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.

Clear cell sarcoma of tendons and aponeuroses in pediatric patients: a report from the Italian and German Soft Tissue Sarcoma Cooperative Group.

BACKGROUND: Clear cell sarcoma (CCS) of tendons and aponeuroses is extremely rare in childhood and little information is available on its clinical management. Originally believed to be a type of melanoma of soft tissue origin, CCS is now considered a distinct clinicopathologic entity that behaves like a high-grade soft tissue sarcoma. We report on a series of 28 pediatric patients treated from 1980 to 2000 by the Soft Tissue Sarcoma Italian Cooperative Group and the German Cooperative Group. METHODS: Patients were treated with a multimodality therapeutic approach. Surgical resection was complete in 17 patients (mutilating in 3), radiotherapy was administered to 8 patients, and 20 patients received chemotherapy. RESULTS: After a median follow-up of 102 months (range, 19-238 months), the 5-year and event-free survival rates were 66.4% and 63.3%, respectively. Seventeen patients were alive in first remission, two were alive in second remission, and nine had died of disease. The response to chemotherapy in the 7 evaluable patients included one partial remission, one minor response, and five no responses. Radiotherapy contributed to achieving local control in four of six Intergroup Rhabdomyosarcoma Study (IRS) Group II patients. Statistically significant differences in outcome were evident according to IRS group, tumor size, and site. CONCLUSIONS: Our study confirms the aggressive behavior of CCS. Complete surgical resection represents the mainstay of treatment, and even the only treatment for patients with small tumors. Radiotherapy may control microscopic residual disease after surgery. Chemotherapy is ineffective and the prognosis is unfavorable for patients with unresectable and large tumors.