Analysis of Genetic Abberations in Paediatric Rhabdomyosarcomas

Tumours of soft tissues are classified according to their phenotypic, morphologic and immunohistochemical resemblance to normal adult tissue. One group among these are rhabdomyosarcomas, which occur frequently in children, and resemble to varying extents developing skeletal muscle cells. Pediatric rhabdomyosarcomas have been classified into two main subgroups: the embryonal and the alveolar rhabdomyosarcoma. Relatively typical genetic aberrations have been identified, but further analysis revealed that neither immunohistochemical patterns nor genetic aberrations are absolutely specific for the diagnosis. In alveolar rhabdomyosarcomas relatively specific translocations have been described; namely t(2;13)(q35;q14) and the variant t(1;13)(p36;q14). This translocation leads to the fusion of the 5` region of the PAX3 or PAX7 gene to the 3` sequence of the FKHR gene and the formation of a fusion gene, which is thought to play an important role in the pathogenesis of this tumour. In the proposed project specific genetic aberrations will be investigated. Tumours with alveolar histology without evidence for the PAX3-FKHR or PAX7-FKHR fusion gene transcripts have been identified. These will be screened by interphase FISH with markers flanking PAX and FKHR genes to look for potential new variant translocations. The frequency and role of recently identified non-reciprocal translocations in the pathogenesis of the embryonal subtype will also be examined using similar methods. In the alveolar subtype amplicons at 13q31, 17q23-24 and 2p24 have recently been identified and, to identify key genes involved, the frequency of the occurrence of these amplicons occur and the associated expression of genes will be examined in situ. Multiple samples will be arrayed onto microscope slides for screening (tissue arrays).