School of Basic Medicine, Shaoyang University, the First Affiliated Hospital of Shaoyang University, Shaoyang, Hunan, China.
Molecular Biology Research Center and Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
Front Immunol. 2023 Apr 3;14:1148483. doi: 10.3389/fimmu.2023.1148483. eCollection 2023.
Lung adenocarcinoma (LUAD), the major lung cancer histotype, represents 40% lung cancers. Currently, outcomes are remarkably different in LUAD patients with similar AJCC/UICC-TNM features. T cell proliferation-related regulator genes (TPRGs) relate to the proliferation, activity and function of T cells and tumor progression. The values of TPRGs in classifying LUAD patients and predicting outcomes remain unknown.
Gene expression profile and corresponding clinical data were downloaded from TCGA and the GEO databases. We systematically analyzed the expression profile characteristics of 35 TPRGs in LUAD patients and investigated the differences in overall survival (OS), biology pathway, immunity and somatic mutation between different TPRGs-related subtypes. Subsequently, we constructed a TPRGs-related risk model in TCGA cohort to quantify risk scores using LASSO cox regression analysis and then validated this risk model in two GEO cohorts. LUAD patients were divided into high- and low-risk subtypes according to the median risk score. We systematically compared the biology pathway, immunity, somatic mutation and drug susceptibility between the two risk subtypes. Finally, we validate biological functions of two TPRGs-encoded proteins (DCLRE1B and HOMER1) in LUAD cells A549.
We identified different TPRGs-related subtypes (including cluster 1/cluster A and its counterpart cluster 2/cluster B). Compared to the cluster 1/cluster A subtype, cluster 2/cluster B subtype tended to have a prominent survival advantage with an immunosuppressive microenvironment and a higher somatic mutation frequency. Then, we constructed a TPRGs-related 6-gene risk model. The high-risk subtype characterized by higher somatic mutation frequency and lower immunotherapy response had a worse prognosis. This risk model was an independent prognostic factor and showed to be reliable and accurate for LUAD classification. Furthermore, subtypes with different risk scores were significantly associated with drug sensitivity. DCLRE1B and HOMER1 suppressed cell proliferation, migration and invasion in LUAD cells A549, which was in line with their prognostic values.
We construed a novel stratification model of LUAD based on TPRGs, which can accurately and reliably predict the prognosis and might be used as a predictive tool for LUAD patients.
肺腺癌（LUAD）是主要的肺癌组织学类型，占肺癌的 40%。目前，具有相似 AJCC/UICC-TNM 特征的 LUAD 患者的预后差异很大。T 细胞增殖相关调节因子基因（TPRGs）与 T 细胞的增殖、活性和功能以及肿瘤进展有关。TPRGs 在 LUAD 患者分类和预后预测中的价值尚不清楚。
从 TCGA 和 GEO 数据库中下载基因表达谱和相应的临床数据。我们系统地分析了 35 个 LUAD 患者 TPRGs 的表达谱特征，并研究了不同 TPRGs 相关亚型之间总生存期（OS）、生物学途径、免疫和体细胞突变的差异。随后，我们使用 LASSO COX 回归分析在 TCGA 队列中构建了一个 TPRGs 相关风险模型，并在两个 GEO 队列中验证了该风险模型。根据中位风险评分，LUAD 患者分为高风险和低风险亚型。我们系统地比较了两种风险亚型之间的生物学途径、免疫、体细胞突变和药物敏感性。最后，我们验证了两个 TPRGs 编码蛋白（DCLRE1B 和 HOMER1）在 LUAD 细胞 A549 中的生物学功能。
我们鉴定了不同的 TPRGs 相关亚型（包括簇 1/簇 A 及其对应簇 2/簇 B）。与簇 1/簇 A 亚型相比，簇 2/簇 B 亚型具有更显著的生存优势，表现为免疫抑制微环境和更高的体细胞突变频率。然后，我们构建了一个 TPRGs 相关的 6 基因风险模型。具有更高体细胞突变频率和更低免疫治疗反应的高危亚型预后较差。该风险模型是 LUAD 分类的一个独立预后因素，具有可靠性和准确性。此外，不同风险评分的亚型与药物敏感性显著相关。DCLRE1B 和 HOMER1 抑制 LUAD 细胞 A549 的增殖、迁移和侵袭，这与它们的预后价值一致。
我们构建了一个基于 TPRGs 的 LUAD 新分层模型，能够准确可靠地预测预后，并可能作为 LUAD 患者的预测工具。
