title: MicroRNA and gene co-expression networks characterize biological and clinical behavior of rhabdomyosarcomas.
abstract: Rhabdomyosarcomas (RMS) in children and adolescents are heterogeneous sarcomas broadly defined by skeletal muscle features and the presence/absence of PAX3/7-FOXO1 fusion genes. MicroRNAs are small non-coding RNAs that regulate gene expression in a cell context specific manner. Sequencing analyses of microRNAs in 64 RMS revealed expression patterns separating skeletal muscle, fusion gene positive and negative RMS. Integration with parallel gene expression data assigned biological functions to 12 co-expression networks/modules that reassuringly included myogenic roles strongly correlated with microRNAs known in myogenesis and RMS development. Modules also correlated with clinical outcome and fusion status. Regulation of microRNAs by the fusion protein was demonstrated after PAX3-FOXO1 reduction, exemplified by miR-9-5p. MiR-9-5p levels correlated with poor outcome, even within fusion gene positive RMS, and were higher in metastatic versus non-metastatic disease. MiR-9-5p reduction inhibited RMS cell migration. Our findings reveal microRNAs in a regulatory framework of biological and clinical significance in RMS.
authors.affiliation: Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Surrey, SM2 5NG, UK.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Missiaglia
authors.affiliation: Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Surrey, SM2 5NG, UK.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Shepherd
authors.affiliation: Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Surrey, SM2 5NG, UK.
authors.forename: Ewa
authors.initials: E
authors.lastname: Aladowicz
authors.affiliation: Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Surrey, SM2 5NG, UK.
authors.forename: David
authors.initials: D
authors.lastname: Olmos
authors.affiliation: Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Surrey, SM2 5NG, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Selfe
authors.affiliation: Unité de Génétique Somatique, Institut Curie, 26 Rue d'Ulm, 75248, Paris Cedex 05, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Pierron
authors.affiliation: Unité de Génétique Somatique, Institut Curie, 26 Rue d'Ulm, 75248, Paris Cedex 05, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.affiliation: Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Surrey, SM2 5NG, UK.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Walters
authors.affiliation: Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Surrey, SM2 5NG, UK. Electronic address: janet.shipley@icr.ac.uk.
authors.forename: Janet
authors.initials: J
authors.lastname: Shipley
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D019295:Computational Biology; D030541:Databases, Genetic; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D015203:Reproducibility of Results; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018233:Rhabdomyosarcoma, Embryonal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; C471563:PAX3-FOXO1A fusion protein, human; C000603228:PAX7-FOXO1A fusion protein, human; D051761:Paired Box Transcription Factors
keywords: Co-expression modules; Fusion protein; MicroRNAs; Next generation sequencing; Rhabdomyosarcoma