Molecular Genetics of Rhabdomyosarcoma


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.

Keywords: rhabdomyosarcoma; PAX3–FOXO1; PAX7–FOXO1; alveolar rhabdomyosarcoma; embryonal rhabdomyosarcoma

Figure 1.

Fusion genes in alveolar rhabdomyosarcoma. The most common fusion involves PAX3/FOXO1 t(2;13) that is created by the fusion of PAX3, located in 2q35 (in blue) and FOXO1, located in 13q14 (in red). The resultant chimeric gene contains the binding domains paired box (PB) and homeodomain (HD) of PAX3, along with the transactivating domain of FOXO1. Reproduced from Gallego Melcon S and Sanchez de Teledo Codina J (2007) Molecular biologty of rhabdomysarcoma. Clin Tronsl. Oncol. 9: 415–419. DOI: 10.1007/S12094‐007‐0079‐3, with permission from FESEO.

Figure 2.

Functional effects of the Pax3–FKHR protein. The chimeric Pax3–FKHR protein resulting from the PAX3–FOXO1 fusion exerts oncogenic effects. Pax3–FKHR induces cell transformation and proliferation while inhibiting myogenic differentiation and apoptosis. Similar effects of Pax7–FKHR depend on PAX7–FOXO1 genomic amplification. Reproduced from Gallego Melcon S and Sanchez de Teledo Codina J (2007) Molecular biologty of rhabdomysarcoma. Clin Tronsl. Oncol. 9: 415–419. DOI: 10.1007/S12094‐007‐0079‐3, with permission from FESEO.



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Further Reading

Charytonowicz E, Cordon‐Cardo C, Matushansky I and Ziman M (2009) Alveolar rhabdomyosarcoma: is the cell of origin a mesenchymal stem cell? Cancer Letters 279: 126–136.

Linardic C (2008) PAX3–FOXO1 fusion gene in rhabdomyosarcoma. Cancer Letters 270: 10–18.

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Gallego, Soledad, De Toledo, Jose Sanchez, and Roma, Josep(Feb 2012) Molecular Genetics of Rhabdomyosarcoma. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023883]