Ewing sarcomas (ESs) are aggressive sarcomas driven by EWS fusion genes. We sought to investigate whether whole-transcriptome sequencing (RNA-seq) could be used to detect patterns associated with chemotherapy response or tumor progression after first-line treatment. Transcriptome sequencing (RNA-seq) of 13 ES cases was performed. Among the differentially expressed pathways, we identified IGF2 expression as a potential driver of chemotherapy response and progression. We investigated the effect of IGF2 on proliferation, radioresistance, apoptosis, and the transcriptome pattern in four ES cell lines and the effect of IGF2 expression in a validation series of 14 patients. Transcriptome analysis identified differentially expressed genes (adj. P < 0.005) and pathways associated with chemotherapy response (285 genes), short overall survival (662 genes), and progression after treatment (447 genes). Imprinting independent promoter P3-mediated IGF2 expression was identified in a subset of cases with aggressive clinical course. In ES cell lines, IGF2 induced proliferation, but promoted radioresistance only in CADO cells. High IGF2 expression was also significantly associated with shorter overall survival in patients with ES. Transcriptome analysis of the clinical samples and the cell lines revealed an IGF-dependent signature, potentially related to a stem cell-like phenotype. Transcriptome analysis is a potentially powerful complementary tool to predict the clinical behavior of ES and may be utilized for clinical trial stratification strategies and personalized oncology. Certain gene signatures, for example, IGF-related pathways, are coupled to biological functions that could be of clinical importance. Finally, our results indicate that IGF inhibition may be successful as a first-line therapy in conjunction with conventional radiochemotherapy for a subset of patients.

中文翻译：

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尤因肉瘤的转录组分析-治疗耐药性途径和IGF依赖性。

尤文氏肉瘤（ESs）是由EWS融合基因驱动的侵袭性肉瘤。我们试图研究是否可以使用全转录组测序（RNA-seq）来检测与一线治疗后化疗反应或肿瘤进展相关的模式。进行了13例ES病例的转录组测序（RNA-seq）。在差异表达的途径中，我们确定了IGF2的表达是化疗反应和进展的潜在驱动因素。我们调查了14个患者验证系列中IGF2对四种ES细胞系增殖，放射抗性，凋亡和转录组模式的影响，以及IGF2表达的影响。转录组分析确定了差异表达的基因（调节P <0.005）和与化疗反应相关的途径（285个基因），总生存期短（662个基因），治疗后进展（447个基因）。印记独立启动子P3介导的IGF2表达在积极的临床过程中被鉴定。在ES细胞系中，IGF2诱导增殖，但仅在CADO细胞中促进放射抗性。IGF2高表达还与ES患者的总体生存期缩短显着相关。临床样品和细胞系的转录组分析表明，IGF依赖的特征可能与干细胞样表型有关。转录组分析是预测ES临床行为的潜在强大补充工具，可用于临床试验分层策略和个性化肿瘤学。某些基因特征，例如与IGF相关的途径，与可能具有临床重要性的生物学功能结合在一起。最后，我们的结果表明，对于一小部分患者，IGF抑制作为一线治疗与常规放射化学治疗相结合可能是成功的。