Dataset Information

Genomic and clinical analysis of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group.

ABSTRACT: 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.

SUBMITTER: Reichek JL

PROVIDER: S-EPMC3060277 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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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 JL Duan Fenghai F Smith Lynette M LM Gustafson Donna M DM O'Connor Roddy S RS Zhang Chune C Dunlevy Mandy J MJ Gastier-Foster Julie M JM Barr Frederic G FG

Clinical cancer research : an official journal of the American Association for Cancer Research 20110110 6

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 cas ...[more]

PMID: 21220470

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Project description:ImportanceDetermining the impact of germline cancer-predisposition variants (CPVs) on outcomes could inform novel approaches to testing and treating children with rhabdomyosarcoma.ObjectiveTo assess whether CPVs are associated with outcome among children with rhabdomyosarcoma.Design, setting, and participantsIn this cohort study, data were obtained for individuals, aged 0.01-23.23 years, newly diagnosed with rhabdomyosarcoma who were treated across 171 Children's Oncology Group sites from March 15, 1999, to December 8, 2017. Data analysis was performed from June 16, 2021, to May 15, 2023.ExposureThe presence of a CPV in 24 rhabdomyosarcoma-associated cancer-predisposition genes (CPGs) or an expanded set of 63 autosomal-dominant CPGs.Main outcomes and measuresOverall survival (OS) and event-free survival (EFS) were the main outcomes, using the Kaplan-Meier estimator to assess survival probabilities and the Cox proportional hazards regression model to adjust for clinical covariates. Analyses were stratified by tumor histology and the fusion status of PAX3 or PAX7 to the FOXO1 gene.ResultsIn this study of 580 individuals with rhabdomyosarcoma, the median patient age was 5.9 years (range, 0.01-23.23 years), and the male-to-female ratio was 1.5 to 1 (351 [60.5%] male). For patients with CPVs in rhabdomyosarcoma-associated CPGs, EFS was 48.4% compared with 57.8% for patients without a CPV (P = .10), and OS was 53.7% compared with 65.3% for patients without a CPV (P = .06). After adjustment, patients with CPVs had significantly worse OS (adjusted hazard ratio [AHR], 2.49 [95% CI, 1.39-4.45]; P = .002), and the outcomes were not better among patients with embryonal histology (EFS: AHR, 2.25 [95% CI, 1.25-4.06]; P = .007]; OS: AHR, 2.83 [95% CI, 1.47-5.43]; P = .002]). These associations were not due to the development of a second malignant neoplasm, and importantly, patients with fusion-negative rhabdomyosarcoma who harbored a CPV had similarly inferior outcomes as patients with fusion-positive rhabdomyosarcoma without CPVs (EFS: AHR, 1.35 [95% CI, 0.71-2.59]; P = .37; OS: AHR, 1.71 [95% CI, 0.84-3.47]; P = .14). There were no significant differences in outcome by CPV status of the 63 CPG set.Conclusions and relevanceThis cohort study identified a group of patients with embryonal rhabdomyosarcoma who had a particularly poor outcome. Other important clinical findings included that individuals with TP53 had poor outcomes independent of second malignant neoplasms and that patients with fusion-negative rhabdomyosarcoma who harbored a CPV had outcomes comparable to patients with fusion-positive rhabdomyosarcoma. These findings suggest that germline CPV testing may aid in clinical prognosis and should be considered in prospective risk-based clinical trials.

Dataset Information

Genomic and clinical analysis of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group.

Publications

Genomic and clinical analysis of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group.

Similar Datasets

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