Abstract
Abstract BACKGROUND: Genomic studies on pediatric soft tissue sarcomas (STS) such as rhabdomyosarcoma (RMS) and Ewing family of tumors (EFT) have shown that the overall burden of somatic mutations in these tumors is relatively low when compared to most adult tumors. This observation along with recent studies suggest that other features such as chromosomal translocations that appear predominantly in these tumors may play an important role in their biology. Genes resulting from these translocations are known to regulate protein-coding genes that are required for tumor formation. Our studies on these tumors show that these chimeric fusion genes can hijack the cellular machinery that comprises both protein-coding and non-coding networks for tumorigenesis. RESULTS: Gene expression signature of the more aggressive RMS subset that comprises of PAX-FKHR-positive alveolar RMS suggested that the protein-coding NOS1 is most strongly associated and prognostically significant gene in this group. Functional assays confirmed that PAX-FKHR directly regulated its expression. Decreasing NOS1 expression using lentiviral vectors resulted in a decrease in cell survival and reduced tumor growth in vivo. Similar expression analyses comparing EFT, which express the fusion gene EWS-FLI1, with other tumors and normal tissues showed that the non-coding features were more strongly associated with EFT than the coding genes. EWS-FLI1 directly regulates a long intergenic non-coding RNA (lincRNA), FEZF1-AS1. Matrigel assays and tail vein injection models suggested that the lincRNA promotes cell invasion and migration. Chromatin-RNA immunoprecipitation assays revealed interaction of the lincRNA with DNA regions, both coding and non-coding, which are involved in invasion and metastasis. CONCLUSIONS: Fusion genes in pediatric STS activate genomic regions that facilitate tumor pathogenesis by regulating the interactive network between coding and non-coding genes. While fusion-positive RMS are dependent on NOS1 for survival, EFT need lincRNA FEZF1-AS1 for cell migration and tumor propagation. EFT are known to be highly metastatic tumors and our results underscore the complex regulatory networks that are required for cellular migration in these tumors. Understanding the importance of these gene interactions will help development of effective tumor-specific drug therapies that improve treatment while decreasing unwanted side-effects. Citation Format: Sheetal A. Mitra, Anirban P. Mitra, Jonathan D. Buckley, Timothy J. Triche. Coding and noncoding gene targets in pediatric soft tissue sarcomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 597. doi:10.1158/1538-7445.AM2015-597
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