Genomic and Clinical Analysis of Amplification of the 13q31 Chromosomal Region in Alveolar Rhabdomyosarcoma: A Report from the Children's Oncology Group

• Published in: Clinical cancer research Vol. 17; no. 6; pp. 1463 - 1473
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-03-2011
• Subjects: Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor - metabolism; Chromosomes, Human, Pair 13 - ultrastructure; Diseases of the osteoarticular system; Forkhead Box Protein O1; Forkhead Transcription Factors - biosynthesis; Humans; In Situ Hybridization, Fluorescence; Medical Oncology - methods; Medical sciences; MicroRNAs - metabolism; Multigene Family; Oligonucleotide Array Sequence Analysis; Paired Box Transcription Factors - biosynthesis; PAX3 Transcription Factor; PAX7 Transcription Factor - biosynthesis; Pharmacology. Drug treatments; Proportional Hazards Models; Reverse Transcriptase Polymerase Chain Reaction; Rhabdomyosarcoma, Alveolar - genetics; Tumors of striated muscle and skeleton; Human; Sarcoma; Report; Genomics; Chromosome D13; Malignant tumor; Striated muscle disease; Gene amplification; Cancerology; Analysis; Genetics; Genome; Child; Alveolar rhabdomyosarcoma; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-10-0091

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.
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.
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.
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.