摘要

      衰老是一个不可避免的过程，其特征是许多生理活动下降，并被认为是多种恶性肿瘤的重要危险因素，但关于肺鳞状细胞癌（LUSC）中衰老相关基因（ARGs）的研究很少。我们设计这项研究是为了探索ARG的预后价值，并建立一个基于ARG的LUSC患者预后标志。从癌症基因组图谱（TCGA）和基因表达总览（GEO）下载LUSC患者的RNA测序和相应的临床病理数据。ARG风险特征是在TCGA训练数据集中（n=492）的LASSO和多变量Cox分析结果的基础上开发的。此外，GSE73403数据集（n=69）验证了该ARG特征的预后性能。免疫组织化学（IHC）染色用于验证签名中ARGs的表达。在TCGA数据集中构建了五个基于ARG的特征，包括A2M、CHEK2、ELN、FOS和PLAU，并将患者分为总生存率显著不同的低风险组和高风险组。在LUSC患者的多变量Cox回归模型中，ARG风险评分仍被视为OS的独立指标。然后，建立了一个将ARG风险评分与T-、N-和M-分类相结合的预后列线图。它在TCGA队列中获得了良好的判别能力，C指数为0.628（95%置信区间[CI]:0.586–0.671），在GSE73403数据集中获得了0.648（95%可信区间：0.535–0.762）。校准曲线显示实际观察结果与诺模图预测的生存率之间非常一致。IHC染色发现这五种ARG在LUSC组织中过度表达。此外，TCGA队列中的免疫浸润分析表明，低风险组和高风险组之间的抗肿瘤免疫细胞浸润明显分化。我们发现了一种新的ARG相关预后信号，它可能作为LUSC患者个体化生存预测和抗肿瘤免疫个性化治疗建议的潜在生物标志物。Aging is an inevitable process characterized by a decline in many physiological activities, and has been known as a significant risk factor for many kinds of malignancies, but there are few studies about aging-related genes (ARGs) in lung squamous carcinoma (LUSC). We designed this study to explore the prognostic value of ARGs and establish an ARG-based prognosis signature for LUSC patients. RNA-sequencing and corresponding clinicopathological data of patients with LUSC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The ARG risk signature was developed on the basis of results of LASSO and multivariate Cox analysis in the TCGA training dataset (n = 492). Furthermore, the GSE73403 dataset (n = 69) validated the prognostic performance of this ARG signature. Immunohistochemistry (IHC) staining was used to verify the expression of the ARGs in the signature. A five ARG-based signature, including A2M, CHEK2, ELN, FOS, and PLAU, was constructed in the TCGA dataset, and stratified patients into low- and high-risk groups with significantly different overall survival (OS) rates. The ARG risk score remained to be considered as an independent indicator of OS in the multivariate Cox regression model for LUSC patients. Then, a prognostic nomogram incorporating the ARG risk score with T-, N-, and M-classification was established. It achieved a good discriminative ability with a C-index of 0.628 (95% confidence interval [CI]: 0.586–0.671) in the TCGA cohort and 0.648 (95% CI: 0.535–0.762) in the GSE73403 dataset. Calibration curves displayed excellent agreement between the actual observations and the nomogram-predicted survival. The IHC staining discovered that these five ARGs were overexpression in LUSC tissues. Besides, the immune infiltration analysis in the TCGA cohort represented a distinctly differentiated infiltration of anti-tumor immune cells between the low- and high-risk groups. We identified a novel ARG-related prognostic signature, which may serve as a potential biomarker for individualized survival predictions and personalized therapeutic recommendation of anti-tumor immunity for patients with LUSC.

https://www.frontiersin.org/articles/10.3389/fcell.2022.770550/full