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
StatePublished - Mar 15 2011

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Alveolar Rhabdomyosarcoma
MicroRNAs
Neoplasms
Gene Fusion
Oligonucleotide Array Sequence Analysis
Fluorescence In Situ Hybridization
Proportional Hazards Models
Reverse Transcription
Research Design
Pediatrics
Gene Expression
Polymerase Chain Reaction
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Genomic and clinical analysis of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma : A report from the children's oncology group. / Reichek, Jennifer L.; Duan, Fenghai; Smith, Lynette M; Gustafson, Donna M.; O'Connor, Roddy S.; Zhang, Chune; Dunlevy, Mandy J.; Gastier-Foster, Julie M.; Barr, Frederic G.

In: Clinical Cancer Research, Vol. 17, No. 6, 15.03.2011, p. 1463-1473.

Research output: Contribution to journalArticle

Reichek, Jennifer L. ; Duan, Fenghai ; Smith, Lynette M ; Gustafson, Donna M. ; O'Connor, Roddy S. ; Zhang, Chune ; Dunlevy, Mandy J. ; Gastier-Foster, Julie M. ; Barr, Frederic G. / Genomic and clinical analysis of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma : A report from the children's oncology group. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 6. pp. 1463-1473.
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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.",
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T1 - Genomic and clinical analysis of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma

T2 - A report from the children's oncology group

AU - Reichek, Jennifer L.

AU - Duan, Fenghai

AU - Smith, Lynette M

AU - Gustafson, Donna M.

AU - O'Connor, Roddy S.

AU - Zhang, Chune

AU - Dunlevy, Mandy J.

AU - Gastier-Foster, Julie M.

AU - Barr, Frederic G.

PY - 2011/3/15

Y1 - 2011/3/15

N2 - 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.

AB - 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.

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