title: High-resolution array CGH identifies common mechanisms that drive embryonal rhabdomyosarcoma pathogenesis.
abstract: Pediatric rhabdomyosarcoma occurs as two biologically distinct histological variants, embryonal (ERMS) and alveolar (ARMS). To identify genomic changes that drive ERMS pathogenesis, we used a new array comparative genomic hybridization (aCGH) platform to examine a specific subset of ERMS tumors, those occurring in children with clinically defined intermediate-risk disease. The aCGH platform used has an average probe spacing ∼1 kb, and can identify genomic changes with single gene resolution. Our data suggest that these tumors share a common genomic program that includes inactivation of a master regulator of the p53 and Rb pathways, CDKN2A/B, and activation of FGFR4, Ras, and Hedgehog (Hh) signaling. The CDKN2A/B tumor suppressor is deleted in most patient samples. FGFR4, which encodes a receptor tyrosine kinase, is activated in 20% of tumors, predominantly by amplification of mutant, activating FGFR4 alleles. Over 50% of patients had low-level gains of a region containing the Hh-pathway transcription factor GLI1, and a gene expression pattern consistent with Hh-pathway activation. We also identified intragenic deletions affecting NF1, a tumor suppressor and inhibitor of Ras, in 15% of tumor samples. Deletion of NF1 and the presence of activating Ras mutations (in 42% of patients) were mutually exclusive, suggesting NF1 loss is an alternative and potentially common mechanism of Ras activation in ERMS. Our data suggest that intermediate-risk ERMS is driven by a common set of genomic defects, a finding that has important implications for the application of targeted therapies to improve the treatment of children diagnosed with this disease.
authors.affiliation: Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Vera
authors.initials: V
authors.lastname: Paulson
authors.forename: Garvin
authors.initials: G
authors.lastname: Chandler
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.forename: Rene L
authors.initials: RL
authors.lastname: Galindo
authors.forename: Kathleen
authors.initials: K
authors.lastname: Wilson
authors.forename: James F
authors.initials: JF
authors.lastname: Amatruda
authors.forename: Scott
authors.initials: S
authors.lastname: Cameron
mesh_terms: D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization / Q000379:methods; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D008297:Male; D009367:Neoplasm Staging; D009456:Neurofibromatosis 1 / Q000235:genetics; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics*; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000473:pathology*; D017384:Sequence Deletion
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4