TY - JOUR
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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U2 - 10.1158/1078-0432.CCR-10-0091
DO - 10.1158/1078-0432.CCR-10-0091
M3 - Article
C2 - 21220470
AN - SCOPUS:79952730384
SN - 1078-0432
VL - 17
SP - 1463
EP - 1473
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -