Abstract
Objective: Ewing sarcoma (EWS) is a rare neuroectodermal-related malignancy affecting bones and soft tissues. The well-known hallmark of genomic alteration in EWS is gene fusion involving the Ewing Sarcoma Breakpoint Region 1 (EWSR1) gene. However, studies have determined that this is not the sole determinant of tumour transformation and indicated the presence of other mutated genes related to signalling pathways and chromatin-modifying genes.
Materials and Methods: This is an in silico analysis of the previously published genomic sequencing of 218 EWS patients and 11 cell lines.
Results: The presence of frequent deleterious mutations in EWSR1 (17%); titin, TTN (16%); stromal antigen 2, STAG2 (14%); and tumour protein P53, TP53 (9%) was determined. An increased prevalence of the co-occurrence of a few mutated driver genes across tumour samples was significantly noted, namely, between TP53 and either EWSR1 or STAG2 and between TTN and complement C3b/C4b receptor 1 (CR1) or zinc finger homeobox 3 (ZFHX3), suggesting their joint contribution to EWS tumour development. Patients carrying the TP53 aberration alone or combined with EWSR1 or STAG2 alterations had much lower survival rates. Functional enrichment analysis high-lighted transcription factors, kinases, and hub proteins that could be putative therapeutic targets for EWS in the future.
Conclusions: The current analysis provides new insights that can be used as a roadmap for future in vitro or in vivo work. A systems biology approach will be required that takes into account the genomic and epigenomic landscapes of EWS for risk stratification and future molecular targeted therapy.