Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

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) in children occurs as two major histological subtypes, embryonal (ERMS) and alveolar (ARMS). ERMS is associated with an 11p15.5 loss of heterozygosity (LOH) and may be confused with nonmyogenic, non-RMS soft tissue sarcomas. ARMS expresses the product of a genomic translocation that fuses FOXO1 (FKHR) with either PAX3 or PAX7 (P-F); however, at least 25% of cases lack these translocations. Here, we describe a genomic-based classification scheme that is derived from the combined gene expression profiling and LOH analysis of 160 cases of RMS and non-RMS soft tissue sarcomas that is at variance with conventional histopathological schemes. We found that gene expression profiles and patterns of LOH of ARMS cases lacking P-F translocations are indistinguishable from conventional ERMS cases. A subset of tumors that has been histologically classified as RMS lack myogenic gene expression. However, classification based on gene expression is possible using as few as five genes with an estimated error rate of less than 5%. Using immunohistochemistry, we characterized two markers, HMGA2 and TFAP2ss, which facilitate the differential diagnoses of ERMS and P-F RMS, respectively, using clinical material. These objectively derived molecular classes are based solely on genomic analysis at the time of diagnosis and are highly reproducible. Adoption of these molecular criteria may offer a more clinically relevant diagnostic scheme, thus potentially improving patient management and therapeutic RMS outcomes.
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PMID:Molecular classification of rhabdomyosarcoma--genotypic and phenotypic determinants of diagnosis: a report from the Children's Oncology Group. 1914 25

Rhabdomyosarcoma is the most common soft tissue tumor seen in children and young adults, and it can be classified into 2 major histological subtypes, alveolar and embryonal. In the alveolar subtype, 2 recurrent chromosomal translocations, t(2;13)(q35;q14) and its variant t(1;13)(p36;q14), have been identified as the specific cytogenetic abnormalities. These translocations produce the PAX3-FOXO1 and PAX7-FOXO1 fusion genes, respectively. In the embryonal subtype, however, no recurrent chromosomal abnormalities have been identified. In this study, we analyzed the complex chromosomal translocation in one case with embryonal rhabdomyosarcoma by means of spectral karyotyping (SKY) and identified a novel translocation involving chromosome band 2q35, which is the locus of PAX3 gene. Furthermore, we identified the novel PAX3 rearrangement using fluorescence in situ hybridization (FISH) analysis. Additional identification of the partner gene may help disclose the molecular mechanism of the development of this embryonal subtype.
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PMID:A novel PAX3 rearrangement in embryonal rhabdomyosarcoma. 1921 90

Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcomas. They resemble developing skeletal muscle and are histologically divided into two main subtypes; alveolar and embryonal RMS. Characteristic genomic aberrations, including the PAX3- and PAX7-FOXO1 fusion genes in alveolar cases, have led to increased understanding of their molecular biology. Here, we determined the effect of genomic copy number on gene expression levels through array comparative genomic hybridization (CGH) analysis of 13 RMS cell lines, confirmed by multiplex ligation-dependent probe amplification copy number analyses, combined with their corresponding expression profiles. Genes altered at the transcriptional level by genomic imbalances were identified and the effect on expression was proportional to the level of genomic imbalance. Extrapolating to a public expression profiling dataset for 132 primary RMS identified features common to the cell lines and primary samples and associations with subtypes and fusion gene status. Genes identified such as CDK4 and MYCN are known to be amplified, overexpressed, and involved in RMS tumorigenesis. Of the many genes identified, those with likely functional relevance included CENPF, DTL, MYC, EYA2, and FGFR1. Copy number and expression of FGFR1 was validated in additional primary material and found amplified in 6 out of 196 cases and overexpressed relative to skeletal muscle and myoblasts, with significantly higher expression levels in the embryonal compared with alveolar subtypes. This illustrates the ability to identify genes of potential significance in tumor development through combining genomic and transcriptomic profiles from representative cell lines with publicly available expression profiling data from primary tumors.
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PMID:Genomic imbalances in rhabdomyosarcoma cell lines affect expression of genes frequently altered in primary tumors: an approach to identify candidate genes involved in tumor development. 1923 22

We report a rare case of neonatal Beckwith-Wiedemann syndrome (BWS) associated with alveolar rhabdomyosarcoma (RMS). Alveolar RMS was diagnosed on the basis of excisional biopsy. Chemotherapy was initiated and followed by bone marrow transplantation. The patient, who is now 3 years and 11 months of age, is alive 46 months after the initial diagnosis, albeit with disease. We could not detect the PAX3-FKHR or PAX7-FKHR transcripts; however, we could observe hypomethylation of the differentially methylated region of the long QT intronic transcript 1. Thus, neonatal alveolar RMS with BWS may result from an alternate molecular pathway.
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PMID:Manifestation of alveolar rhabdomyosarcoma as primary cutaneous lesions in a neonate with Beckwith-Wiedemann syndrome. 1930 42

Gene expression profiling has revealed that the gene coding for cannabinoid receptor 1 (CB1) is highly up-regulated in rhabdomyosarcoma biopsies bearing the typical chromosomal translocations PAX3/FKHR or PAX7/FKHR. Because cannabinoid receptor agonists are capable of reducing proliferation and inducing apoptosis in diverse cancer cells such as glioma, breast cancer, and melanoma, we evaluated whether CB1 is a potential drug target in rhabdomyosarcoma. Our study shows that treatment with the cannabinoid receptor agonists HU210 and Delta(9)-tetrahydrocannabinol lowers the viability of translocation-positive rhabdomyosarcoma cells through the induction of apoptosis. This effect relies on inhibition of AKT signaling and induction of the stress-associated transcription factor p8 because small interfering RNA-mediated down-regulation of p8 rescued cell viability upon cannabinoid treatment. Finally, treatment of xenografts with HU210 led to a significant suppression of tumor growth in vivo. These results support the notion that cannabinoid receptor agonists could represent a novel targeted approach for treatment of translocation-positive rhabdomyosarcoma.
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PMID:Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma. 1950 71

The fusion oncoproteins PAX3-FOXO1 [t(2;13)(q35;q14)] and PAX7-FOXO1 [t(1;13)(p36;q14)] typify alveolar rhabdomyosarcoma (ARMS); however, 20-30% of cases lack these specific translocations. In this study, cytogenetic and/or molecular characterization to include FISH, reverse transcription polymerase chain reaction (RT-PCR), and sequencing analyses of five rhabdomyosarcomas [four ARMS and one embryonal rhabdomyosarcoma (ERMS)] with novel, recurrent t(2;2)(p23;q35) or t(2;8)(q35;q13) revealed that these noncanonical translocations fuse PAX3 to NCOA1 or NCOA2, respectively. The PAX3-NCOA1 and PAX3-NCOA2 transcripts encode chimeric proteins composed of the paired-box and homeodomain DNA-binding domains of PAX3, and the CID domain, the Q-rich region, and the activation domain 2 (AD2) domain of NCOA1 or NCOA2. To investigate the biological function of these recurrent variant translocations, the coding regions of PAX3-NCOA1 and PAX3-NCOA2 cDNA constructs were introduced into expression vectors with tetracycline-regulated expression. Both fusion proteins showed transforming activity in the soft-agar assay. Deletion of the AD2 portion of the PAX3-NCOA fusion proteins reduced the transforming activity of each chimeric protein. Similarly, but with greater impact, CID domain deletion fully abrogated the transforming activity of the chimeric protein. These studies (1) expand our knowledge of PAX3 variant translocations in RMS with identification of a novel PAX3-NCOA2 fusion, (2) show that both PAX3-NCOA1 and PAX3-NCOA2 represent recurrent RMS rearrangements, (3) confirm the transforming activity of both translocation events and demonstrate the essentiality of intact AD2 and CID domains for optimal transforming activity, and (4) provide alternative approaches (FISH and RT-PCR) for detecting PAX-NCOA fusions in nondividing cells of RMS. The latter could potentially be used as aids in diagnostically challenging cases.
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PMID:Recurrent t(2;2) and t(2;8) translocations in rhabdomyosarcoma without the canonical PAX-FOXO1 fuse PAX3 to members of the nuclear receptor transcriptional coactivator family. 1995 35

Childhood rhabdomyosarcoma (RMS) has two major histological subtypes: alveolar (aRMS) and embryonal. The aim of the study was to monitor minimal disseminated disease (MDD) using real-time quantitative reverse-transcription PCR (RQ-RT-PCR) of the PAX3-FKHR, PAX7-FKHR fusion genes and myoD1 gene. We prepared an assay using RQ-RT-PCR for a quantitative assessment of MDD in aRMS by using hydrolysis probe for quantification of PAX3-FKHR, PAX7-FKHR and myoD1 genes and beta-2-microglobulin housekeeping gene. Primary tumor samples (44), samples of local recurrences (26) from 48 patients with aRMS were examined by nested RT-PCR and RQ-RT-PCR techniques. Additionally, bone marrow samples (115), peripheral blood progenitor cell samples (27), and peripheral blood samples (25) from 33 aRMS patients were tested. PAX3/7-FKHR and myoD1 transcripts proved to be a sensitive tool for detection of MDD in RMS. We were able to identify 15/25 patients with bone marrow (BM) involvement at the time of presentation using RQ-RT-PCR. We analyzed PAX3-FKHR or PAX7-FKHR expression during the course of the disease. The RQ-RT-PCR results correlated well with nested RT-PCR results (p < 0.0001). The presence of metastases is the most adverse prognostic factor in RMS, and bone marrow is a frequent site of the tumor dissemination in RMS, especially in aRMS. Our results detecting the fusion transcripts or myoD1 transcript in the BM or peripheral blood suggest that patients with positive findings are at high risk of the tumor progression.
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PMID:Detection and clinical significance of bone marrow involvement in patients with rhabdomyosarcoma. 2040 98

Sclerosing rhabdomyosarcoma (SRMS) is an infrequent variant of rhabdomyosarcoma characterized by extensive intercellular hyaline fibrosis. We report the case of a 37 year-old male with a 9 x 6 cm SRMS on the right elbow. Histologically, the tumor showed an abundant extracellular hyaline matrix with extratumoral vascular emboli and microscopic foci of fusocellular embryonal rhabdomyosarcoma (FRMS) separated by a fibrotic band from the sclerosing areas. One year later the patient presented with a right intratesticular tumor of 1.2 x 0.8 cm, which was reported as pure FRMS. Immunohistochemically, SRMS was positive only for MyoD1 and Vimentin and negative for Myogenin and Desmin. Both the elbow emboli with the extratumoral foci of FRMS and the intratesticular tumor were positive for Myogenin, MyoD1, Vimentin and Desmin. Using fluorescent in situ hybridization (FISH), the SRMS and the FRMS tumor cells of the elbow and the FRMS tumor cells of the testis were found to be negative for FOXO1A translocation in chromosome 13. PCR chimeric transcriptional products PAX3-FKHR and PAX7-FKHR were not found. Six months following testicular resection, the patient died of multiple metastases in the mediastinum, lung and right thigh.
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PMID:Testicular fusocellular rhabdomyosarcoma as a metastasis of elbow sclerosing rhabdomyosarcoma: A clinicopathologic, immunohistochemical and molecular study of one case. 2070

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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