Identification of key genes and pathways in Ewing's sarcoma patients associated with metastasis and poor prognosis

Background: Ewing sarcoma (ES) is the second commonest primary malignant bone neoplasm. Metastatic status at diagnosis strongly predicted poor prognosis of Ewing sarcoma patients. Yet little was known about the underlying mechanism of ES metastasis. Purpose:This study intended to identify the relationship between key genes/pathways and metastasis/poor prognosis in Ewing's sarcoma patients by using bioinformatic method. Methods: In this study, multi-center sequencing data were obtained from the GEO database, including gene and miRNA expression profile and prognosis information of ES patients. Differentially expressed genes (DEGs) were identified between primary and metastasis ES samples by the GEO2R online tool. Gene ontology (Go) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses of DEGs were performed. And PPI network analyses were conducted. The ES patient's prognostic information was employed for survival analysis, and the potential relationship between miRNAs and key genes was analyzed. Results: The results showed that a total of 298 and 428 DEGs were screened out in metastasis samples based on GSE17618 and GSE12102 dataset compared to primary samples respectively. The most significantly enriched KEGG pathway was the mismatch repair (MMR) pathway. MSH2, MSH6, RPA2, and RFC2 that belong to the MMR pathway were identified as key genes. Moreover, the expression of key genes was increased in metastasis samples compared with primary ones and was associated with poor event-free and overall survival of ES patients. The negative correlation of the expression level of the key genes with patients prognosis also supported by TCGA sarcoma database. Furthermore, knockdown of EWSR/FLI1 fusion in ES cell line A673 down-regulates the expression of the 4 key genes was revealed by GDS4962. Conclusion: In conclusion, the present study indicated that the key genes promote our understanding of the molecular mechanisms underlying the development of ES metastasis, and might be used as molecular targets and diagnostic biomarkers for the treatment of ES.