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 (PB) and (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.



Anderson J, Gordon T, McManus A et al. (2001a) Detection of the PAX3‐FKHR fusion gene in rhabdomyosarcoma: a reproducible predictor of outcome? British Journal of Cancer 85: 831–835.

Anderson J, Ramsay A, Gould S and Pritchard‐Jones K (2001b) PAX3‐FKHR induces morphological changes and enhances cellular proliferation and invasion in rhabdomyosarcoma. American Journal of Pathology 159: 1089–1096.

Barr FG (2001) Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma. Oncogene 20: 5736–5746.

Bridge JA, Liu J, Weibolt V et al. (2000) Novel genomic imbalances in embryonal rhabdomyosarcoma revealed by comparative genomic hybridization: an intergroup rhabdomyosarcoma study. Genes Chromosomes & Cancer 27: 337–344.

Davicioni E, Finckenstein FG, Shahbazian V et al. (2006) Identification of a PAX–FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas. Cancer Research 66: 6936–6946.

Davis RJ, D'Cruz CM, Lowell MA et al. (1994) Fusion of PAX7 to the FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcomas. Cancer Research 54: 2869–2872.

De Pitta C, Tombolan L, Albiero G et al. (2006) Gene expression profiling identifies potential relevant genes in alveolar rhabdomyosarcoma pathogenesis and discriminates PAX3‐FKHR positive and negative tumors. International Journal of Cancer 118: 2772–2781.

Epstein JA, Shapiro DN, Cheng J et al. (1996) Pax3 modulates expression of the c‐Met receptor during limb muscle development. Proceedings of the National Academy of Sciences of the USA 93: 4213–4218.

Galili N, Davis RJ, Fredericks WJ et al. (1993) Fusion of a fork head domain gene to PAX 3 in the solid tumour alveolar rhabdomyosacoma. Nature Genetics 5: 230–235.

Ginsberg JP, Davis RJ, Bennicelli JL et al. (1998) Up‐regulation of MET but not neural cell adhesion molecule expression by the PAX3–FKHR fusion protein in alveolar rhabdomyosarcoma. Cancer Research 58: 3542–3546.

Hettmer S and Wagers AJ (2010) Muscling in: uncovering the origins of rhabdomyosarcoma. Nature Medicine 16: 171–173.

Kelly KM, Womer RB, Sorensen PH et al. (1997) Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. Journal of Clinical Oncology 15: 1831–1837.

Khan J, Simon R, Bittner M et al. (1998) Gene expression profiling of alveolar rhabdomyosarcoma with cDNA microarrays. Cancer Research 58: 5009–5013.

Kohashi K, Oda Y, Yamamoto H et al. (2008) Alterations of RB1 gene in embryonal and alveolar rhabdomyosarcoma: special reference to utility of pRB immunoreactivity in differential diagnosis of rhabdomyosarcoma subtype. Journal of Cancer Research & Clinical Oncology 134: 1097–1103.

Li HG, Wang Q, Li HM et al. (2007) PAX3 and PAX3–FKHR promote rhabdomyosarcoma cell survival through downregulation of PTEN. Cancer Letters 253: 215–223.

Linardic CM, Naini S, Herndon J et al. (2007) The PAX3–FKHR fusion gene of rhabdomyosarcoma cooperates with loss of p16INK4A to promote bypass of cellular senescence. Cancer Research 67: 6691–6699.

Liu J, Guzman MA, Pezanowski D et al. (2011) FOXO1–FGFR1 fusion and amplification in a solid variant of alveolar rhabdomyosarcoma. Modern Pathology 24: 1327–1335.

Margue CM, Bernasconi M, Barr FG and Schafer BW (2000) Transcriptional modulation of the anti‐apoptotic protein BCL‐XL by the paired box transcription factors PAX3 and PAX3/FKHR. Oncogene 19: 2921–2929.

Meyer WH and Spunt SL (2004) Soft tissue sarcomas of childhood. Cancer Treatment Reviews 30: 269–280.

Onisto M, Slongo ML, Gregnanin L et al. (2005) Expression and activity of vascular endothelial growth factor and metalloproteinases in alveolar and embryonal rhabdomyosarcoma cell lines. International Journal of Oncology 27: 791–798.

Paulson V, Chandler G, Rakheja D et al. (2011) High‐resolution array CGH identifies common mechanisms that drive embryonal rhabdomyosarcoma pathogenesis. Genes Chromosomes & Cancer 50: 397–408.

Raney RB, Anderson JR, Barr FG et al. (2001) Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for intergroup rhabdomyosarcoma study V. Journal of Pediatric Hematolology and Oncology 23: 215–220.

Ren YX, Finckenstein FG, Abdueva DA et al. (2008) Mouse mesenchymal stem cells expressing PAX–FKHR form alveolar rhabdomyosarcomas by cooperating with secondary mutations. Cancer Research 68: 6587–6597.

Roeb W, Boyer A, Cavenee WK and Arden KC (2007) PAX3–FOXO1 controls expression of the p57Kip2 cell‐cycle regulator through degradation of EGFR1. Proceedings of the National Academy of Sciences of the USA 104: 18085–18090.

Romualdi C, De Pitta C, Tombolan L et al. (2006) Defining the gene expression signature of rhabdomyosarcoma by meta‐analysis. BMC Genomics 7: 287–295.

Rubin BP, Nishijo K, Chen HH et al. (2011) Evidence for an unanticipated relationship between undifferentiated pleomorphic sarcoma and embryonal rhabdomyosarcoma. Cancer Cell 19: 177–191.

Schaaf GJ, Ruijter JM, van Zwijnenburg RF et al. (2005) Full transcriptome analysis of rhabdomyosarcoma, normal, and fetal skeletal muscle: statistical comparison of multiple SAGE libraries. FASEB Journal 19: 404–406.

Scheidler S, Fredericks WJ, Rauscher FJ III et al. (1996) The hybrid PAX3–FKHR fusion protein of alveolar Rabdomyosarcoma transforms fibroblasts in culture. Proceedings of the National Academy of Sciences of the USA 93: 9805–9809.

Sorensen PHB, Lynch JC, Qualman SJ et al. (2002) PAX3–FKHR and PAX7–FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group. Journal of Clinical Oncology 20: 2672–2679.

Sumegi J, Streblow R, Frayer RW et al. (2010) Recurrent t(2;2) and t(2;8) translocations in rhabdomyosarcoma without the canonical PAX–FOXO1 fuse PAX3 to members of the nuclear receptor transcriptional coactivator family. Genes Chromosomes Cancer 49: 224–236.

Taulli R, Scuoppo C, Bersani F et al. (2006) Validation of met as a therapeutic target in alveolar and embryonal rhabdomyosarcoma. Cancer Research 66: 4742–4749.

Tostar U, Malm CJ, Meis‐Kindblom JM et al. (2006) Deregulation of the hedgehog signaling pathway: a possible role for the PTCH and SUSU genes in human rhabdomyoma and rhabdomyosarcoma development. Journal of Pathology 208: 17–25.

Visser M, Sijmons C, Bras J et al. (1997) Allelotype of pediatric rhabdomyosarcoma. Oncogene 15: 1309–1314.

Wachtel M, Dettling M, Koscielnak E et al. (2004) Gene expression signatures identify rhabdomyosarcoma subtypes and detect a novel t(2;2)(q35;p23) translocation fusing PAX3 to NCOA1. Cancer Research 64: 5539.

Wang H, Garzon R, Sun H et al. (2008) NF‐kappaB‐YY1‐miR‐29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma. Cancer Cell 14: 369–381.

Williamson D, Missiaglia E, de Reynies A et al. (2010) Fusion gene‐negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. Journal of Clinical Oncology 28: 2151–2158.

Yan Y, Frisen J, Lee MH et al. (1997) Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development. Genes Development 11: 973–983.

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
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]