RAN 是肺腺癌的预后标志物并与免疫浸润相关

RAN is a prognostic marker and correlates with immune infiltration in lung adenocarcinoma

摘要

目的：基于生物信息学分析探讨 RAN 基因在肺腺癌(LUAD)中的临床意义和生物学功能。方法：基于癌症基因组图谱(TCGA),提取 LUAD 中 RAN 表达和相应的临床信息。使用 R3.6.2 软件进行统计分析。比较 TCGA⁃LUAD 队列中肿瘤组织与正常组织之间 RAN 的表达,以及临床病理参数与 RAN 表达水平之间的关系。根据 RAN 表达的中位数,将 TCGA LUAD 患者分为高表达组和低表达组。使用 Kaplan⁃Meier 法评估 LUAD 患者 RAN 表达与不同临床特征生存率的相关性，计算 95% 置信区间的风险比（HR）和 log⁃rank P 值，并进行单因素和多因素 Cox 回归分析确定与 LUAD 预后相关的危险因素。使用 rms 包构建预测 LUAD 患者 1 年、3 年和 5 年 OS 率的列线图模型。利用 CIBERSORT 算法预测 LUAD 肿瘤样本和正常样本中 22 种浸润性免疫细胞的丰度,并分析 RAN 表达与免疫浸润细胞之间的相关性。并应用基因集富集分析（GSEA）来评估主要在 RAN 高表达与低表达组之间富集的潜在生物过程。结果：RAN 基因在 LUAD 肿瘤组织中的表达均低于配对和非配对样本正常组织(P<0.05)。RAN 高表达 LUAD 患者的不同临床特征生存率明显低于低表达患者。多因素 Cox 回归分析显示,T 分期、N 分期和 RAN 表达是影响 LUAD 预后的独立影响因素(P<0.05)。基于 RAN 表达、T 分期和 N 分期构建的列线图模型的预测结果与实际观测值高度一致。校准曲线中的偏差修正线接近理想曲线,提示列线图模型的预测结果与观测结果较吻合。基因集富集分析显示 RAN 高表达组主要与铁死亡、细胞周期、细胞凋亡等有关。14 种免疫浸润细胞在 RAN 高表达组和低表达组之间差异有统计学意义(P<0.05)，包括巨噬细胞、CD8⁺ T 细胞和浆细胞等。结论：RAN 的表达与LUAD 患者预后和免疫细胞浸润有关,可能是预测NSCLC 预后的有价值生物标志物。

Abstract

Objective: To investigate the clinical significance and biological function of the RAN gene in lung adenocarcinoma (LUAD) based on bioinformatics analysis. Methods: Based on The Cancer Genome Atlas (TCGA), RAN expression and associated clinical information for LUAD was extracted. R3.6.2 software was adopted for statistical analysis, and the expression of RAN was compared between tumour tissues and normal tissues in the TCGA⁃LUAD cohort, as well as the relationship between clinicopathological parameters and RAN expression levels. According to the median expression of RAN, TCGA⁃LUAD patients were divided into high expression group and low expression group. The correlation between RAN expression and survival rates was evaluated by using the Kaplan⁃Meier method in LUAD patients with different clinical features. Univariate and multivariate Cox regression analysis was adopted to determine the risk factors associated with LUAD prognosis. A logistic regression model was constructed using the RMS package to predict the 1⁃year, 3⁃year and 5⁃year OS rates of LUAD patients. The CIBERSORT algorithm was used to predict the abundance of 22 infiltrating immune cells in LUAD tumour samples and normal samples, and to analyze the correlation between RAN expression and immune infiltrating cells. And gene set enrichment analysis (GSEA) was applied to evaluate the potential biological processes enriched between the RAN high⁃expression and low⁃expression groups. Results: The expression of the RAN gene in LUAD tumour tissues was lower than in paired and unpaired normal tissues (P<0.05). The survival rate of LUAD patients with high RAN expression and different clinical features was significantly lower than that of patients with low RAN expression. Multivariate Cox regression analysis showed that T stage, N stage, and RAN expression were independent factors influencing the prognosis of LUAD (P<0.05). A nomogram model was constructed based on RAN expression, T stage, and N stage, and its predicted outcomes were highly consistent with actual observed values. The deviation correction line in the calibration curve was close to the ideal curve, indicating that the predicted results of the column chart model were in good agreement with the observed results. Gene enrichment analysis showed that the RAN high⁃expression group was mainly associated with ferroptosis, cell cycle, apoptosis and other pathways. There were significant differences (P<0.05) in the abundance of 14 types of immune infiltrating cells between the high and low expression groups of RAN, including macrophages, CD8⁺ T cells and plasma cells. Conclusion: RAN expression is associated with prognosis and immune cell infiltration in LUAD patients and may be a valuable biomarker for predicting NSCLC prognosis.

关键词

非小细胞肺癌 / 肺腺癌 / Ras 相关核蛋白 / 免疫细胞浸润 / 预后

Key words

Non⁃Small Cell Lung Cancer / Lung Adenocarcinoma / Ras⁃Related Nuclear Proteins / Immune Cell Infiltration / Prognosis

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