title: Genomic and clinical analysis of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group.
abstract: OBJECTIVE
  This study determined the molecular characteristics and clinical significance of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma (ARMS), an aggressive pediatric cancer with frequent PAX3-FOXO1 and PAX7-FOXO1 gene fusions.
  
  
  METHODS
  The 13q31 amplicon was localized in an initial panel of ARMS cases using oligonucleotide arrays. A fluorescence in situ hybridization assay for this localized region was designed, and applied to more ARMS cases to determine the frequency and distribution of amplification. Quantitative reverse transcription-PCR assays were applied to measure gene expression. The clinical significance of copy number and expression was determined with Kaplan-Meier and Cox proportional hazard models.
  
  
  RESULTS
  We localized the 13q31 amplicon to a 0.15 Mb region containing the MIR17HG gene encoding the polycistronic microRNA cluster, miR-17-92. This amplicon is present in 23% of ARMS cases with a marked preference for PAX7-FOXO1-positive cases. In tumors with 13q31 amplification, there is significantly increased expression of 5 of 6 microRNA's within the miR-17-92 cluster (miR-17, miR-19a, miR-19b, miR-20a, and miR-92a). In addition, a subset of nonamplified tumors with copy number-independent overexpression of all 6 microRNA's was identified. In clinical analyses, there was a significantly worse outcome associated with increased expression of the 5 microRNA's described above in 13q31-amplified cases when compared to nonamplified cases. There was also an improved outcome in 13q31-amplified cases with lower expression of these microRNA's.
  
  
  CONCLUSIONS
  13q31 amplification and expression of the miR-17-92 cluster provide novel markers for identifying good and poor prognostic subsets of PAX7-FOXO1-positive ARMS.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Reichek
authors.forename: Fenghai
authors.initials: F
authors.lastname: Duan
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Smith
authors.forename: Donna M
authors.initials: DM
authors.lastname: Gustafson
authors.forename: Roddy S
authors.initials: RS
authors.lastname: O'Connor
authors.forename: Chune
authors.initials: C
authors.lastname: Zhang
authors.forename: Mandy J
authors.initials: MJ
authors.lastname: Dunlevy
authors.forename: Julie M
authors.initials: JM
authors.lastname: Gastier-Foster
authors.forename: Frederic G
authors.initials: FG
authors.lastname: Barr
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002882:Chromosomes, Human, Pair 13 / Q000648:ultrastructure*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008495:Medical Oncology / Q000379:methods; D035683:MicroRNAs / Q000378:metabolism; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor / Q000096:biosynthesis; D051761:Paired Box Transcription Factors / Q000096:biosynthesis; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D035683:MicroRNAs; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human; D051761:Paired Box Transcription Factors