Genes, chromosomes, and rhabdomyosarcoma

Rhabdomyosarcomas are a heterogeneous group of malignant tumors and are the most common soft-tissue sarcoma of childhood. Rhabdomyosarcomas resemble d eveloping skeletal muscle, notably in their expression of the MRF family of transcription factors and the PAX3 and PAX7 genes. These PAX genes are als o involved through specific translocations, t(2; 13)(q35; q14) and variant t(1; 13)(p36; q14) in the alveolar subtype, which result in PAX3-FKHR and P AX7-FKHR fusion genes, respectively. The fusion genes are thought criticall y to affect downstream targets of PAX3 and PAX7 or possibly have novel targ ets. Similar downstream changes may also be involved in embryonal and fusio n gene negative cases. Genomic amplification of such genes as MYCN, MDM2, C DK4, and PAX7-FKHR is a feature mainly of the alveolar subtype, while speci fic chromosomal gains, including chromosomes 2, 8, 12, and 13, are associat ed with the embryonal subtype. Loss of alleles and imprinting at 11p15.5 an d disruption of genes such as IGF2, ATR, PTC, P16, and TP53 have also been implicated in rhabdomyosarcoma development. Whereas there is now a realisti c possibility of cure in the majority of cases, there remains a subset that is resistant to multimodality therapy, including high-dose chemotherapy. C haracterization of the defining molecular features of tumors that are likel y to behave aggressively represents a particular challenge. Current researc h is leading toward a better understanding of rhabdomyosarcoma tumorigenesi s, which may ultimately result in novel therapeutic strategies that increas e the overall cure. (C) 1999 Wiley-Liss, Inc.