■骨肉瘤(OS)在治疗中提出了重大挑战,并且缺乏可靠的预后标志物。表观遗传改变在疾病进展中起着至关重要的作用。这项研究旨在使用表观遗传修饰基因(EMGs)为OS开发准确的预后标志。
分析了产生有效治疗(TARGET)-OS队列的治疗适用研究。单变量Cox分析确定了生存相关的EMGs。基于最小绝对收缩和选择算子(LASSO)回归和多变量分析,在测试队列中获得了6个基因的预后特征,称为表观遗传修饰相关预后特征(EMRPS).Kaplan-Meier和受试者工作特征(ROC)曲线分析通过内部和外部验证(GEO登录号GSE21257)证实了预测准确性。构建了包含EMRPS和临床特征的预后列线图。转录组分析,包括差异基因表达,基因本体论(GO),基因集富集分析(GSEA),并进行了免疫浸润分析,以探讨将EMRPS与OS预后联系起来的机制。此外,预测EMRPS对药物敏感性的影响。
■成功开发了包含DDX24,DNAJC1,HDAC4,SIRT7,SP140和UHRF2的6基因EMRPS。高危人群的生存期明显缩短,在内部和外部验证中始终观察到。EMRPS对1-,3-,和5年总生存率,在训练中曲线下面积(AUC)>0.85,在测试中~0.7。整合年龄的列线图,性别,转移状态,基于一致性指数分析,EMRPS表现出很高的预测性能。机制分析显示低危组免疫浸润和活性增加,免疫检查点表达较高。反映了免疫激活的肿瘤微环境(TME)适用于免疫治疗。药物敏感性分析显示低风险组对顺铂的敏感性增加,一线OS化疗。
■我们的研究成功建立了高效的EMRPS和列线图,强调它们作为新的预后标志物和指标的潜力,在OS治疗中选择合适的免疫治疗和化疗候选。
UNASSIGNED: Osteosarcoma (OS) poses significant challenges in treatment and lacks reliable prognostic markers. Epigenetic alterations play a crucial role in disease progression. This study aimed to develop an accurate prognostic signature for OS using epigenetic modification genes (EMGs).
UNASSIGNED: The Therapeutically Applicable Research to Generate Effective Treatments (TARGET)-OS cohort was analyzed. Univariate Cox analysis identified survival-associated EMGs. Based on least absolute shrinkage and selection operator (LASSO) regression and multivariate analysis, a 6-gene prognostic signature termed the epigenetic modification-related prognostic signature (EMRPS) was derived in the testing cohort. Kaplan-Meier and receiver operating characteristic (ROC) curve analysis confirmed predictive accuracy through internal and external validation (GEO accession GSE21257). A prognostic nomogram incorporating EMRPS and clinical features was constructed. Transcriptomic analysis including differential gene expression, Gene Ontology (GO), gene set enrichment analysis (GSEA), and immune infiltration analysis was conducted to explore mechanisms linking EMRPS to OS prognosis. Additionally, EMRPS impact on drug sensitivity was predicted.
UNASSIGNED: A 6-gene EMRPS comprising DDX24, DNAJC1, HDAC4, SIRT7, SP140 and UHRF2 was successfully developed. The high-risk group showed significantly shorter survival, consistently observed in both internal and external validation. EMRPS demonstrated high predictive efficacy for 1-, 3-, and 5-year overall survival, with area under curve (AUC) >0.85 in training and ~0.7 in testing. The nomogram integrating age, gender, metastasis status, and EMRPS exhibited high predictive performance based on concordance index analysis. Mechanistic analysis indicated the low-risk group had increased immune infiltration and activity with higher immune checkpoint expression, reflecting an immune-activated tumor microenvironment (TME) suitable for immunotherapy. Drug sensitivity analysis revealed the low-risk group had increased sensitivity to cisplatin, a first-line OS chemotherapy.
UNASSIGNED: Our study successfully established an efficient EMRPS and nomogram, highlighting their potential as novel prognostic markers and indicators for selecting appropriate immunotherapy and chemotherapy candidates in OS treatment.