Genetic Profiling of Primary Versus Metastatic Ewing Sarcoma for Therapeutic Target Identification

Ewing sarcoma (ES) is a bone malignancy primarily, well known by its t(11;22)(q24;q12) chromosomal translocation. Despite high initial treatment success, ES frequently recurs, likely due to micrometastatic disease present at diagnosis but undetected during primary treatment. This study aims to characterize transcriptomic differences between primary and metastatic ES to identify genes and pathways associated with the metastatic phenotype. Using the Search Tag Analyze Resource for National Center for Biotechnology Information’s Gene Expression Omnibus, seven independent gene expression series were identified, yielding 37 metastatic and 82 primary ES tumor samples. Differentially expressed genes were defined using a significance threshold of p < 0.05 and absolute experimental log ratio > 0.1 and were analyzed using Ingenuity Pathway Analysis. This integrative transcriptomic analysis identified 753 significant molecules. Metastatic ES was characterized by upregulation of lung-associated surfactant proteins and secretoglobin family members, along with downregulation of genes involved in extracellular matrix organization. Additional genes of interest included SLC6A14, CXCL14, and TBX3, which have been implicated in tumor progression in other malignancies. These findings provide a computationally derived molecular profile associated with metastatic ES and highlight candidate genes and pathways that warrant further validation. This integrative approach offers a framework for future studies focused on understanding metastatic biology in rare pediatric cancers.