Table3_A ubiquitin-related gene signature for predicting prognosis and constructing molecular subtypes in osteosarcoma.docx

Background: Ubiquitination is medicated by three classes of enzymes and has been proven to involve in multiple cancer biological processes. Moreover, dysregulation of ubiquitination has received a growing body of attention in osteosarcoma (OS) tumorigenesis and treatment. Therefore, our study aimed to identify a ubiquitin-related gene signature for predicting prognosis and immune landscape and constructing OS molecular subtypes.Methods: Therapeutically Applicable Research to Generate Effective Treatments (TARGET) was regarded as the training set through univariate Cox regression, Lasso Cox regression, and multivariate Cox regression. The GSE21257 and GSE39055 served as the validation set to verify the predictive value of the signature. CIBERSORT was performed to show immune infiltration and the immune microenvironment. The NMF algorithm was used to construct OS molecular subtypes.Results: In this study, we developed a ubiquitin-related gene signature including seven genes (UBE2L3, CORO6, DCAF8, DNAI1, FBXL5, UHRF2, and WDR53), and the gene signature had a good performance in predicting prognosis for OS patients (AUC values at 1/3/5 years were 0.957, 0.890, and 0.919). Multivariate Cox regression indicated that the risk score model and prognosis stage were also independent prognostic prediction factors. Moreover, analyses of immune cells and immune-related functions showed a significant difference in different risk score groups and the three clusters. The drug sensitivity suggested that IC50 of proteasome inhibitor (MG-132) showed a notable significance between the risk score groups (p < 0.05). Through the NMF algorithm, we obtained the three clusters, and cluster 3 showed better survival outcomes. The expression of ubiquitin-related genes (CORO6, UBE2L3, FBXL5, DNAI1, and DCAF8) showed an obvious significance in normal and osteosarcoma tissues.Conclusion: We developed a novel ubiquitin-related gene signature which showed better predictive prognostic ability for OS and provided additional information on chemotherapy and immunotherapy. The OS molecular subtypes would also give a useful guide for individualized therapy.

背景：泛素化过程由三类酶催化，并已被证实参与多种癌症的生物学过程。此外，泛素化过程的失调在骨肉瘤（OS）的发生发展和治疗中受到了越来越多的关注。因此，本研究旨在鉴定一个泛素相关基因特征，用于预测预后和免疫景观，以及构建OS分子亚型。方法：通过单变量Cox回归、Lasso Cox回归和多变量Cox回归，将治疗相关研究生成有效治疗（TARGET）视为训练集。GSE21257和GSE39055作为验证集，以验证该基因特征的预测价值。采用CIBERSORT方法展示免疫浸润和免疫微环境。利用NMF算法构建OS分子亚型。结果：在本研究中，我们开发了一个包括七个基因（UBE2L3、CORO6、DCAF8、DNAI1、FBXL5、UHRF2和WDR53）的泛素相关基因特征，该基因特征在预测OS患者的预后方面表现出良好的性能（1年、3年和5年的AUC值分别为0.957、0.890和0.919）。多变量Cox回归表明，风险评分模型和预后阶段也是独立的预后预测因素。此外，对免疫细胞和免疫相关功能的分析显示，不同风险评分组和三个聚类之间存在显著差异。药物敏感性分析表明，蛋白酶体抑制剂（MG-132）的IC50值在不同风险评分组之间表现出显著差异（p < 0.05）。通过NMF算法，我们获得了三个聚类，其中第3个聚类显示出更好的生存结果。泛素相关基因（CORO6、UBE2L3、FBXL5、DNAI1和DCAF8）在正常组织和骨肉瘤组织中的表达表现出明显的显著性。结论：我们开发了一个新的泛素相关基因特征，该特征在预测OS预后方面表现出更高的预测能力，并为化疗和免疫治疗提供了额外的信息。OS分子亚型也将为个体化治疗提供有益的指导。