Forkhead box protein O1, also known as forkhead in rhabdomyosarcoma (FKHR) is encoded by the FOXO1 gene.  It is a transcription factor that negatively regulates adipogenesis and functions as a tumour suppressor gene, inactivated by fusions with PAX7 and PAX3 in alveolar rhabdomyosarcoma, the most common soft tissue malignancy in childhood.  These features are used in the differential diagnosis from embryonal rhabdomyosarcoma and spindle cell/sclerosing rhabdomyosarcoma, in which therapeutic modalities are distinct and which typically do not harbour fusions.  FOXO1 amplification has been described in 93% of PAX7-FOXO1 and 9% of PAX3-FOXO1 fusions by one study, and was associated with significantly improved outcome compared with the respective unamplified aberrations.

A positive FOXO1 gene rearrangement result is considered to be supportive evidence where a pathological diagnosis of alveolar rhabdomyosarcoma is being considered.

FOXO1 gene rearrangements are detected by break-apart fluorescence in-situ hybridisation (FISH) analysis.  The method will identify a chromosomal rearrangement involving the FOXO1 locus at 13q14, but not the specific gene fusion partner.

For clinical advice on appropriate investigations, please contact our Molecular Pathology team.