Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma

Abstract

We have examined the structure and expression of the products associated with the t(2;13)(q35;q14) translocation associated with alveolar rhabdomyosarcoma. The chromosome 13 gene (FKHR) is identified as a member of the fork head domain family of transcription factors characterized by a conserved DNA binding motif. Polymerase chain reaction analysis demonstrates that a 5'PAX3-3' FKHR chimaeric transcript is expressed in all eight alveolar rhabdomyosarcomas investigated. Immunoprecipitation experiments detect the predicted fusion protein. These findings indicate that the t(2;13) generates a potentially tumorigenic fusion transcription factor consisting of intact PAX3 DNA binding domains, a truncated fork head DNA binding domain and C-terminal FKHR regions.

Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma

“…Similarly in Ewing's sarcoma, the 5' region of the EWS gene at 22q12 can become fused to the FLI1, ERG and ETV1 genes, three members of the family of transcription factor genes located respectively on chromosomes 11, 21 and 7 (Zucman et al, 1993;Jeon et al, 1995). In alveolar rhabdomyosarcoma 3' FKHR sequences on chromosome 13 can become joined to either 5' PAX3 sequences located on chromosome 2 or 5' PAX7 sequences on chromosome 1 (Galili et al, 1993;Davis et al, 1994).…”

Identification of novel molecular markers which correlate with HPV-induced tumor progression

“…A number of these genes are known to be associated with human disease. For example, MN1 (Buijs et al, 1995;, FKHR (Barr, 1997;Galili et al, 1993;Scheidler et al, 1996) and FUS/TLS (Aman et al, 1996;Calvio et al, 1995;Zinszner et al, 1997) are frequently a ected by chromosomal translocations in malignancies. Others, such as Mi-2 (Seelig et al, 1995;Ge et al, 1995), desmoplakin and calpastatin (Despres et al, 1995) are autoantigenic.…”

Rhabdomyosarcoma – working out the pathways

“…Embryonal and alveolar RMS can be distinguished cytogenetically (Scrable et al, 1989). Approximately 90% of alveolar RMS carry a characteristic chromosomal translocation juxtaposing the 5' DNA-binding domains (paired box and homeodomain) of PAX, a member of the Paired Box transcription factor family, to the transactivation domain at the 3' portion of FKHR, a member of the forkhead/HNF-3 transcription factor family Galili et al, 1993;Davis et al, 1994). The majority of these structural rearrangements translocate the PAX3 gene at 2q35 to the FKHR gene at 13q14 (t(2;13)(q35;q14)); less frequently, a t(1;3)(q36;q14) translocation fuses PAX7 to FKHR.…”

“…This LOI can lead to a twofold gene dosage e ect, and may contribute to the characteristic overexpression of IGF2 observed in these tumors (Zhan et al, 1994). LOH studies have Barr et al, 1993;Galili et al, 1993Davis et al, 1994Besnard-Gue rin et al, 1996Visser et al, 1997Stratton et al, 1990Mulligan et al, 1990;Felix et al, 1992El-Badry et al, 1990Zhan et al, 1994Meddeb et al, 1996Keleti et al, 1996;Fiddler et al, 1996Khatib et al, 1993Knudsen et al, 1998Ferracini et al, 1996Garson et al, 1986Mitani et al, 1986;Bayani et al, 1995Weber-Hall et al, 1996Smith et al, 1998Iolascon et al, 1996Schweigerer et al, 1987De Giovanni et al, 1995Chardin et al, 1985Stratton et al, 1989 *Denotes alterations seen commonly in both RMS cell lines and tumor tissue; other lesions occur occasionally, and/or have been infrequently reported. LOH, loss of heterozygosity; LOI, loss of imprinting also suggested the existence of putative RMSassociated tumor suppressor genes residing at 11q and 16q (Loh et al, 1992;Visser et al, 1997).…”