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

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

doi:10.1158/1078-0432.ccr-10-0091

Cited by 58 publications

(47 citation statements)

References 25 publications

(36 reference statements)

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“…The latter and red modules were both linked to Sonic hedgehog (SHH) signaling. Together this is consistent with high expression of the miR17-92 cluster being genomically amplified in around 20% of RMS and MYCN driven, mostly in those with PAX7-FOXO1 fusion genes, and possible involvement of the cluster in proliferation through SHH signaling [47], [48].…”

Section: Discussionsupporting

confidence: 77%

MicroRNA and gene co-expression networks characterize biological and clinical behavior of rhabdomyosarcomas

et al. 2017

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Rhabdomyosarcomas (RMS) in children and adolescents are heterogeneous sarcomas broadly defined by skeletal muscle features and the presence/absence of PAX3/7-FOXO1 fusion genes. MicroRNAs are small non-coding RNAs that regulate gene expression in a cell context specific manner. Sequencing analyses of microRNAs in 64 RMS revealed expression patterns separating skeletal muscle, fusion gene positive and negative RMS. Integration with parallel gene expression data assigned biological functions to 12 co-expression networks/modules that reassuringly included myogenic roles strongly correlated with microRNAs known in myogenesis and RMS development. Modules also correlated with clinical outcome and fusion status. Regulation of microRNAs by the fusion protein was demonstrated after PAX3-FOXO1 reduction, exemplified by miR-9-5p. MiR-9-5p levels correlated with poor outcome, even within fusion gene positive RMS, and were higher in metastatic versus non-metastatic disease. MiR-9-5p reduction inhibited RMS cell migration. Our findings reveal microRNAs in a regulatory framework of biological and clinical significance in RMS.

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Section: Discussionsupporting

confidence: 77%

MicroRNA and gene co-expression networks characterize biological and clinical behavior of rhabdomyosarcomas

et al. 2017

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“…(44) Although GPC5 expression was absent in normal skeletal muscle, more than half of the RMS samples represented expressions of GPC5 in this study, suggesting that aberrant GPC5 activity might play a role in RMS oncogenesis.…”

Section: Discussionmentioning

confidence: 56%

Characterization of genetic lesions in rhabdomyosarcoma using a high‐density single nucleotide polymorphism array

et al. 2013

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Rhabdomyosarcoma (RMS) is a common solid tumor in childhood divided into two histological subtypes, embryonal (ERMS) and alveolar (ARMS). The ARMS subtype shows aggressive clinical behavior with poor prognosis, while the ERMS subtype has a more favorable outcome. Because of the rarity, diagnostic diversity and heterogeneity of this tumor, its etiology remains to be completely elucidated. Thus, to identify genetic alterations associated with RMS development, we performed single nucleotide polymorphism array analyses of 55 RMS samples including eight RMS-derived cell lines. The ERMS subtype was characterized by hyperploidy, significantly associated with gains of chromosomes 2, 8 and 12, whereas the majority of ARMS cases exhibited neardiploid copy number profiles. Loss of heterozygosity of 15q was detected in 45.5% of ARMS that had been unrecognized in RMS to date. Novel amplifications were also detected, including IRS2 locus in two fusion-positive tumors, and KRAS or NRAS loci in three ERMS cases. Of note, gain of 13q was significantly associated with good patient outcome in ERMS. We also identified possible application of an ALK inhibitor to RMS, as ALK amplification and frequent expression of ALK were detected in our RMS cohort. These findings enhance our understanding of the genetic mechanisms underlying RMS pathogenesis and support further studies for therapeutic development of RMS. (Cancer Sci 2013; 104: 856-864) R habdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Two major histological subtypes are recognized: alveolar (ARMS) and embryonal (ERMS). The ERMS subtype (approximately 60% of all RMS cases) is usually a localized disease with a favorable prognosis, typically occurring in younger children.(1) It presents mostly as a disease of the head, neck or genitourinary tract.(1) In contrast, the ARMS subtype, which accounts for approximately 20% of RMS, commonly involves the extremities in older children, exhibiting aggressive clinical behavior with frequent metastatic diseases.(1) Approximately 75% of ARMS exhibit characteristic chromosomal translocations, t(2;13)(q35:q14) and t(1;13)(p36: q14), which generate aberrant fusion transcription factors PAX3-FOXO1 and PAX7-FOXO1, respectively.(2,3) Loss of heterozygosity (LOH) at 11p15.5 is a common chromosomal aberration in ERMS as well as other pediatric tumors, for example, Wilms tumor and hepatoblastoma.(4) According to previous reports using array-based comparative genomic hybridization, numerical changes primarily involving gains of chromosomes 2, 8 and 12 are generally associated with ERMS, and ARMS are typically characterized by genomic amplifications (5)(6)(7)(8) including co-amplifications of PAX3 ⁄ 7 and FOXO1 loci in fusion-positive tumors. (5,(7)(8)(9) Although these genetic findings suggest that the two subtypes represent discrete clinicopathological entities, their molecular basis has not been completely elucidated.In the present study, we performed high-density single nucleotide polymorphism (SNP) array analysis of 55 RM...

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“…High-resolution SNP arrays corroborated 90% of high confidence SV when a copy number change was present (see Methods). Forty-eight genes were recurrently affected by SV, including genes previously implicated in RMS pathology ( MIR17HG, CNR1, CDKN2A ) (14-16), tyrosine kinase signaling ( ERBB4, RPTOR, FRS2, CACNA1A ) and muscle development ( NRG1, FOXP2 ) (Supplementary Table S4). Frequently (341/553, 61%), junction events occurred in areas of complex rearrangement or tandem duplications most often associated with regions of high copy number amplification.…”

Section: Resultsmentioning

confidence: 99%

Comprehensive Genomic Analysis of Rhabdomyosarcoma Reveals a Landscape of Alterations Affecting a Common Genetic Axis in Fusion-Positive and Fusion-Negative Tumors

et al. 2014

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Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma (RMS) remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs. Two genotypes are evident in RMS tumors; those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in RMS is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations of NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, we found novel recurrent mutations in FBXW7, and BCOR providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/RAS/PIK3CA axis affects 93% of cases providing a framework for genomics directed therapies that might improve outcomes for RMS patients.

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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

Cited by 58 publications

References 25 publications

MicroRNA and gene co-expression networks characterize biological and clinical behavior of rhabdomyosarcomas

MicroRNA and gene co-expression networks characterize biological and clinical behavior of rhabdomyosarcomas

Characterization of genetic lesions in rhabdomyosarcoma using a high‐density single nucleotide polymorphism array

Comprehensive Genomic Analysis of Rhabdomyosarcoma Reveals a Landscape of Alterations Affecting a Common Genetic Axis in Fusion-Positive and Fusion-Negative Tumors

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