High‐resolution array CGH identifies common mechanisms that drive embryonal rhabdomyosarcoma pathogenesis

Paulson, Vera; Chandler, Garvin L.; Rakheja, Dinesh; Galindo, Rene L.; Wilson, Kathleen; Amatruda, James F.; Cameron, Scott A.

doi:10.1002/gcc.20864

Cited by 97 publications

(105 citation statements)

References 43 publications

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“…(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.…”

mentioning

confidence: 99%

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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“…(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.…”

mentioning

confidence: 99%

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

et al. 2013

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“…This is corroborated by another study showing absence of PTCH1 loss-of-function mutations or SMO amplifications in 26 NRMS examined [41]. Also, a recent whole-genome sequencing (WGS) analysis on 16 RMS tumors ruled out the presence of mutations in components of the Hh pathway [48].…”

Section: Role Of Hedgehog Pathway In Rmsmentioning

confidence: 58%

“…Subsequently, the generation of mice heterozygous for Ptch confirmed the involvement of Hh pathway over-activation in RMS tumorigenesis [38]. Accordingly, up-regulation of Hh target genes such as GLI1 and PTCH1 has been demonstrated by retrospective analysis of RMS patient samples or in human RMS cell lines [39][40][41][42][43]. Additionally, activation of Hh pathway seems to be specific for fusion negative RMS (NRMS) and significantly identifies patients with poor prognosis [40,41,44,45].…”

Section: Role Of Hedgehog Pathway In Rmsmentioning

confidence: 96%

“…Accordingly, up-regulation of Hh target genes such as GLI1 and PTCH1 has been demonstrated by retrospective analysis of RMS patient samples or in human RMS cell lines [39][40][41][42][43]. Additionally, activation of Hh pathway seems to be specific for fusion negative RMS (NRMS) and significantly identifies patients with poor prognosis [40,41,44,45]. Despite this recognized role of Hh in RMS, the contribution of the ligand-based signaling versus non-canonical pathway activation in sporadic RMS is still unclear.…”

Section: Role Of Hedgehog Pathway In Rmsmentioning

confidence: 99%

“…Also, a recent whole-genome sequencing (WGS) analysis on 16 RMS tumors ruled out the presence of mutations in components of the Hh pathway [48]. SHH immunoreactivity is not common in RMS and the higher Hh activity in NRMS compared to fusion positive RMS (PRMS) does not correlate with SHH mRNA levels, which are unchanged between the two subtypes [39][40][41]. However, we previously found a positive correlation of IHH and DHH mRNA levels with the expression of Hh target genes in RMS supporting the hypothesis of a ligand-mediated activation of Hh pathway [45].…”

Section: Role Of Hedgehog Pathway In Rmsmentioning

confidence: 99%

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Interfering with Hedgehog Pathway: New Avenues for Targeted Therapy in Rhabdomyosarcoma

Manzella¹,

Schäfer

2016

CDT

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Rhabdomyosarcoma (RMS) is the most frequent pediatric soft-tissue tumor accounting for about 7% of childhood malignancies. Multimodal therapy is the standard treatment for individuals with RMS but generally fails to cure high-risk group patients and can result in long-term side effects. Therefore, understanding the mechanisms driving RMS might help to find new candidate targets for more specific and effective therapeutic modalities. One of the molecular machineries, which is often deregulated in cancer and specifically involved in the tumorigenesis of RMS, is Hedgehog (Hh) signaling. There is increasing evidence that targeting this developmental pathway may hold promise in future treatment strategies for RMS. In this review, we discuss the contribution of the Hh pathway in RMS, the challenges of inhibiting this embryonic signaling in children with an update on recent preclinical data and ongoing clinical trials.

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Molecular Genetics of Rhabdomyosarcoma

Gallego¹,

Toledo²,

Roma³

2012

Encyclopedia of Life Sciences

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. There are two main histologic subtypes, embryonal and alveolar, with different clinical behaviour and prognosis. Embryonal RMS is commonly localised with favourable prognosis, whereas alveolar RMS is more frequently metastatic and its prognosis is poor. These clinical differences reflect different molecular genetics. Alveolar RMS has recurrent reciprocal translocations that are absent in embryonal tumours. These translocations, t(2;13)(q35;q14) and t(1;13)(p36;q14), generate the fusion genes PAX3–FOXO1 and PAX7–FOXO1, respectively. The resulting fusion proteins exert effects on differentiation, proliferation and apoptosis, thereby bestowing a survival advantage on RMS cells. Recent advances in the identification of the cell of origin of RMS and a deeper knowledge of deregulated signalling pathways offer an opportunity for novel therapeutic approaches for patients with this tumour. Key Concepts: Embryonal and alveolar RMS have different molecular and genetic features and different clinical behaviours. Fusion‐negative alveolar RMS have expression profiles resembling those of embryonal RMS. The chimeric proteins resulting from the characteristic translocations of alveolar rhabdomyosarcomas exert oncogenic effects. Numerous signalling pathways are deregulated in rhabdomyosarcoma. Rhabdomyosarcoma derives from myogenic progenitor cells that undergo malignant transformation under the effects of a regulator programme that involves p53 and Rb pathways.

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High‐resolution array CGH identifies common mechanisms that drive embryonal rhabdomyosarcoma pathogenesis

Cited by 97 publications

References 43 publications

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

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

Interfering with Hedgehog Pathway: New Avenues for Targeted Therapy in Rhabdomyosarcoma

Molecular Genetics of Rhabdomyosarcoma

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