Fusion Gene–Negative Alveolar Rhabdomyosarcoma Is Clinically and Molecularly Indistinguishable From Embryonal Rhabdomyosarcoma

Williamson, Daniel; Missiaglia, Edoardo; Reyniès, Aurélien de; Pierron, Gaëlle; Thuille, Bénédicte; Palenzuela, Gilles; Thway, Khin; Orbach, Daniel; Laé, Marick; Fréneaux, Paul; Pritchard‐Jones, Kathy; Oberlin, Odile; Shipley, Janet; Delattre, Olivier

doi:10.1200/jco.2009.26.3814

Cited by 428 publications

(435 citation statements)

References 28 publications

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“…It is interesting to note that we consistently found that gene expression profiles of fusion gene-negative ARMS closely resembled that of ERMS. This is in line with recent reports that ARMS cases lacking PAX3/7-FOXO1 chromosomal translocations are indistinguishable in their gene expression profiles from ERMS (Davicioni et al, 2009;Williamson et al, 2010).…”

Section: Discussionsupporting

confidence: 93%

“…Furthermore, Myf5 is regulated by Hh signaling (Gustafsson et al, 2002;Gerber et al, 2007). Initially, we assessed expression profiles of these markers in a group of 103 RMS patients that we recently characterized (cohort 1) (Williamson et al, 2010). In addition, we analyzed a previously published separate group of 132 RMS patients to validate our results (cohort 2) (Davicioni et al, 2006).…”

Section: Hh Pathway Activation In Rms Subtypesmentioning

confidence: 99%

“…Cohort 1 (n ¼ 103) (Williamson et al, 2010) and cohort 2 (n ¼ 132) (Davicioni et al, 2006) of RMS patients were described previously. Patients' characteristics of cohort 3 are summarized in Table 4.…”

Section: Patientsmentioning

confidence: 99%

“…ERMS accounts for approximately two-thirds of all RMS and is typically associated with a more favorable prognosis compared with the alveolar subtype (Dagher and Helman, 1999). Recently, we have shown that fusion gene-negative ARMS are clinically and biologically similar to ERMS and distinct from ARMS with PAX3/PAX7-FOXO1 fusion genes (Williamson et al, 2010). At the molecular level, ERMS frequently shows loss of heterozygosity at chromosome 11p15 and not the chromosomal translocations that are typical for ARMS (Merlino and Helman, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…These translocations lead to characteristic fusion genes that typically consist of the DNA-binding domain of the PAX3 or PAX7 genes located on chromosome 2 or chromosome 1 and the transactivation domain of the forkhead transcription factor FOXO1 gene that is located on chromosome 13 (Merlino and Helman, 1999). However, at least 25% of ARMS lack this translocation despite classical alveolar histology (Barr et al, 2002;Sorensen et al, 2002;Williamson et al, 2010). ERMS accounts for approximately two-thirds of all RMS and is typically associated with a more favorable prognosis compared with the alveolar subtype (Dagher and Helman, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma

et al. 2010

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Section: Discussionsupporting

confidence: 93%

Section: Hh Pathway Activation In Rms Subtypesmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma

et al. 2010

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FGF7–FGFR2 autocrine signaling increases growth and chemoresistance of fusion‐positive rhabdomyosarcomas

et al. 2021

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Rhabdomyosarcomas are aggressive pediatric soft‐tissue sarcomas and include high‐risk PAX3–FOXO1 fusion‐gene‐positive cases. Fibroblast growth factor receptor 4 (FGFR4) is known to contribute to rhabdomyosarcoma progression; here, we sought to investigate the involvement and potential for therapeutic targeting of other FGFRs in this disease. Cell‐based screening of FGFR inhibitors with potential for clinical repurposing (NVP‐BGJ398, nintedanib, dovitinib, and ponatinib) revealed greater sensitivity of fusion‐gene‐positive versus fusion‐gene‐negative rhabdomyosarcoma cell lines and was shown to be correlated with high expression of FGFR2 and its specific ligand, FGF7. Furthermore, patient samples exhibit higher mRNA levels of FGFR2 and FGF7 in fusion‐gene‐positive versus fusion‐gene‐negative rhabdomyosarcomas. Sustained intracellular mitogen‐activated protein kinase (MAPK) activity and FGF7 secretion into culture media during serum starvation of PAX3–FOXO1 rhabdomyosarcoma cells together with decreased cell viability after genetic silencing of FGFR2 or FGF7 was in keeping with a novel FGF7–FGFR2 autocrine loop. FGFR inhibition with NVP‐BGJ398 reduced viability and was synergistic with SN38, the active metabolite of irinotecan. In vivo , NVP‐BGJ398 abrogated xenograft growth and warrants further investigation in combination with irinotecan as a therapeutic strategy for fusion‐gene‐positive rhabdomyosarcomas.

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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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Fusion Gene–Negative Alveolar Rhabdomyosarcoma Is Clinically and Molecularly Indistinguishable From Embryonal Rhabdomyosarcoma

Cited by 428 publications

References 28 publications

Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma

Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma

FGF7–FGFR2 autocrine signaling increases growth and chemoresistance of fusion‐positive rhabdomyosarcomas

Molecular Genetics of Rhabdomyosarcoma

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