Abstract
PURPOSE: Desmoplastic small round blue-cell tumors (DSRCTs) are sarcomas that contain the t(11;22) (p13;q12) translocation EWS-WT1 fusion protein. Because this is a rare tumor type, prospective clinical trials in DSRCT are challenging. Patients are treated in a manner similar to those with Ewing sarcoma; however, differences in prognosis and clinical presentation suggest fundamental differences in biology and potentially different therapeutic implications. This study aimed to characterize the molecular characteristics of DSRCT tumors to explore unique therapeutic options for this extremely rare and aggressive cancer type. METHODS: Thirty-five DSRCT tumors were assessed using next-generation sequencing, protein expression (immunohistochemistry), and gene amplification (chromogenic in situ hybridization or fluorescence in situ hybridization). Three patients had tumor mutational load, which was calculated as somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Gene expression data were obtained for an additional seven DSRCT tumors. Molecular alterations were compared with 88 Ewing sarcomas. RESULTS: The most common alterations that distinguished DSRCTs from Ewing sarcoma included higher androgen receptor (AR), TUBB3, epidermal growth factor receptor, and TOPO2A expression. Independent analysis by RNA sequencing confirmed higher AR expression from an independent data set of EWS-WT1 fusion-positive DSRCTs compared with Ewing sarcoma and a pan-cancer analysis. DSRCTs had somatic mutations that were identified in TP53 and FOXO3, averaged five mutations per megabase, and no programmed death-ligand 1 expression was detected in any DSRCT samples. CONCLUSION: The current analysis provides the first comparative analysis, to our knowledge, of molecular aberrations that distinguish DSRCT from Ewing sarcoma. High AR expression seems to be a defining event in these malignancies, and additional investigation of the responsiveness of AR inhibitors in this disease is encouraged.