Abstract
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.
Highlights
Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood, representing 5– 8% of all malignancies in children [1]
A leave-one-out cross validation study for estimating the misclassification risk in out-of-sample classification yielded the benchmark of 0% error-rate with a wide range of genes applying four different statistical methods including a newly developed method based on gene groups called Pelora (Ref. 10; Fig. 1B). This demonstrates that fusion-positive alveolar rhabdomyosarcoma are characterized by an expression signature, which separates this group with very high accuracy from other rhabdomyosarcoma
The chimeric protein includes both DNA-binding domains of together, these findings extend the results from the hierarchical clus- PAX3, paired-box and homeodomain, and a long COOH-terminal part tering and demonstrate that rhabdomyosarcoma subgroups can be of NCOA1 presumably acting as transactivation domain (Fig. 3D)
Summary
Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood, representing 5– 8% of all malignancies in children [1]. On the basis of histological criteria, rhabdomyosarcoma tumors are classified into two major subgroups, namely the more frequent embryonal rhabdomyosarcoma (60%) and the rarer alveolar rhabdomyosarcoma (20%). These subtypes are associated with distinct clinical behavior whereby embryonal rhabdomyosarcoma are associated generally with a more favorable prognosis [2]. The resulting fusion products are composed of the NH2-terminal DNA-binding domain of PAX3 or PAX7 and the COOH-terminal transactivation domain of FKHR. These fusion proteins are more potent transcriptional activators than the wild-type PAX proteins, suggesting that PAX-specific target genes may be deregulated and thereby involved in the oncogenic transformation of the fusion-positive alveolar rhabdomyosarcoma cells
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