Table3_Ferroptosis-Related Gene Signature and Patterns of Immune Infiltration Predict the Overall Survival in Patients With Lung Adenocarcinoma.DOCX

Background: Lung adenocarcinoma (LUAD) is a malignant tumor with high heterogeneity and poor prognosis. Ferroptosis, a form of regulated cell-death–related iron, has been proven to trigger inflammation-associated immunosuppression in the tumor microenvironment, which promotes tumor growth. Therefore, the clinical prognostic value of ferroptosis-related genes in LUAD needs to be further explored.
Method: In this study, we downloaded the mRNA expression profiles and corresponding clinical data of LUAD patients from the Cancer Genome Atlas database. The least absolute shrinkage and selection operator (LASSO) Cox regression model was utilized to construct ferroptosis-related gene signature. Based on these, we established the nomograms for prognosis prediction and validated the model in the GSE72094 dataset. The cell type was identified using the CIBERSORT algorithm for estimating relative subsets of RNA transcripts, which was then used to screen significant tumor immune-infiltrating cells associated with the LUAD prognosis prediction model. Subsequently, we applied co-expression analysis to reveal the relationship between ferroptosis-related genes and significant immune cells.
Results: The univariate COX regression analysis showed that 20 genes were associated with the overall survival (OS) as prognostic differentially expressed genes (DEGs) (FDR <0.05). Patients were divided into two risk groups using a 13-gene signature, with the high-risk group having a significantly worse OS than their low-risk counterparts (p < 0.001). We used receiver operating characteristic (ROC) curve analysis to confirm the predictive capacity of the signature. Besides, we identified seven pairs of ferroptosis-related genes and tumor-infiltrating immune cells associated with the prognosis of LUAD patients.
Conclusion: In this study, we construct a ferroptosis-related gene signature that can be used for prognostic prediction in LUAD. In addition, we reveal a potential connection between ferroptosis and tumor-infiltrating immune cells.

背景：肺腺癌（Lung adenocarcinoma, LUAD）是一种异质性高、预后不良的恶性肿瘤。铁死亡（Ferroptosis）是一种铁依赖性调控性细胞死亡形式，现已被证实可诱发肿瘤微环境中炎症相关的免疫抑制，进而促进肿瘤生长。因此，铁死亡相关基因在肺腺癌中的临床预后价值仍有待进一步探究。
方法：本研究从癌症基因组图谱（Cancer Genome Atlas, TCGA）数据库下载了肺腺癌患者的mRNA表达谱及其对应临床数据。采用最小绝对收缩与选择算子（Least Absolute Shrinkage and Selection Operator, LASSO）Cox回归模型构建铁死亡相关基因特征。基于此，我们建立了用于预后预测的列线图（nomograms），并在GSE72094数据集内对模型进行验证。利用CIBERSORT算法识别细胞类型以估算RNA转录本的相对丰度，随后筛选出与肺腺癌预后预测模型显著相关的肿瘤免疫浸润细胞。后续通过共表达分析揭示铁死亡相关基因与显著免疫细胞之间的关联。
结果：单因素Cox回归分析显示，共有20个基因作为预后差异表达基因（differentially expressed genes, DEGs）与总生存期（overall survival, OS）相关（错误发现率（False Discovery Rate, FDR）<0.05）。通过13个基因构成的特征将患者分为两个风险组，高风险组患者的总生存期显著差于低风险组（p<0.001）。我们采用受试者工作特征（Receiver Operating Characteristic, ROC）曲线分析验证了该特征的预测能力。此外，我们还识别出7对与肺腺癌患者预后相关的铁死亡相关基因与肿瘤浸润免疫细胞组合。
结论：本研究构建了可用于肺腺癌预后预测的铁死亡相关基因特征。此外，本研究还揭示了铁死亡与肿瘤浸润免疫细胞之间的潜在关联。