Li Zhichao, Xue Yong, Huang Xianxing, Xiao Gang
Orthopedics Ward 2, Shaowu Municipal Hospital of Fujian Province, Nanping, China.
Department of Thoracic Surgery, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.
Transl Cancer Res. 2024 Jul 31;13(7):3556-3574. doi: 10.21037/tcr-23-2300. Epub 2024 Jul 22.
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).
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.
A 6-gene EMRPS comprising , , , , and 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.
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.
骨肉瘤（OS）在治疗方面面临重大挑战且缺乏可靠的预后标志物。表观遗传改变在疾病进展中起关键作用。本研究旨在利用表观遗传修饰基因（EMG）开发一种准确的骨肉瘤预后特征。
分析了治疗性可应用研究以产生有效治疗方法（TARGET）-OS队列。单因素Cox分析确定了与生存相关的EMG。基于最小绝对收缩和选择算子（LASSO）回归及多因素分析，在测试队列中得出了一个6基因预后特征，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。构建了一个包含EMRPS和临床特征的预后列线图。进行了包括差异基因表达、基因本体（GO）、基因集富集分析（GSEA）和免疫浸润分析在内的转录组分析，以探索将EMRPS与骨肉瘤预后联系起来的机制。此外，预测了EMRPS对药物敏感性的影响。
成功开发了一个由 、 、 、 、 和 组成的6基因EMRPS。高风险组的生存期明显较短，在内部和外部验证中均一致观察到。EMRPS对1年、3年和5年总生存期显示出高预测效能，训练时曲线下面积（AUC）>0.85，测试时约为0.7。基于一致性指数分析，整合年龄、性别、转移状态和EMRPS的列线图表现出高预测性能。机制分析表明，低风险组免疫浸润和活性增加，免疫检查点表达更高，反映出适合免疫治疗的免疫激活肿瘤微环境（TME）。药物敏感性分析显示，低风险组对一线骨肉瘤化疗药物顺铂的敏感性增加。
我们的研究成功建立了一种有效的EMRPS和列线图，突出了它们作为新型预后标志物以及在骨肉瘤治疗中选择合适免疫治疗和化疗候选者指标的潜力。
