The resultant chromosomal translocation causes the EWS trans-activation domain (which is usually silent in the wild type) to become very active, this leads to the translation of a new EWS-FLI1 fusion protein. EWS proteins are involved in meiosis, B-lymphocyte maturation, hematopoietic stem cell renewal, DNA repair and cell senescence. ETS transcription factors are involved in cell differentiation and cell cycle control. The EWS-FLI1 fusion protein has phase transition properties, allowing it to transition into liquid-like, phase separated compartments consisting of membrane-less organelles. This phase transition property allows the fusion protein to access and activate micro-satellite regions of the genome that would otherwise be inaccessible. This fusion protein can convert usually silent chromatin regions into fully active enhancers leading to oncogenesis of the cells.The EWS-FLI1 fusion protein also causes variable expression of the genome via epigenetic mechanisms. The fusion protein does this by recruiting enzymes that affect DNA methylation, histone acetylation and direct inhibition of non-coding microRNA. EWS-FLI1 promotes histone acetylation, which leads to uncoiling of DNA (which is usually tightly wound around histones); this chromatin relaxation leads to the DNA being more accessible to transcription factors and thus enhancing the expression of the associated genes. DNA methylation leads to gene silencing as it prevents transcription factor binding. EWS-FLI1 reduces DNA methylation (which occurs mostly in areas corresponding to transcription enhancers), leading to increased gene expression. The EWS-FLI1 fusion protein inhibits certain microRNAs of cells (such as miRNA-145). MiRNA-145 normally activates RNA-induced silencing complexes (RISCs) to inhibit or degrade mRNA that is involved in cell pluripotency.
Treatment lengths vary depending on location and stage of the disease at diagnosis. Radical chemotherapy may be as short as six treatments at three-week cycles, but most people undergo chemotherapy for 6–12 months and radiation therapy for 5–8 weeks. Radiotherapy has been used for localized disease. The tumor has a unique property of being highly sensitive to radiation, sometimes acknowledged by the phrase "melting like snow", but the main drawback is that it recurs dramatically after some time.Antisense oligodeoxynucleotides have been proposed as possible treatment by down-regulating the expression of the oncogenic fusion protein associated with the development of Ewing sarcoma resulting from the EWS-ETS gene translocation. In addition, the synthetic retinoid derivative fenretinide (4-hydroxy(phenyl)retinamide) has been reported to induce high levels of cell death in Ewing sarcoma cell lines in vitro and to delay growth of xenografts in in vivo mouse models.In most pediatric cancers including sarcoma, proton beam radiation (also known as proton therapy) delivers an equally effective dose to the tumor with less damage to the surrounding normal tissue compared to photon radiation. Prognosis
Staging attempts to distinguish people with localized from those with metastatic disease. The most common areas of metastasis are the lungs, bone and bone marrow with less common areas of metastasis being the lymph nodes, liver and brain.