title: Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma.
abstract: OBJECTIVE
  To determine whether the clinical and molecular biologic characteristics of the alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) subtypes have relevance independent of the presence or absence of the PAX/FOXO1 fusion gene.
  
  
  METHODS
  The fusion gene status of 210 histopathologically reviewed, clinically annotated rhabdomyosarcoma samples was determined by reverse transcriptase polymerase chain reaction. Kaplan-Meier analysis was used to assess event-free survival and overall survival in fusion gene-negative ARMS (ARMSn; n = 39), fusion gene-positive ARMS (ARMSp; n = 94), and ERMS (n = 77). A total of 101 RMS samples were also profiled for whole-genome expression, and 128 were profiled for genomic copy number imbalances. Profiling data were analyzed by supervised and unsupervised methods to compare features related to histopathology and fusion gene status. Results were also projected by meta-analysis techniques across three separate publically available data sets.
  
  
  RESULTS
  Overall and event-free survival, frequency of metastases, and distribution of site at initial presentation were not significantly different between ARMSn and ERMS. Consistent with this, analysis of gene expression signatures could not reproducibly distinguish ARMSn from ERMS whereas fusion gene-positive cases were distinct. ARMSn and ERMS frequently show whole-chromosome copy number changes, notably gain of chromosome 8 with associated high levels of expression of genes from this chromosome.
  
  
  CONCLUSIONS
  The clinical behavior and molecular characteristics of alveolar cases without a fusion gene are indistinguishable from embryonal cases and significantly different from fusion-positive alveolar cases. This implies that fusion gene status irrespective of histology is a critical factor in risk stratification of RMS.
authors.affiliation: INSERM Unité 830, Unité de Génétique Somatique, Institut Curie, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Williamson
authors.forename: Edoardo
authors.initials: E
authors.lastname: Missiaglia
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reyniès
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Pierron
authors.forename: Benedicte
authors.initials: B
authors.lastname: Thuille
authors.forename: Gilles
authors.initials: G
authors.lastname: Palenzuela
authors.forename: Khin
authors.initials: K
authors.lastname: Thway
authors.forename: Daniel
authors.initials: D
authors.lastname: Orbach
authors.forename: Marick
authors.initials: M
authors.lastname: Laé
authors.forename: Paul
authors.initials: P
authors.lastname: Fréneaux
authors.forename: Kathy
authors.initials: K
authors.lastname: Pritchard-Jones
authors.forename: Odile
authors.initials: O
authors.lastname: Oberlin
authors.forename: Janet
authors.initials: J
authors.lastname: Shipley
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
mesh_terms: D002648:Child; D002675:Child, Preschool; D002898:Chromosomes, Human, Pair 8; D003937:Diagnosis, Differential; D018572:Disease-Free Survival; D005260:Female; D005602:France; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005820:Genetic Testing; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor / Q000235:genetics*; D051761:Paired Box Transcription Factors / Q000235:genetics*; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018232:Rhabdomyosarcoma, Alveolar / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018233:Rhabdomyosarcoma, Embryonal / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D015514:Oncogene Proteins, Fusion; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; C471563:PAX3-FOXO1A fusion protein, human; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human; D051761:Paired Box Transcription Factors; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1