Background: Ewing Sarcoma (ES)/PNET and Desmoplastic Small Round Cell Tumor (DSRCT) are sarcomas with distinct chromosomal translocations involving the EWS gene (predominately EWS-FLI1 and EWS-WT1; respectively). Their diagnosis and treatment has been difficult due to the rarity, diverse clinical presentation, overlapping histologic features and genetic complexity (Taylor BS et al, 2011). Therefore, novel approaches in clinical management are warranted. Methods: Seventeen cases (9 ES and 8 DSRCT) were analyzed using a commercial molecular profiling service (CarisTargetNow, Caris Life Sciences, Phoenix, AZ). The whole genome transcriptome analysis (29285 transcripts) was performed using HumanHT-12 beadChip (Illuminia Inc, San Diego, CA) and comparison to pooled soft tissue reference sample. Additionally, a select number of chemotherapy-predictive (theranostic) biomarkers were evaluated using immunohistochemistry, FISH, and DNA sequencing. Results: We observed 160 commonly up and 357 commonly down regulated genes between ES and DSRCT in transcriptome analysis. Cell cycle signaling, DNA replication and E2F mediated pathway genes were most commonly up regulated. In addition, higher expression of SOX-2, a recently identified cancer stem cell marker (Riggi et al, 2010), were observed in DSRCT than in ES, suggesting EWS-WT1 translocation might result in reprogramming of DSRCT to express cancer stem cells. Above threshold expression of TOP2A and TOPO1was observed in approximately 50% of all cases. Additional theranostic biomarkers (ERCC1, TS, SPARC and MGMT) showed significant inter-individual variations. No KRAS mutations or EGFR gene amplification were observed in any case. Conclusions: 1. Our transcriptome analyses might provide future therapeutic targets in cell cycle regulation, DNA replication, receptor TKI pathways and stem cell reprogramming. 2. Using multimodality test approaches, we confirmed and refined the benefits in both tumor types of individualized therapeutic assessment including predicted susceptibilities to anthracycline, irinotecan, platinum analogs, fluorouracil, and temozolomide.