title: A study of alveolar rhabdomyosarcoma copy number alterations by single nucleotide polymorphism analysis.
abstract: Rhabdomyosarcoma, the most common pediatric soft tissue malignancy arises in 2 major histologic forms: embryonal and alveolar. Classically, the alveolar subtype is characterized by a chromosomal translocation t(2;13)(q35;q14) or t(1;13)(p36;q14) fusing the PAX3 or PAX7 gene, respectively, to the FOXO1 gene, although fusion-negative cases of alveolar rhabdomyosarcoma (ARMS) occur; these share considerably more with the genomic profiles and biological behavior of embryonal rhabdomyosarcoma than with fusion-positive ARMS. The current understanding of any additional genetic aberrations in fusion-positive ARMS is limited. In this study, we evaluated tumor-specific copy number alterations in a cohort of fusion-positive ARMSs using high-resolution technology. The results presented here include previously described changes as well as completely novel findings of copy number alterations in BCR and DICER. The study furthermore highlights associations between fusion type and genotype, as well as outcomes and genotype. Rearrangement of PAX7 is strongly associated with copy number alteration of Glypican 5 (GPC5) and moderately with amplification of IGF1R. There is a moderate association between death from/relapse of disease and, on the one hand, amplification of 12q13.3 (DDIT3; Gli1), and on the other hand, copy number alteration of Wnt6 or LRP1B. Gains of both LRP1B and Gli1 in turn are strongly associated with MycN amplification.
authors.affiliation: National Children's Research Centre, Crumlin, Dublin, Ireland.
authors.forename: Miriam
authors.initials: M
authors.lastname: Lynn
authors.forename: Naisha
authors.initials: N
authors.lastname: Shah
authors.forename: Judith
authors.initials: J
authors.lastname: Conroy
authors.forename: Sean
authors.initials: S
authors.lastname: Ennis
authors.forename: Thomas
authors.initials: T
authors.lastname: Morris
authors.forename: David
authors.initials: D
authors.lastname: Betts
authors.forename: Maureen
authors.initials: M
authors.lastname: O'Sullivan
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D015331:Cohort Studies; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005260:Female; D005784:Gene Amplification; D053673:Glypicans / Q000235:genetics; D006801:Humans; D007223:Infant; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality; D008297:Male; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D051763:PAX7 Transcription Factor / Q000235:genetics; D051761:Paired Box Transcription Factors / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000401:mortality; D043244:Ribonuclease III / Q000235:genetics*; D016019:Survival Analysis; D015534:Trans-Activators / Q000235:genetics; D051742:Transcription Factor CHOP / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics; D000071676:Zinc Finger Protein GLI1
chemical_list: C106228:GPC5 protein, human; D053673:Glypicans; C434476:LRP1B protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; C471563:PAX3-FOXO1A fusion protein, human; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human; D051761:Paired Box Transcription Factors; D011973:Receptors, LDL; D015534:Trans-Activators; C490674:WNT6 protein, human; D051153:Wnt Proteins; D000071676:Zinc Finger Protein GLI1; D051742:Transcription Factor CHOP; D017526:Receptor, IGF Type 1; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases