Gene expression signatures identify rhabdomyosarcoma subtypes and detect a novel t(2;2)(q35;p23) translocation fusing PAX3 to NCOA1.
Rhabdomyosarcoma is a pediatric tumor type, which is classified based on histological criteria into two major subgroups, namely embryonal rhabdomyosarcoma and alveolar rhabdomyosarcoma. The majority, but not all, alveolar rhabdomyosarcoma carry the specific PAX3(7)/FKHR-translocation, whereas there is no consistent genetic abnormality recognized in embryonal rhabdomyosarcoma. To gain additional insight into the genetic characteristics of these subtypes, we used oligonucleotide microarrays to measure the expression profiles of a group of 29 rhabdomyosarcoma biopsy samples (15 embryonal rhabdomyosarcoma, and 10 translocation-positive and 4 translocation-negative alveolar rhabdomyosarcoma). Hierarchical clustering revealed expression signatures clearly discriminating all three of the subgroups. Differentially expressed genes included several tyrosine kinases and G protein-coupled receptors, which might be amenable to pharmacological intervention. In addition, the alveolar rhabdomyosarcoma signature was used to classify an additional alveolar rhabdomyosarcoma case lacking any known PAX3 or PAX7 fusion as belonging to the translocation-positive group, leading to the identification of a novel translocation t(2;2)(q35;p23), which generates a fusion protein composed of PAX3 and the nuclear receptor coactivator NCOA1, having similar transactivation properties as PAX3/FKHR. These experiments demonstrate for the first time that gene expression profiling is capable of identifying novel chromosomal translocations.
University Children's Hospital, Division of Oncology, Zurich, Switzerland.
Marco
M
Wachtel
Marcel
M
Dettling
Eva
E
Koscielniak
Sabine
S
Stegmaier
Jörn
J
Treuner
Katja
K
Simon-Klingenstein
Peter
P
Bühlmann
Felix K
FK
Niggli
Beat W
BW
Schäfer
D001483:Base Sequence; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D020869:Gene Expression Profiling; D051548:Histone Acetyltransferases; D006801:Humans; D008969:Molecular Sequence Data; D056920:Nuclear Receptor Coactivator 1; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics* / Q000378:metabolism; D018233:Rhabdomyosarcoma, Embryonal / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; C068686:Pax3 protein, mouse; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1