Genomic and clinical analysis of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma: A report from the children's oncology group

Jennifer L. Reichek, Fenghai Duan, Lynette M Smith, Donna M. Gustafson, Roddy S. O'Connor, Chune Zhang, Mandy J. Dunlevy, Julie M. Gastier-Foster, Frederic G. Barr

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Abstract

Purpose: 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. Experimental Design: 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.

Original languageEnglish (US)
Pages (from-to)1463-1473
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number6
DOIs
Publication statusPublished - Mar 15 2011

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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