Table_9_Genomic Landscape of RTK/RAS Pathway and Tumor Immune Infiltration as Prognostic Indicator of Lung Adenocarcinoma.xlsx

The RTK/RAS pathway is an oncogenic signaling pathway for which many targeted drugs have been developed; however, survival remains poor. A combination of targeted therapy and immunotherapy has emerged as an option for improving cancer treatment responses. In this study, on the basis of the expression, survival, single nucleotide variation (SNV), copy number variation (CNV), and methylation data of lung adenocarcinoma (LUAD) from The Cancer Genome Atlas database, we comprehensively analyzed the genomic changes in the RTK/RAS pathway and their associations with tumor-infiltrating lymphocytes (TIL) and prognosis in LUAD to provide the genomics landscape of RTK/RAS with TIL and prognosis. We found that two rarely mutated genes, mitogen-activated protein kinase kinase 1 and insulin-like growth factor 1 receptor, were significantly associated with the worse survival of patients with LUAD. Patients with LUAD and co-mutation of KRAS proto-oncogene (KRAS) and neurofibromin 1 genes had worse survival, and the underlying mechanism could be insufficient for protein synthesis and intracellular signal deactivation. Methylation of the Rac family small GTPase 1 (RAC1) was associated with better survival. The SNVs of the top mutated genes, including epidermal growth factor receptor (12.7%), neurotrophic receptor tyrosine kinase 3 (7.8%), erb-b2 receptor tyrosine kinase 4 (8.5%), and KRAS (29.6%), were associated with T cell exhaustion in LUAD. To construct nomograms, we further screened the genes whose genomic changes were closely associated with survival and immune infiltration. The nomograms performed well in predicting disease-specific survival (DSS) with a concordance index of 0.7 (0.589, 0.811) and overall survival with a concordance index of 0.689 (0.603, 0.775) in test set; they also showed good correspondence between actual and ideal nomogram predictions. Tumor stage, RAC1 methylation, and type 1 regulatory T cells greatly contributed to DSS and OS nomograms. In summary, we provided a comprehensive genomic profile of the RTK/RAS pathway in LUAD and its association with immune cell infiltration and prognosis of LUAD. This profile would serve as a basis for developing better therapeutic strategies, improving patient prognosis, and understanding the mechanisms of immune disturbance from the perspective of oncogenic pathways of LUAD.

RTK/RAS通路是一类致癌信号通路，目前已针对该通路开发出多种靶向药物，但患者的生存预后仍不理想。靶向治疗联合免疫治疗已逐渐成为改善癌症治疗响应的可选方案。本研究基于癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据库中肺腺癌（lung adenocarcinoma, LUAD）的表达谱、生存数据、单核苷酸变异（single nucleotide variation, SNV）、拷贝数变异（copy number variation, CNV）及甲基化数据，全面分析了RTK/RAS通路的基因组改变及其与LUAD中肿瘤浸润淋巴细胞（tumor-infiltrating lymphocytes, TIL）和患者预后的关联，旨在构建RTK/RAS通路结合TIL浸润与患者预后的基因组全景图谱。研究发现，两个罕突变基因——丝裂原活化蛋白激酶激酶1（mitogen-activated protein kinase kinase 1）与胰岛素样生长因子1受体（insulin-like growth factor 1 receptor），与LUAD患者的不良预后显著相关。同时携带KRAS原癌基因（KRAS proto-oncogene, KRAS）与神经纤维蛋白1（neurofibromin 1）基因共突变的LUAD患者预后更差，其潜在机制可能与蛋白质合成不足及胞内信号失活缺陷有关。Rac家族小GTP酶1（Rac family small GTPase 1, RAC1）的甲基化水平与更好的生存预后相关。高频突变基因的SNV，包括表皮生长因子受体（epidermal growth factor receptor，占比12.7%）、神经营养性受体酪氨酸激酶3（neurotrophic receptor tyrosine kinase 3，7.8%）、erb-B2受体酪氨酸激酶4（erb-b2 receptor tyrosine kinase 4，8.5%）及KRAS（29.6%），与LUAD中的T细胞耗竭显著相关。为构建列线图（nomograms）模型，本研究进一步筛选出基因组改变与生存及免疫浸润密切相关的基因。在测试集中，该列线图对疾病特异性生存期（disease-specific survival, DSS）的预测表现良好，一致性指数（concordance index）为0.7（95%置信区间：0.589, 0.811）；对总生存期（overall survival, OS）的预测一致性指数为0.689（95%置信区间：0.603, 0.775），且实际预测值与理想预测值之间具有良好的一致性。肿瘤分期、RAC1甲基化水平及1型调节性T细胞对DSS与OS列线图的构建贡献最大。综上，本研究全面解析了LUAD中RTK/RAS通路的基因组特征，并阐明了其与LUAD免疫细胞浸润及患者预后的关联。该基因组特征图谱可为开发更优化的治疗策略、改善患者预后，以及从LUAD致癌通路角度解析免疫紊乱机制提供理论依据。