Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood. Common abnormalities seen in tumour cells include translocations involving FKHR and either the PAX3 or PAX7 genes. Specific translocations, t(2;13)(q35;q14) and variant t(1;13)(p36;q14) are most frequent in alveolar rhabdomyosarcoma, resulting in PAX3-FKHR and PAX7-FKHR fusion genes, respectively.

Amplification of MYCN, MDM2 and CDK4 genes occurs in some rhabdomyosarcomas. Other genes implicated in rhabdomyosarcoma include IGF2, ATR, PTCH, CDKN2A (P16 INK4A), CDKN2B, and TP53. A wide range of other chromosomal abnormalities have also been reported; particularly gain of material in chromosomes 2, 8, 12, and 13, which are associated with the embryonal subtype.

See also: Rhabdomyosarcoma - clinical resources (13)

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • PAX3
  • Chromosome 1
  • MYCN
  • Molecular Sequence Data
  • DNA-Binding Proteins
  • Karyotyping
  • CCND1
  • Gene Expression Profiling
  • NRAS
  • Immunohistochemistry
  • Polymerase Chain Reaction
  • CDKN2A
  • Paired Box Transcription Factors
  • PNN
  • Muscle, Skeletal
  • PAX3 Transcription Factor
  • HRAS
  • Cell Proliferation
  • Oligonucleotide Array Sequence Analysis
  • Adolescents
  • Forkhead Box Protein O1
  • Mutation
  • PAX7
  • Oncogene Fusion Proteins
  • Homeodomain Proteins
  • FISH
  • Apoptosis
  • Biomarkers, Tumor
  • Gene Amplification
  • CDK4
  • Chromosome 2
  • NOV
  • Alveolar Rhabdomyosarcoma
  • Base Sequence
  • Nuclear Proteins
  • Forkhead Transcription Factors
  • Cell Differentiation
  • FOXO1
  • Chromosome Aberrations
  • United Kingdom
  • Childhood Cancer
  • Chromosome 13
  • Sequence Homology, Nucleic Acid
  • DUX4
  • p53 Protein
  • MDM2
  • Cancer Gene Expression Regulation
  • MyoD Protein
  • MYOG
  • Infant
  • Rhabdomyosarcoma
  • AR
  • Messenger RNA
Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (19)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

PAX7 1p36.13 HUP1, RMS2, PAX7B Translocation
-t(1;13)(p36;q14) in Rhabdomyosarcoma
-PAX7 and Rhabdomyosarcoma
MDM2 12q14.3-q15 HDMX, hdm2, ACTFS -MDM2 and Rhabdomyosarcoma
TP53 17p13.1 P53, BCC7, LFS1, TRP53 -TP53 and Rhabdomyosarcoma
HRAS 11p15.5 CTLO, HAMSV, HRAS1, RASH1, p21ras, C-H-RAS, H-RASIDX, C-BAS/HAS, C-HA-RAS1 -HRAS germline mutation in Costello Syndrome
MYCN 2p24.3 NMYC, ODED, MODED, N-myc, bHLHe37 -MYCN Amplification in Rhabdomyosarcoma
MYOD1 11p15.1 PUM, MYF3, MYOD, bHLHc1 -MYOD1 and Rhabdomyosarcoma
CDK4 12q14 CMM3, PSK-J3 -CDK4 Amplification in Rhabdomyosarcoma
AR Xq12 KD, AIS, AR8, TFM, DHTR, SBMA, HYSP1, NR3C4, SMAX1, HUMARA -AR and Rhabdomyosarcoma
MYOG 1q31-q41 MYF4, myf-4, bHLHc3 -MYOG and Rhabdomyosarcoma
CDKN2A 9p21.3 ARF, MLM, P14, P16, P19, CMM2, INK4, MTS1, TP16, CDK4I, CDKN2, INK4A, MTS-1, P14ARF, P19ARF, P16INK4, P16INK4A, P16-INK4A -CDKN2A and Rhabdomyosarcoma
NRAS 1p13.2 NS6, CMNS, NCMS, ALPS4, N-ras, NRAS1 -NRAS and Rhabdomyosarcoma
HGF 7q21.1 SF, HGFB, HPTA, F-TCF, DFNB39 -HGF and Rhabdomyosarcoma
FOS 14q24.3 p55, AP-1, C-FOS -FOS and Rhabdomyosarcoma
NOV 8q24.1 CCN3, NOVh, IBP-9, IGFBP9, IGFBP-9 -NOV and Rhabdomyosarcoma
CCND1 11q13.3 BCL1, PRAD1, U21B31, D11S287E -CCND1 and Rhabdomyosarcoma
DUX4L1 4q35 DUX4, DUX10 -DUX4 and Rhabdomyosarcoma
PNN 14q21.1 DRS, DRSP, SDK3, memA -PNN and Rhabdomyosarcoma
FOXO1 13q14.1 FKH1, FKHR, FOXO1A Translocation
-t(2;13)(q35;q14) in Rhabdomyosarcoma
-t(1;13)(p36;q14) in Rhabdomyosarcoma
PAX3 2q35 WS1, WS3, CDHS, HUP2 Translocation
-t(2;13)(q35;q14) in Rhabdomyosarcoma

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Poniewierska-Baran A, Schneider G, Sun W, et al.
Human rhabdomyosarcoma cells express functional pituitary and gonadal sex hormone receptors: Therapeutic implications.
Int J Oncol. 2016; 48(5):1815-24 [PubMed] Free Access to Full Article Related Publications
Evidence has accumulated that sex hormones play an important role in several types of cancer. Because they are also involved in skeletal muscle development and regeneration, we were therefore interested in their potential involvement in the pathogenesis of human rhabdomyosarcoma (RMS), a skeletal muscle tumor. In the present study, we employed eight RMS cell lines (three fusion positive and five fusion negative RMS cell lines) and mRNA samples obtained from RMS patients. The expression of sex hormone receptors was evaluated by RT-PCR and their functionality by chemotaxis, adhesion and direct cell proliferation assays. We report here for the first time that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) receptors are expressed in established human RMS cell lines as well as in primary tumor samples isolated from RMS patients. We also report that human RMS cell lines responded both to pituitary and gonadal sex hormone stimulation by enhanced proliferation, chemotaxis, cell adhesion and phosphorylation of MAPKp42/44 and AKT. In summary, our results indicate that sex hormones are involved in the pathogenesis and progression of RMS, and therefore, their therapeutic application should be avoided in patients that have been diagnosed with RMS.

Ueno T, Uehara S, Nakahata K, Okuyama H
Survivin selective inhibitor YM155 promotes cisplatin‑induced apoptosis in embryonal rhabdomyosarcoma.
Int J Oncol. 2016; 48(5):1847-54 [PubMed] Related Publications
Survivin, a member of the inhibitor of apoptosis protein family, functions as a key regulator of programmed cell death. YM155 is a small molecule that selectively inhibits survivin. We investigated the effect of YM155 on survivin suppression in the human rhabdomyosarcoma (RMS) cell line RD. The efficacy of YM155 in combination with cisplatin was also determined in a xenograft model. The effect of YM155 on survivin expression in the RD cell line was examined at both mRNA and protein levels using real-time PCR and western blot analysis. RD cells were cultured with various concentrations of YM155, then cisplatin was added to the medium and the anti-proliferation response was determined. Cell growth was evaluated by WST-8 assay. Finally, the efficacy of YM155 combined with cisplatin was examined in an established xenograft model. Survivin mRNA levels in the RD cell line were decreased to 72 and 24% at 24 and 48 h, respectively, after 10 nM of YM155 was added. YM155 also decreased the levels of survivin protein. YM155 treatment (10 nM) inhibited cell proliferation of RD in a dose-dependent manner in vitro, with 58% of cells viable at 48 h. When cultured with 10 nM of YM155 and 10 µM cisplatin, RD cells demonstrated only 25% of the growth observed when cultured with cisplatin alone. YM155 in combination with cisplatin significantly inhibited tumor growth by 13% compared with control (P<0.0001) in RD xenograft tumors. YM155 increased the sensitivity of cisplatin by suppressing survivin in the embryonal RMS cell line RD. Further studies should investigate the use of YM155 as an apoptosis inducer, either alone or in combination with cisplatin, for the treatment of malignant RMS.

Arnold MA, Anderson JR, Gastier-Foster JM, et al.
Histology, Fusion Status, and Outcome in Alveolar Rhabdomyosarcoma With Low-Risk Clinical Features: A Report From the Children's Oncology Group.
Pediatr Blood Cancer. 2016; 63(4):634-9 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Distinguishing alveolar rhabdomyosarcoma (ARMS) from embryonal rhabdomyosarcoma (ERMS) is of prognostic and therapeutic importance. Criteria for classifying these entities evolved significantly from 1995 to 2013. ARMS is associated with inferior outcome; therefore, patients with alveolar histology have generally been excluded from low-risk therapy. However, patients with ARMS and low-risk stage and group (Stage 1, Group I/II/orbit III; or Stage 2/3, Group I/II) were eligible for the Children's Oncology Group (COG) low-risk rhabdomyosarcoma (RMS) study D9602 from 1997 to 1999. The characteristics and outcomes of these patients have not been previously reported, and the histology of these cases has not been reviewed using current criteria.
PROCEDURE: We re-reviewed cases that were classified as ARMS on D9602 using current histologic criteria, determined PAX3/PAX7-FOXO1 fusion status, and compared these data with outcome for this unique group of patients.
RESULTS: Thirty-eight patients with ARMS were enrolled onto D9602. Only one-third of cases with slides available for re-review (11/33) remained classified as ARMS by current histologic criteria. Most cases were reclassified as ERMS (17/33, 51.5%). Cases that remained classified as ARMS were typically fusion-positive (8/11, 73%), therefore current classification results in a similar rate of fusion-positive ARMS for all clinical risk groups. In conjunction with data from COG intermediate-risk treatment protocol D9803, our data demonstrate excellent outcomes for fusion-negative ARMS with otherwise low-risk clinical features.
CONCLUSIONS: Patients with fusion-positive RMS with low-risk clinical features should be classified and treated as intermediate risk, while patients with fusion-negative ARMS could be appropriately treated with reduced intensity therapy.

Glumac S, Pejic S, Kovacevic R, et al.
Immunohistochemical expression of nestin in rhabdomyosarcoma: implications for clinicopathology and patient outcome.
Genet Mol Res. 2015; 14(4):14649-59 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) is a highly malignant cancer. Over the last two decades, prognosis for RMS patients has significantly improved, with the exception of those in the high-risk group. In order to identify new prognostic factors, we investigated the expression of nestin in RMS cells and its correlation with clinicopathological features and patient outcome. The analysis of overall survival for all patients (N = 30) revealed 1-, 2-, 3-, 4-, and 5-year survival rates of 93.3, 83.3, 66.7, 63.3, and 63.3%, respectively. Nestin overexpression significantly correlated with survival (P = 0.044). Survival of patients with ≤ 50% nestin-positive cells was 90, 70, and 40% after 1, 2, and 3 years, respectively, and remained unchanged until the end of the investigation period. The study group composed of patients exhibiting nestin expression in >50% of cells showed 1-, 2-, 3-, and 4-year survival rates of 95, 90, 80, and 75%, respectively, remaining stable at 75% for the fifth year of observation. A nestin-positive expression rate lower than 50% was observed more frequently in older patients (43.60 ± 27.58 years; P = 0.028). In addition, higher rates of nestin expression were observed in most embryonal RMS specimens and low-grade tumors, in early stages of the disease, and among younger patients. Our results lead us to propose nestin as possible positive prognostic factor in RMS.

Kuda M, Kohashi K, Yamada Y, et al.
FOXM1 expression in rhabdomyosarcoma: a novel prognostic factor and therapeutic target.
Tumour Biol. 2016; 37(4):5213-23 [PubMed] Related Publications
The transcription factor Forkhead box M1 (FOXM1) is known to play critical roles in the development and progression of various types of cancer, but the clinical significance of FOXM1 expression in rhabdomyosarcoma (RMS) is unknown. This study aimed to determine the role of FOXM1 in RMS. We investigated the expression levels of FOXM1 and vascular endothelial growth factor (VEGF) and angiogenesis in a large series of RMS clinical cases using immunohistochemistry (n = 92), and we performed clinicopathologic and prognostic analyses. In vitro studies were conducted to examine the effect of FOXM1 knock-down on VEGF expression, cell proliferation, migration, and invasion in embryonal RMS (ERMS) and alveolar RMS (ARMS) cell lines, using small interference RNA (siRNA). High FOXM1 expression was significantly increased in the cases of ARMS, which has an adverse prognosis compared to ERMS (p = 0.0310). The ERMS patients with high FOXM1 expression (n = 25) had a significantly shorter survival than those with low FOXM1 expression (n = 24; p = 0.0310). FOXM1 expression was statistically correlated with VEGF expression in ERMS at the protein level as shown by immunohistochemistry and at the mRNA level by RT-PCR. The in vitro study demonstrated that VEGF mRNA levels were decreased in the FOXM1 siRNA-transfected ERMS and ARMS cells. FOXM1 knock-down resulted in a significant decrease of cell proliferation and migration in all four RMS cell lines and invasion in three of the four cell lines. Our results indicate that FOXM1 overexpression may be a prognostic factor of RMS and that FOXM1 may be a promising therapeutic target for the inhibition of RMS progression.

Alaggio R, Zhang L, Sung YS, et al.
A Molecular Study of Pediatric Spindle and Sclerosing Rhabdomyosarcoma: Identification of Novel and Recurrent VGLL2-related Fusions in Infantile Cases.
Am J Surg Pathol. 2016; 40(2):224-35 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Sclerosing rhabdomyosarcoma (ScRMS) and spindle cell rhabdomyosarcoma (SRMS) have been recently reclassified as a stand-alone pathologic entity, separate from embryonal RMS. Genetically, a subset of the congenital cases display NCOA2 gene rearrangements, whereas tumors occurring in older children or adults harbor MYOD1 gene mutations with or without coexisting PIK3CA mutations. Despite these recent advances, a significant number of tumors lack known genetic alterations. In this study we sought to investigate a large group of pediatric SRMS/ScRMS, spanning a diverse clinical and pathologic spectrum, by using a combined fluorescence in situ hybridization, targeted DNA, and whole-transcriptome sequencing methodology for a more definitive molecular classification. A total of 26 SRMS and ScRMS cases were selected from the 2 participating institutions for the molecular analysis. Ten of the 11 congenital/infantile SRMS showed recurrent fusion genes: with novel VGLL2 rearrangements seen in 7 (63%), including VGLL2-CITED2 fusion in 4 and VGLL2-NCOA2 in 2 cases. Three (27%) cases harbored the previously described NCOA2 gene fusions, including TEAD1-NCOA2 in 2 and SRF-NCOA2 in 1. All fusion-positive congenital/infantile SRMS patients with available long-term follow-up were alive and well, none developing distant metastases. Among the remaining 15 SRMS patients older than 1 year, 10 (67%) showed MYOD1 L122R mutations, most of them following a fatal outcome despite an aggressive multimodality treatment. All 4 cases harboring coexisting MYOD1/PIK3CA mutations shared sclerosing morphology. All 5 fusion/mutation-negative SRMS cases presented as intra-abdominal or paratesticular lesions.

Walther C, Mayrhofer M, Nilsson J, et al.
Genetic heterogeneity in rhabdomyosarcoma revealed by SNP array analysis.
Genes Chromosomes Cancer. 2016; 55(1):3-15 [PubMed] Related Publications
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.

Hingorani P, Missiaglia E, Shipley J, et al.
Clinical Application of Prognostic Gene Expression Signature in Fusion Gene-Negative Rhabdomyosarcoma: A Report from the Children's Oncology Group.
Clin Cancer Res. 2015; 21(20):4733-9 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: Pediatric rhabdomyosarcoma (RMS) has two common histologic subtypes: embryonal (ERMS) and alveolar (ARMS). PAX-FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology, whereas fusion gene-negative (FN) ARMS patients are clinically similar to ERMS patients. A five-gene expression signature (MG5) previously identified two diverse risk groups within the fusion gene-negative RMS (FN-RMS) patients, but this has not been independently validated. The goal of this study was to test whether expression of the MG5 metagene, measured using a technical platform that can be applied to routine pathology material, would correlate with outcome in a new cohort of patients with FN-RMS.
EXPERIMENTAL DESIGN: Cases were taken from the Children's Oncology Group (COG) D9803 study of children with intermediate-risk RMS, and gene expression profiling for the MG5 genes was performed using the nCounter assay. The MG5 score was correlated with clinical and pathologic characteristics as well as overall and event-free survival.
RESULTS: MG5 standardized score showed no significant association with any of the available clinicopathologic variables. The MG5 signature score showed a significant correlation with overall (N = 57; HR, 7.3; 95% CI, 1.9-27.0; P = 0.003) and failure-free survival (N = 57; HR, 6.1; 95% CI, 1.9-19.7; P = 0.002).
CONCLUSIONS: This represents the first, validated molecular prognostic signature for children with FN-RMS who otherwise have intermediate-risk disease. The capacity to measure the expression of a small number of genes in routine pathology material and apply a simple mathematical formula to calculate the MG5 metagene score provides a clear path toward better risk stratification in future prospective clinical trials.

Poniewierska-Baran A, Suszynska M, Sun W, et al.
Human rhabdomyosarcoma cells express functional erythropoietin receptor: Potential therapeutic implications.
Int J Oncol. 2015; 47(5):1989-97 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The erythropoietin receptor (EpoR) is expressed by cells from the erythroid lineage; however, evidence has accumulated that it is also expressed by some solid tumors. This is an important observation, because recombinant erythropoietin (EPO) is employed in cancer patients to treat anemia related to chemo/radiotherapy. In our studies we employed eight rhabdomyosarcoma (RMS) cell lines (three alveolar-type RMS cell lines and five embrional-type RMS cell lines), and mRNA samples obtained from positive, PAX7-FOXO1-positive, and fusion-negative RMS patient samples. Expression of EpoR was evaluated by RT-PCR, gene array and FACS. The functionality of EpoR in RMS cell lines was evaluated by chemotaxis, adhesion, and direct cell proliferation assays. In some of the experiments, RMS cells were exposed to vincristine (VCR) in the presence or absence of EPO to test whether EPO may impair the therapeutic effect of VCR. We report for a first time that functional EpoR is expressed in human RMS cell lines as well as by primary tumors from RMS patients. Furthermore, EpoR is detectably expressed in both embryonal and alveolar RMS subtypes. At the functional level, several human RMS cell lines responded to EPO stimulation by enhanced proliferation, chemotaxis, cell adhesion, and phosphorylation of MAPKp42/44 and AKT. Moreover, RMS cells became more resistant to VCR treatment in the presence of EPO. Our findings have important potential clinical implications, indicating that EPO supplementation in RMS patients may have the unwanted side effect of tumor progression.

Shern JF, Yohe ME, Khan J
Pediatric Rhabdomyosarcoma.
Crit Rev Oncog. 2015; 20(3-4):227-43 [PubMed] Related Publications
Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood, and despite clinical advances, subsets of these patients continue to suffer high levels of morbidity and mortality associated with their disease. Recent genetic and molecular characterization of these tumors using sophisticated genomics techniques, including next-generation sequencing experiments, has revealed multiple areas that can be exploited for new molecularly targeted therapies for this disease.

Hackman S, Calvey L, Bernreuter K, et al.
Cryptic insertion of 3'FOXO1 into inverted chromosome arm 2q in the presence of two normal chromosome 13s and 13 small interstitial duplications in a patient with alveolar rhabdomyosarcoma.
Cancer Genet. 2015; 208(9):428-33 [PubMed] Related Publications
Alveolar rhabdomyosarcoma (ARMS) is a pediatric soft tissue neoplasm with a characteristic translocation, t(2;13)(q35;q14), which is detected in 70-80% of cases. This well-described translocation produces the gene fusion product PAX3-FOXO1. Cryptic rearrangements of this fusion have never before been reported in ARMS. Here we describe a patient with ARMS that showed, by fluorescence in situ hybridization and G-banded chromosomes, a cryptic insertion of 3'FOXO1 into inverted chromosome 2q. The inversion breakpoints were depicted by array comparative genomic hybridization as two small interstitial duplications, one of which involved the PAX3 gene. In addition, the array comparative genomic hybridization results revealed 1q gain, 16q loss, and 11 more small duplications, with one of them involving the FOXO1 gene. Although the pathogenesis in classic ARMS cases is thought to be driven by the 5'PAX3-3'FOXO1 fusion on derivative chromosome 13, here we report a novel cryptic insertion of 3'FOXO1 resulting in a pathogenic fusion with 5'PAX3 on inverted chromosome 2q.

Sun M, Huang F, Yu D, et al.
Autoregulatory loop between TGF-β1/miR-411-5p/SPRY4 and MAPK pathway in rhabdomyosarcoma modulates proliferation and differentiation.
Cell Death Dis. 2015; 6:e1859 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The origin of rhabdomyosarcoma (RMS) remains controversial. However, specific microRNAs (miRNAs) are downregulated in RMS and it is possible that re-expression of these miRNAs may lead to differentiation. Transforming growth factor-β1 (TGF-β1) is known to block differentiation of RMS. We therefore analyzed miRNA microarrays of RMS cell lines with or without TGF-β1 knockdown and identified a novel anti-oncogene miR-411-5p. Re-expression of miR-411-5p inhibited RMS cell proliferation in vitro and tumorigenicity in vivo. Using a luciferase reporting system and sequence analysis, the potential target of miR-411-5p was identified as sprouty homolog 4 (SPRY4), which inhibits protein kinase Cα-mediated activation of mitogen-activated protein kinases (MAPKs), especially p38MAPK phosphorylation. These results revealed an inverse correlation between TGF-β1/SPRY4 and miR-411-5p levels. SPRY4 small interfering RNA and miR-411-5p both activated p38MAPK phosphorylation and also promoted apoptosis and myogenic differentiation, indicated by increased caspase-3, myosin heavy chain, and myosin expression. SPRY4 and miR-411 mRNA levels correlated with TGF-β1 expression levels in RMS tissues, which was confirmed by immunohistochemical staining for TGF-β1, SPRY4, and phosphorylated p38MAPK proteins. Overall, these results indicate that miR-411-5p acts as an RMS differentiation-inducing miRNA prompting p38MAPK activation via directly downregulating SPRY4. These results establish an autoregulatory loop between TGF-β1/miR-411-5p/SPRY4 and MAPK in RMS, which governs the switch between proliferation and differentiation.

Sun W, Chatterjee B, Wang Y, et al.
Distinct methylation profiles characterize fusion-positive and fusion-negative rhabdomyosarcoma.
Mod Pathol. 2015; 28(9):1214-24 [PubMed] Related Publications
Rhabdomyosarcoma comprises two major subtypes, fusion positive (PAX3-FOXO1 or PAX7-FOXO1) and fusion negative. To investigate the significance of DNA methylation in these subtypes, we analyzed methylation profiles of 37 rhabdomyosarcoma tumors and 10 rhabdomyosarcoma cell lines, as well as 8 normal tissues. Unsupervised clustering of DNA methylation clearly distinguished the fusion-positive and fusion-negative subsets. The fusion-positive tumors showed substantially lower overall levels of methylation compared with fusion-negative tumors. Comparison with the methylation pattern of normal skeletal muscle and bone marrow indicates that fusion-negative rhabdomyosarcoma is more similar to these normal tissues compared with fusion-positive rhabdomyosarcoma, and suggests that many of the methylation differences between these subtypes arise from 'aberrant' hyper- and hypomethylation events in fusion-positive rhabdomyosarcoma. Integrative methylation and gene expression analysis revealed that methylation differences between fusion-positive and fusion-negative tumors could either be positively or negatively associated with mRNA expression. There was no significant difference in the distribution of PAX3-FOXO1-binding sites between genes with and without differential methylation. However, the finding that PAX3-FOXO1-binding sites were enriched among genes that were both differentially methylated and differentially expressed suggests that the fusion protein interacts with DNA methylation to regulate target gene expression. An 11-gene DNA methylation signature, classifying the rhabdomyosarcoma tumors into fusion-positive and fusion-negative subsets, was established and validated by pyrosequencing assays. Notably, EMILIN1 (part of the 11-gene signature) showed higher methylation and lower mRNA expression in fusion-positive compared with fusion-negative tumors, and demonstrated demethylation and re-expression in multiple fusion-positive cell lines after treatment with 5-aza-2'-deoxycytidine. In conclusion, our study demonstrates that fusion-positive and fusion-negative rhabdomyosarcoma tumors possess characteristic methylation profiles that contribute to the expression differences between these fusion subtypes. These findings indicate an important relationship between fusion status and epigenetic changes in rhabdomyosarcoma, present a novel approach for ascertaining fusion status, and may identify new therapeutic targets in rhabdomyosarcoma.

Li Z, Yu X, Shen J, et al.
MicroRNA dysregulation in rhabdomyosarcoma: a new player enters the game.
Cell Prolif. 2015; 48(5):511-6 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) is the most common of the soft tissue sarcomas with resultant high morbidity, frequently occuring in paediatric patients and young adults. While the molecular basis of RMS has received considerable attention, exact mechanisms underlying its development and metastasis remain unclear. MicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs that negatively regulate gene expression via translational inhibition or mRNA degradation. Deregulated expression of miRNA has been implicated in initiation, progression, and metastasis of RMS. miRNAs have emerged as key regulators of several physiological and pathophysiological processes and have opened new avenues for diagnosis and treatment of RMS. This review summarizes deregulation and functional roles of miRNAs in RMS and their potential applications for diagnosis, prognosis and treatment of this malignancy. As a rapidly evolving field in basic and translational medicine, it is hopeful that miRNA research will ultimately improve management of RMS.

Gatz SA, Shipley JM
Less Can Be More for Gene Dose and Drug Sensitivity.
Clin Cancer Res. 2015; 21(21):4750-2 [PubMed] Related Publications
CDK4 is preclinically validated as a therapeutic target in PAX3-FOXO1 fusion gene-positive rhabdomyosarcomas. Pharmacologic targeting showed sensitivity but, contrary to expectation, CDK4 genomic amplification and overexpression associated with 25% of cases that exhibited the lowest sensitivities. This emphasizes the importance of tumor-specific preclinical studies to define and understand drug sensitivity.

La Starza R, Nofrini V, Pierini T, et al.
Molecular Cytogenetics Detect an Unbalanced t(2;13)(q36;q14) and PAX3-FOXO1 Fusion in Rhabdomyosarcoma With Mixed Embryonal/Alveolar Features.
Pediatr Blood Cancer. 2015; 62(12):2238-41 [PubMed] Related Publications
Distinguishing between alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) is crucial because treatment and prognosis are different. We describe a case of paratesticular rhabdomyosarcoma (RMS), which was classified as mixed ERMS/ARMS. Fluorescence in situ hybridization (FISH) detected losses of 3'PAX3 and 5'FOXO1, suggesting they had undergone an unbalanced rearrangement that probably produced the PAX3-FOXO1 fusion. Double-color FISH and reverse transcription-polymerase chain reaction (RT-PCR) revealed PAX3-FOXO1, which is characteristic of high-risk RMS. This finding highlights the importance of supplementing histology with genetics so that atypical RMS is appropriately classified and patients are correctly stratified and treated.

Seki M, Nishimura R, Yoshida K, et al.
Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma.
Nat Commun. 2015; 6:7557 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood. Here we studied 60 RMSs using whole-exome/-transcriptome sequencing, copy number (CN) and DNA methylome analyses to unravel the genetic/epigenetic basis of RMS. On the basis of methylation patterns, RMS is clustered into four distinct subtypes, which exhibits remarkable correlation with mutation/CN profiles, histological phenotypes and clinical behaviours. A1 and A2 subtypes, especially A1, largely correspond to alveolar histology with frequent PAX3/7 fusions and alterations in cell cycle regulators. In contrast, mostly showing embryonal histology, both E1 and E2 subtypes are characterized by high frequency of CN alterations and/or allelic imbalances, FGFR4/RAS/AKT pathway mutations and PTEN mutations/methylation and in E2, also by p53 inactivation. Despite the better prognosis of embryonal RMS, patients in the E2 are likely to have a poor prognosis. Our results highlight the close relationships of the methylation status and gene mutations with the biological behaviour in RMS.

Kephart JJ, Tiller RG, Crose LE, et al.
Secreted Frizzled-Related Protein 3 (SFRP3) Is Required for Tumorigenesis of PAX3-FOXO1-Positive Alveolar Rhabdomyosarcoma.
Clin Cancer Res. 2015; 21(21):4868-80 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: Rhabdomyosarcoma (RMS) is a soft tissue sarcoma associated with the skeletal muscle lineage. Of the two predominant subtypes, known as embryonal (eRMS) and alveolar (aRMS), aRMS has the poorer prognosis, with a five-year survival rate of <50%. The majority of aRMS tumors express the fusion protein PAX3-FOXO1. As PAX3-FOXO1 has proven chemically intractable, this study aims to identify targetable proteins that are downstream from or cooperate with PAX3-FOXO1 to support tumorigenesis.
EXPERIMENTAL DESIGN: Microarray analysis of the transcriptomes of human skeletal muscle myoblasts expressing PAX3-FOXO1 revealed alteration of several Wnt pathway gene members, including secreted frizzled related protein 3 (SFRP3), a secreted Wnt pathway inhibitor. Loss-of-function using shRNAs against SFRP3 was used to interrogate the role of SFRP3 in human aRMS cell lines in vitro and conditional murine xenograft systems in vivo. The combination of SFRP3 genetic suppression and the chemotherapeutic agent vincristine was also examined.
RESULTS: In vitro, suppression of SFRP3 inhibited aRMS cell growth, reduced proliferation accompanied by a G1 arrest and induction of p21, and induced apoptosis. In vivo, doxycycline-inducible suppression of SFRP3 reduced aRMS tumor growth and weight by more than three-fold, in addition to increasing myogenic differentiation and β-catenin signaling. The combination of SFRP3 suppression and vincristine was more effective at reducing aRMS cell growth in vitro than either treatment alone, and ablated tumorigenesis in vivo.
CONCLUSIONS: SFRP3 is necessary for the growth of human aRMS cells both in vitro and in vivo and is a promising new target for investigation in aRMS.

San-Miguel T, Pinto S, Navarro L, et al.
Expression of the Chemokine Receptors CXCR3, CXCR4, CXCR7 and Their Ligands in Rhabdomyosarcoma.
Pathol Oncol Res. 2015; 21(4):1191-9 [PubMed] Related Publications
Rhabdomyosarcomas (RMS) are soft tissue malignant tumors of childhood and adolescents. The mechanisms underlying their aggressiveness are still poorly understood. Chemokines are chemotactic proteins involved in pathological processes that have been intensely studied in several types of cancers because of their influence in migration, angiogenesis, or metastases. We analyzed the expression of the chemokine receptors CXCR3, CXCR4 and CXCR7 and their ligands CXCL9, CXCL10, CXCL11 and CXCL12, in 15 RMS samples derived from nine patients. Expression was measured in tumors and primary cultures of RMS by Real-Time Polymerase Chain Reaction, immunostaining and flow cytometry. Our results show that these receptors are widely expressed in RMS. A significant difference between CXCL12/CXCR4, CXCL12/CXCR7, CXCL11/CXCR7 expression ratios was found in alveolar versus embryonal RMS and similarly between CXCL12/CXCR4 and CXCL11/CXCR3 ratios in primary versus recurrent tumors. These findings suggest a possible association between the interrelation of chemokine/chemokine-receptor and an aggressive biological behavior in RMS.

Kubo T, Shimose S, Fujimori J, et al.
Prognostic value of PAX3/7-FOXO1 fusion status in alveolar rhabdomyosarcoma: Systematic review and meta-analysis.
Crit Rev Oncol Hematol. 2015; 96(1):46-53 [PubMed] Related Publications
PURPOSE: The objective of this systematic review is to provide an unprecedented summary of the prognostic impact of PAX3/7-FOXO1 fusion status in alveolar rhabdomyosarcoma.
METHODS: Studies evaluating PAX3/7-FOXO1 fusion gene or its variants as a prognostic marker were systematically searched and comparative meta-analysis of overall survival was carried out.
RESULTS: A total of 7 studies comprising 993 patients with rhabdomyosarcoma were included. Three eligible studies showed no significant difference of survival between fusion positive and negative alveolar rhabdomyosarcoma. Four eligible studies showed that PAX3-FOXO1 fusion variant may indicate a lower survival probability than PAX7-FOXO1, although the effect did not reach a level of statistical significance (pooled hazard ratios, 1.66; 95% CI, 0.95-2.89; p=0.07).
CONCLUSIONS: There was no significant difference in the overall survival between patients with the positive and negative fusion gene, but there were indications of PAX3-FOXO1 being an unfavorable prognostic factor.

Mikhailov VF, Shishkina AA, Vasilyeva IM, et al.
[Comparative analysis of natural and synthetic antimutagens as regulators of gene expression in human cells under exposure to ionizing radiation].
Genetika. 2015; 51(2):147-55 [PubMed] Related Publications
This paper studies the effect of plant peptides of thionine Ns-W2 extracted from seeds of fennel flower (Nigella sativa) and β-purothionine from wheat germs (Triticum kiharae), as well as a synthetic antimutagen (crown-compound), on the expression of several genes involved in the.control of cellular homeostasis, processes of carcinogenesis, and radiation response in human rhabdomyosarcoma cells (RD cells), T-lymphoblastoid cell line Jurkat, and blood cells. All of these agents acted as antimutagens-anticarcinogens, reducing the expression of genes involved in carcinogenesis (genes of families MMP, TIMP, and IAP and G-protein genes) in a tumor cell. A pronounced reduction in the mRNA level of these genes was caused by thionine Ns-W2, and the least effect was demonstrated by β-purothionine. Antimutagens had very little effect on the mRNA levels of the several studied genes in normal blood cells.

Thway K, Wang J, Wren D, et al.
The comparative utility of fluorescence in situ hybridization and reverse transcription-polymerase chain reaction in the diagnosis of alveolar rhabdomyosarcoma.
Virchows Arch. 2015; 467(2):217-24 [PubMed] Related Publications
Fluorescence in situ hybridization (FISH) for FOXO1 gene rearrangement and reverse transcription-polymerase chain reaction (PCR) for PAX3/7-FOXO1 fusion transcripts have become routine ancillary tools for the diagnosis of alveolar rhabdomyosarcomas (ARMS). Here we summarize our experience of these adjunct diagnostic modalities at a tertiary center, presenting the largest comparative series of FISH and PCR for suspected or possible ARMS to date. All suspected or possible ARMS tested by FISH or PCR for FOXO1 rearrangement or PAX3/7-FOXO1 fusion transcripts over a 7-year period were included. FISH and PCR results were correlated with clinical and histologic findings. One hundred samples from 95 patients had FISH and/or PCR performed. FISH had higher rates of technical success (96.8 %) compared with PCR (88 %). Where both tests were utilized successfully, there was high concordance rate between them (94.9 %). In 24 histologic ARMS tested for FISH or PCR, 83.3 % were translocation-positive (all for PAX3-FOXO1 by PCR) and included 3 histologic solid variants. In 76 cases where ARMS was excluded, there were 3 potential false-positive cases with FISH but none with PCR. PCR had similar sensitivity (85.7 %) and better specificity (100 %) in aiding the diagnosis of ARMS, compared with FISH (85 and 95.8 %, respectively). All solid variant ARMS harbored FOXO1 gene rearrangements and PAX3-FOXO1 ARMS were detected to the exclusion of PAX7-FOXO1. In comparative analysis, both FISH and PCR are useful in aiding the diagnosis of ARMS and excluding its sarcomatous mimics. FISH is more reliable technically but has less specificity than PCR. In cases where ARMS is in the differential diagnosis, it is optimal to perform both PCR and FISH: both have similar sensitivities for detecting ARMS, but FISH may confirm or exclude cases that are technically unsuccessful with PCR, while PCR can detect specific fusion transcripts that may be useful prognostically.

de Kock L, Druker H, Weber E, et al.
Ovarian embryonal rhabdomyosarcoma is a rare manifestation of the DICER1 syndrome.
Hum Pathol. 2015; 46(6):917-22 [PubMed] Related Publications
Embryonal rhabdomyosarcoma (ERMS), a soft tissue sarcoma, is one of the most common pediatric cancers. Certain ERMSs are associated with the DICER1 syndrome, a tumor predisposition syndrome caused by germ-line DICER1 mutations. Characteristic somatic mutations have also been identified in DICER1-associated tumor types. These "hotspot" mutations affect the catalytic activity of the DICER1 ribonuclease IIIb domain. Primary ovarian ERMS (oERMS) is extremely rare. We present a case of a 6-year-old girl with an oERMS harboring 2 DICER1 mutations. The girl also exhibited other DICER1 phenotypes: cystic nephroma (CN) and multinodular goiter. Somatic investigations of the CN identified a hotspot DICER1 mutation different from that in the oERMS. Significantly, the CN presented at 12 years of age, which is much older than the previously reported age range of susceptibility. This report documents the occurrence of DICER1 mutations in a case of oERMS, expanding the spectrum of DICER1-associated tumors.

Nitzki F, Tolosa EJ, Cuvelier N, et al.
Overexpression of mutant Ptch in rhabdomyosarcomas is associated with promoter hypomethylation and increased Gli1 and H3K4me3 occupancy.
Oncotarget. 2015; 6(11):9113-24 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Mice with heterozygous loss of the tumor suppressor Patched1 (Ptch) develop rhabdomyosarcoma (RMS)-like tumors. However, Ptch transcripts are consistently overexpressed in these tumors. We have recently shown that the upregulated transcripts are derived from the mutated Ptch allele thus leading to the hypothesis that the wild-type allele is repressed during RMS development. Here we describe epigenetic changes taking place at the Ptch locus during RMS development. We showed a lower degree of DNA-methylation in methylation-sensitive CpG regions of the Ptch promoter in RMS compared to normal muscle from heterozygous Ptch animals. In agreement with these results, treatment of heterozygous Ptch mice with the DNA demethylating agent 5-aza-2-deoxycytidine (5-aza-dC) between embryonic days E9.5-E11.5 significantly accelerated RMS formation. Since Ptch promoter methylation occurs after/around E13.5, the window for RMS initiation during embryogenesis, these results provide additional evidence that Ptch promoter hypomethylation may contribute to RMS formation. We have also demonstrated increased trimethylation of histone H3 lysine 4 (H3K4me3) and preferential binding of Gli1, a known Ptch activator, to the mutant locus in RMS. Together, these findings support an alternative model for RMS formation in heterozygous Ptch mice including loss of methylation and concomitant occupancy by activating histone marks of mutant Ptch.

Olanich ME, Sun W, Hewitt SM, et al.
CDK4 Amplification Reduces Sensitivity to CDK4/6 Inhibition in Fusion-Positive Rhabdomyosarcoma.
Clin Cancer Res. 2015; 21(21):4947-59 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and includes a PAX3- or PAX7-FOXO1 fusion-positive subtype. Amplification of chromosomal region 12q13-q14, which contains the CDK4 proto-oncogene, was identified in an aggressive subset of fusion-positive RMS. CDK4/6 inhibitors have antiproliferative activity in CDK4-amplified liposarcoma and neuroblastoma, suggesting CDK4/6 inhibition as a potential therapeutic strategy in fusion-positive RMS.
EXPERIMENTAL DESIGN: We examined the biologic consequences of CDK4 knockdown, CDK4 overexpression, and pharmacologic CDK4/6 inhibition by LEE011 in fusion-positive RMS cell lines and xenografts.
RESULTS: Knockdown of CDK4 abrogated proliferation and transformation of 12q13-14-amplified and nonamplified fusion-positive RMS cells via G1-phase cell-cycle arrest. This arrest was mediated by reduced RB phosphorylation and E2F-responsive gene expression. Significant differences in E2F target expression, cell-cycle distribution, proliferation, or transformation were not observed in RMS cells overexpressing CDK4. Treatment with LEE011 phenocopied CDK4 knockdown, decreasing viability, RB phosphorylation, and E2F-responsive gene expression and inducing G1-phase cell-cycle arrest. Although all fusion-positive cell lines showed sensitivity to CDK4/6 inhibition, there was diminished sensitivity associated with CDK4 amplification and overexpression. This variable responsiveness to LEE011 was recapitulated in xenograft models of CDK4-amplified and nonamplified fusion-positive RMS.
CONCLUSIONS: Our data demonstrate that CDK4 is necessary but overexpression is not sufficient for RB-E2F-mediated G1-phase cell-cycle progression, proliferation, and transformation in fusion-positive RMS. Our studies indicate that LEE011 is active in the setting of fusion-positive RMS and suggest that low CDK4-expressing fusion-positive tumors may be particularly susceptible to CDK4/6 inhibition.

Schmitt-Ney M, Camussi G
The PAX3-FOXO1 fusion protein present in rhabdomyosarcoma interferes with normal FOXO activity and the TGF-β pathway.
PLoS One. 2015; 10(3):e0121474 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PAX3-FOXO1 (PAX3-FKHR) is the fusion protein produced by the genomic translocation that characterizes the alveolar subtype of Rhabdomyosarcoma, a pediatric sarcoma with myogenic phenotype. PAX3-FOXO1 is an aberrant but functional transcription factor. It retains PAX3-DNA-binding activity and functionally overlaps PAX3 function while also disturbing it, in particular its role in myogenic differentiation. We herein show that PAX3-FOXO1 interferes with normal FOXO function. PAX3-FOXO1 affects FOXO-family member trans-activation capability and the FOXO-dependent TGF-β response. PAX3-FOXO1 may contribute to tumor formation by inhibiting the tumor suppressor activities which are characteristic of both FOXO family members and TGF-β pathways. The recognition of this mechanism raises new questions about how FOXO family members function.

Chen L, Shern JF, Wei JS, et al.
Clonality and evolutionary history of rhabdomyosarcoma.
PLoS Genet. 2015; 11(3):e1005075 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
To infer the subclonality of rhabdomyosarcoma (RMS) and predict the temporal order of genetic events for the tumorigenic process, and to identify novel drivers, we applied a systematic method that takes into account germline and somatic alterations in 44 tumor-normal RMS pairs using deep whole-genome sequencing. Intriguingly, we find that loss of heterozygosity of 11p15.5 and mutations in RAS pathway genes occur early in the evolutionary history of the PAX-fusion-negative-RMS (PFN-RMS) subtype. We discover several early mutations in non-RAS mutated samples and predict them to be drivers in PFN-RMS including recurrent mutation of PKN1. In contrast, we find that PAX-fusion-positive (PFP) subtype tumors have undergone whole-genome duplication in the late stage of cancer evolutionary history and have acquired fewer mutations and subclones than PFN-RMS. Moreover we predict that the PAX3-FOXO1 fusion event occurs earlier than the whole genome duplication. Our findings provide information critical to the understanding of tumorigenesis of RMS.

Rapino F, Abhari BA, Jung M, Fulda S
NIK is required for NF-κB-mediated induction of BAG3 upon inhibition of constitutive protein degradation pathways.
Cell Death Dis. 2015; 6:e1692 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Recently, we reported that induction of the co-chaperone Bcl-2-associated athanogene 3 (BAG3) is critical for recovery of rhabdomyosarcoma (RMS) cells after proteotoxic stress upon inhibition of the two constitutive protein degradation pathways, that is, the ubiquitin-proteasome system by Bortezomib and the aggresome-autophagy system by histone deacetylase 6 (HDAC6) inhibitor ST80. In the present study, we investigated the molecular mechanisms mediating BAG3 induction under these conditions. Here, we identify nuclear factor-kappa B (NF-κB)-inducing kinase (NIK) as a key mediator of ST80/Bortezomib-stimulated NF-κB activation and transcriptional upregulation of BAG3. ST80/Bortezomib cotreatment upregulates mRNA and protein expression of NIK, which is accompanied by an initial increase in histone H3 acetylation. Importantly, NIK silencing by siRNA abolishes NF-κB activation and BAG3 induction by ST80/Bortezomib. Furthermore, ST80/Bortezomib cotreatment stimulates NF-κB transcriptional activity and upregulates NF-κB target genes. Genetic inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor (IκBα-SR) or by knockdown of p65 blocks the ST80/Bortezomib-stimulated upregulation of BAG3 mRNA and protein expression. Interestingly, inhibition of lysosomal activity by Bafilomycin A1 inhibits ST80/Bortezomib-stimulated IκBα degradation, NF-κB activation and BAG3 upregulation, indicating that IκBα is degraded via the lysosome in the presence of Bortezomib. Thus, by demonstrating a critical role of NIK in mediating NF-κB activation and BAG3 induction upon ST80/Bortezomib cotreatment, our study provides novel insights into mechanisms of resistance to proteotoxic stress in RMS.

Lagutina IV, Valentine V, Picchione F, et al.
Modeling of the human alveolar rhabdomyosarcoma Pax3-Foxo1 chromosome translocation in mouse myoblasts using CRISPR-Cas9 nuclease.
PLoS Genet. 2015; 11(2):e1004951 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Many recurrent chromosome translocations in cancer result in the generation of fusion genes that are directly implicated in the tumorigenic process. Precise modeling of the effects of cancer fusion genes in mice has been inaccurate, as constructs of fusion genes often completely or partially lack the correct regulatory sequences. The reciprocal t(2;13)(q36.1;q14.1) in human alveolar rhabdomyosarcoma (A-RMS) creates a pathognomonic PAX3-FOXO1 fusion gene. In vivo mimicking of this translocation in mice is complicated by the fact that Pax3 and Foxo1 are in opposite orientation on their respective chromosomes, precluding formation of a functional Pax3-Foxo1 fusion via a simple translocation. To circumvent this problem, we irreversibly inverted the orientation of a 4.9 Mb syntenic fragment on chromosome 3, encompassing Foxo1, by using Cre-mediated recombination of two pairs of unrelated oppositely oriented LoxP sites situated at the borders of the syntenic region. We tested if spatial proximity of the Pax3 and Foxo1 loci in myoblasts of mice homozygous for the inversion facilitated Pax3-Foxo1 fusion gene formation upon induction of targeted CRISPR-Cas9 nuclease-induced DNA double strand breaks in Pax3 and Foxo1. Fluorescent in situ hybridization indicated that fore limb myoblasts show a higher frequency of Pax3/Foxo1 co-localization than hind limb myoblasts. Indeed, more fusion genes were generated in fore limb myoblasts via a reciprocal t(1;3), which expressed correctly spliced Pax3-Foxo1 mRNA encoding Pax3-Foxo1 fusion protein. We conclude that locus proximity facilitates chromosome translocation upon induction of DNA double strand breaks. Given that the Pax3-Foxo1 fusion gene will contain all the regulatory sequences necessary for precise regulation of its expression, we propose that CRISPR-Cas9 provides a novel means to faithfully model human diseases caused by chromosome translocation in mice.

Ju H, Yang Y, Sheng A, Jiang X
Role of microRNAs in skeletal muscle development and rhabdomyosarcoma (review).
Mol Med Rep. 2015; 11(6):4019-24 [PubMed] Related Publications
Skeletal muscle accounts for ~40% of total body mass. The principle functions of skeletal muscle include supporting the body structure, controlling motor movements and storing energy. Rhabdomyosarcoma (RMS) is a skeletal muscle‑derived soft tissue tumor widely occurring in the pediatric population. In previous years, microRNAs (miRNAs) have been demonstrated to be important in skeletal muscle development, function and the pathogenesis of various diseases, including RMS. The present review provided an overview of current knowledge on the muscle‑specific and ubiquitously‑expressed miRNAs involved in skeletal muscle differentiation and their dysregulation in RMS. Additionally, the potential use and challenges of miRNAs as therapeutic targets in this soft‑tissue sarcoma were examined and the future prospects for miRNAs in muscle biology and muscle disorders were discussed.

Recurrent Structural Abnormalities

Selected list of common recurrent structural abnormalities

Abnormality Type Gene(s)
t(1;13)(p36;q14) in RhabdomyosarcomaTranslocationFOXO1 (13q14.1)PAX7 (1p36.13)
t(2;13)(q35;q14) in RhabdomyosarcomaTranslocationPAX3 (2q35)FOXO1 (13q14.1)

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. Rhabdomyosarcoma, Cancer Genetics Web: http://www.cancer-genetics.org/X2002.htm Accessed:

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