seen in four tumors, as double minutes or in the form of homogeneously staining regions. Overexpression of MYCN oncogene was found in two ARMS; N-myc DNA probe detected oncogene amplification located on the double minutes of these cases. Analysis of the regulatory genes responsible for G1- to S-phase transition showed a homozygous deletion of the 9p21 locus genes in a spindle-cell ERMS.
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PMID:Cytogenetic and molecular findings related to rhabdomyosarcoma. An analysis of seven cases. 1285 Mar 75

Rhabdomyosarcoma (RMS) is a common paediatric soft tissue sarcoma that resembles developing foetal skeletal muscle. Tumours of the alveolar subtype frequently harbour one of two characteristic translocations that juxtapose PAX3 or PAX7, and the forkhead-related gene FKHR (FOXO1A). The embryonal subtype of RMS is not generally associated with these fusion genes. Here, we have quantified the relative levels of chimaeric and wild-type PAX transcripts in various subtypes of RMS (n=34) in order to assess the relevance of wild-type PAX3 and PAX7 gene expression in these tumours. We found that upregulation of wild-type PAX3 is independent of the presence of either fusion gene and is unlikely to contribute to tumorigenesis. Most strikingly, upregulated PAX7 expression is almost entirely restricted to cases without PAX3-FKHR or PAX7-FKHR fusion genes and may contribute to tumorigenesis in the absence of chimaeric PAX transcription factors. Furthermore, as myogenic satellite cells are known to express PAX7, this pattern of PAX7 expression suggests this cell type as the origin of these tumours. This is corroborated by the detection of MET (c-met) expression, a marker for the myogenic satellite cell lineage, in all RMS samples expressing wild-type PAX7.
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PMID:PAX7 expression in embryonal rhabdomyosarcoma suggests an origin in muscle satellite cells. 1286 25

Rhabdomyosarcoma (RMS), the most common pediatric soft-tissue sarcoma, has two major histological subtypes: embryonal RMS (ERMS), which has a favorable prognosis, and alveolar RMS (ARMS), which has a poor outcome. Although both forms of RMS express muscle cell-specific markers, only ARMS cells express PAX3-FOXO1a or PAX7-FOXO1a chimeric proteins. In mice, Pax3 and Pax7 play key roles in muscle cell development and differentiation, and FoxO1a regulates myoblast differentiation and fusion; thus, the aberrant regulation of these proteins may contribute to the development of ARMS. In this paper, we report that FOXO1a is not expressed in primary ARMS tumors or ARMS-derived tumor cell lines and that restoration of FOXO1a expression in ARMS cells is sufficient to induce cell cycle arrest and apoptosis. Strikingly, the effects of FOXO1a are selective, as enforced expression of FOXO1a in ERMS-derived tumor cell lines had no effect. Furthermore, FOXO1a induced apoptosis in ARMS by directly activating the transcription of caspase-3. We conclude that FOXO1a is a potent and specific tumor suppressor in ARMS, suggesting that agents that restore or augment FOXO1a activity may be effective as ARMS therapeutics.
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PMID:FOXO1a acts as a selective tumor suppressor in alveolar rhabdomyosarcoma. 2773 3

Rhabdomyosarcoma is the most frequent soft tissue sarcoma in the pediatric population. Two main histopathologic variants have been described, embryonal (ERMS) and alveolar (ARMS), which demonstrate clinical and genetic differences. In particular, most ARMS but not ERMS tumors are characterized by the presence of recurrent chromosomal translocations, which have been cytogenetically defined as t(2;13)(q35;q14) and t(1;13)(p36;q14). These translocations form PAX3-FKHR and PAX7-FKHR gene fusions, which encode chimeric transcription factors. These chimeric proteins are hypothesized to generate a novel transcriptional program in the target cell, thereby contributing to multiple aspects of ARMS tumorigenesis. This review highlights recent advances in numerous areas of biomedical investigation that are providing new insights into the biology, molecular pathology, and translational science of ARMS: the identification of downstream targets of PAX3-FKHR and collaborating events in the process of tumorigenesis and metastasis; generation of animal models based on the gene fusion and collaborating events; development of new assays for diagnosis, prognosis, and detection of minimal disseminated disease; and exploration of immune recognition of this tumor and the fusion protein. These findings highlight the continued importance of the fusion proteins in understanding the biology of this tumor and developing improved diagnostics for this tumor, and have led to the initiation of efforts to explore therapeutic strategies based on the increasing understanding of the biology of these fusion proteins.
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PMID:Fusions involving PAX and FOX genes in the molecular pathogenesis of alveolar rhabdomyosarcoma: recent advances. 1731 32

Ewing's sarcoma is a common malignancy of bone and soft tissue that occurs most often in children and young adults. Differentiating Ewing's sarcoma from other round blue cell tumors can be a diagnostic challenge because of their similarity in histology and clinical presentation. Thus, ancillary molecular tests for detecting disease-defining translocations are important for confirming the diagnosis. We analyzed 65 round blue cell tumors, including 53 Ewing's sarcoma samples from 50 unique cases. Samples were processed for RNA from archived formalin-fixed paraffin-embedded tissue blocks. Real-time RT-PCR assays specific for Ewing's sarcoma (EWS-FLI1, EWS-ERG, EWS-ETV1, EWS-ETV4, and EWS-FEV), synovial sarcoma (SYT-SSX1 and SYT-SSX2), and rhabdomyosarcoma (PAX3-FKHR and PAX7-FKHR) were tested across the samples. The translocation panel had a sensitivity of 81% (43 out of 53 samples) for diagnosing Ewing's sarcoma when using the histological criteria as the 'gold' standard. None of the Ewing's specific translocations were found in the non-Ewing's samples (100% specificity). Of the 43 samples with translocations detected, 26 (60%) had an EWS-FLI1 type 1 translocation, 13 (30%) had an EWS-FLI1 type 2 translocation, 3 (7%) had an EWS-ERG translocation, 1 had an EWS-ETV1 translocation, and 1 sample had both an EWS-FLI1 type 1 and type 2 translocation. Our real-time RT-PCR assay for detecting sarcoma translocations has high sensitivity and specificity for Ewing's sarcoma and has clinical utility in differentiating small round blue cell tumors in the clinical lab.
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PMID:Differentiating Ewing's sarcoma from other round blue cell tumors using a RT-PCR translocation panel on formalin-fixed paraffin-embedded tissues. 1733 32

Alveolar rhabdomyosarcoma (ARMS) is a pediatric sarcoma that typically occurs in older children predominantly arising in the trunk and extremities, and exhibits a worse prognosis than other types of rhabdomyosarcomas. Most ARMS tumors have t(2; 13) or t(1; 13) translocations, involving PAX3-FKHR and PAX7-FKHR fusion genes, respectively. These genetic events result in a molecular gain of function of the fusion protein which is proposed, in a yet unspecified mechanism, to perturb the differentiation of muscle progenitor cells. While a significant amount of work has been done characterizing PAX-FKHR fusion proteins in ARMS and elucidating their involvement in the sarcomagenic process, their relationship to normal skeletal muscle differentiation remains unestablished. In this manuscript we will explore a potential role for mesenchymal stem cells as the cell of origin of ARMS, and the possibility that PAX-FKHR fusion genes may commit these cells to a myogenic lineage while inhibiting terminal differentiation, thus contributing to ARMS formation. We will also review the structure and function of alternate transcripts of PAX3, PAX7, FKHR and the fusion genes PAX3-FKHR and PAX7-FKHR, and discuss the role of these genes and their downstream targets in development of ARMS. Additionally, we will review transgenic mouse models and their ability to mimic the formation of ARMS.
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PMID:Alveolar rhabdomyosarcoma: is the cell of origin a mesenchymal stem cell? 1900 39

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence. Despite advances in therapy, patients with a histologic variant of RMS known as alveolar (aRMS) have a 5-year survival rate of <30%. aRMS tissues exhibit a number of genetic changes, including loss-of-function of the p53 and Rb tumor suppressor pathways, amplification of MYCN, stabilization of telomeres, and most characteristically, reciprocal translocation of loci involving the PAX and FKHR genes, generating the PAX7-FKHR or PAX3-FKHR fusion proteins. We previously showed that PAX3-FKHR expression in primary human myoblasts, cells that can give rise to RMS, cooperated with loss of p16INK4A to promote extended proliferation. To better understand the genetic events required for aRMS formation, we then stepwise converted these cells to their transformed counterpart. PAX3-FKHR, the catalytic unit of telomerase hTERT, and MycN, in cooperation with down-regulation of p16INK4A/p14ARF expression, were necessary and sufficient to convert normal human myoblasts into tumorigenic cells that gave rise to aRMS tumors. However, the order of expression of these transgenes was critical, as only those cells expressing PAX3-FKHR early could form tumors. We therefore suggest that the translocation of PAX3 to FKHR drives proliferation of myoblasts, and a selection for loss of p16INK4A/p14ARF. These early steps, coupled with MycN amplification and telomere stabilization, then drive the cells to a fully tumorigenic state.
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PMID:Defining the cooperative genetic changes that temporally drive alveolar rhabdomyosarcoma. 1904 33

PAX5 is a member of the paired box transcription factors involved in development and its expression has been well characterized among hematopoietic malignancies of B-cell lineage. Its expression has also been reported in a subset of neuroendocrine carcinomas, urothelial tumors, Merkel cell carcinoma, glioblastoma, and neuroblastoma cell lines. As such, we sought to assess it as a diagnostic marker in the evaluation of pediatric small round blue cell tumors. Tumors selected for evaluation included embryonal rhabdomyosarcoma (55 cases), alveolar rhabdomyosarcoma (ARMS) (51 cases), neuroblastoma (22 cases), Wilms tumor (18 cases), Ewing Family of Tumors (11 cases), lymphoblastic lymphoma (8 cases), hepatoblastoma (6 cases), and granulocytic sarcoma (3 cases) as either cores in a tissue microarray or whole mount sections. All cases were immunostained using an antibody directed toward PAX5 and immunoreactivity was scored semiquantitatively according to percentage of nuclear staining. As expected, all B-cell lymphoblastic lymphomas were strongly immunoreactive against PAX5. Additionally, all Wilms tumors showed staining of variable intensity, most intensely in the epithelial component. Of the rhabdomyosarcoma cases, 34 of 51 (67%) ARMS were immunoreactive whereas none of the 55 embryonal rhabdomyosarcoma cases stained. No other tumor type on the array was immunoreactive toward PAX5. Genetic information was available on 7 ARMS, 5 of which had characteristic translocations involving PAX genes, either t(2:13) or t(1;13). Of the translocation-positive cases, all showed nuclear reactivity toward PAX5, and both the translocation-negative cases did not. Possible explanations of PAX5 staining include aberrant expression of the PAX5 transcription factor, PAX5 expression in normal tissue at the time the tumors most closely recapitulates in development or crossreactivity with another member of the PAX family. PAX3 and PAX7 fusion genes characterize the majority of ARMS making crossreactivity with these proteins an attractive theory, and suggest that PAX5 immunoreactivity may be specific for translocation-positive ARMS. Further study in a larger series of rhabdomyosarcomas is warranted to assess the sensitivity and specificity of PAX5 immunoreactivity for the ARMS variant.
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PMID:PAX immunoreactivity identifies alveolar rhabdomyosarcoma. 1914 2

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and comprises two major histological subtypes: alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS). Seventy-five percent of ARMS harbor reciprocal chromosomal translocations leading to fusion genes of the forkhead transcription factor FOXO1 and PAX3 or PAX7. The hedgehog (Hh) pathway has been implied in tumor formation and progression of various cancers including RMS. However, whether Hh pathway activation presents a general feature of RMS or whether it is restricted to specific subgroups has not yet been addressed. Here, we report that marker genes of active Hh signaling, that is, Patched1 (Ptch1), Gli1, Gli3 and Myf5, are expressed at significantly higher levels in ERMS and fusion gene-negative ARMS compared with fusion gene-positive ARMS in two distinct cohorts of RMS patients. Consistently, Gli1 expression correlates with Ptch1 expression in ERMS and fusion gene-negative ARMS, but not in fusion gene-positive ARMS. In addition, expression levels of MyoD1 are significantly lower in ERMS and fusion gene-negative ARMS, pointing to an inverse association of Hh activation and early muscle differentiation. Moreover, Myf5 is identified as a novel excellent class predictor for RMS by receiver operating characteristic analysis. Importantly, high expression of Ptch1 or low MyoD1 expression significantly correlate with reduced cumulative survival in fusion gene-negative RMS underscoring the clinical relevance of these findings. By showing that Hh signaling is preferentially activated in specific subgroups of RMS, our study has important implications for molecular targeted therapies, such as small molecule Hh inhibitors, in RMS.
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PMID:Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma. 2081 40


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