An Immune Panel Signature Predicts Prognosis of Lung Adenocarcinoma Patients and Correlates With Immune Microenvironment

Background: Lung cancer, especially lung adenocarcinoma (LUAD) with high incidence, seriously endangers human life. The immune microenvironment is one of the malignant foundations of LUAD, but its impact at the molecular level is incompletely understood.Method: A total of 34 LUAD samples from Xiangya Hospital were collected for immune oncology (IO) profiling. Univariate Cox analysis was performed to profile prognostic immune genes based on our immune panel sequencing data. The least absolute shrinkage and selection operator (LASSO) algorithm was applied to construct a risk signature. The cut-off threshold of risk score was determined using X-tile software. Kaplan–Meier survival curves and receiver operating characteristic (ROC) curves were employed to examine the performance of this risk signature for predicting prognosis. The immune infiltration was estimated using a single-sample gene set enrichment analysis (ssGSEA) algorithm.Result: Thirty-seven immune genes were profiled to be significantly correlated with the progression-free survival (PFS) in our cohort. Among them, BST2, KRT7, LAMP3, MPO, S100A8, and TRIM29 were selected to construct a risk signature. Patients with a higher risk score had a significantly shorter PFS (p = 0.007). Time-dependent ROC curves indicated that our risk signature had a robust performance in accurately predicting survival. Specifically, the 6-, 12-, and 18-month area under curve (AUC) was 0.800, 0.932, and 0.912, respectively. Furthermore, the risk signature was positively related to N stage, tumor stage, and tumor malignancy. These results were validated using two external cohorts. Finally, the risk signature was significantly and uniquely correlated with abundance of neutrophil.Conclusion: Our study revealed an immune panel-based signature that could predict the prognosis of LUAD patients and was associated with the infiltration of neutrophils.

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Profiles of Immune Infiltration and Prognostic Immunoscore in Lung Adenocarcinoma

BioMed Research International ◽

10.1155/2020/5858092 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Yanyan Li ◽

Liping Tao ◽

Weiyang Cai

Keyword(s):

Lung Adenocarcinoma ◽

Immune Cells ◽

Cox Regression ◽

Meta Analysis ◽

Immune Therapy ◽

Interaction Network ◽

Principal Component ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Immune Microenvironment

Lung tissue is abundant with immune cells that form a powerful first defense against exotic particles and microbes. The malignant phenotype of lung adenocarcinoma (LUAD) is defined not only by intrinsic tumor cells but also by tumor-infiltrating immune cells (TIICs) recruited to the immune microenvironment. Understanding more about the immune microenvironment of LUAD could function in sorting out patients more likely with high risk and benefit from immunotherapy. Twenty-two types of TIICs were estimated based on large public LUAD cohorts from the TCGA and GEO datasets using the CIBERSORT algorithm. Then principal component analysis (PCA), meta-analysis, and single-sample gene set enrichment analysis (ssGSEA) were used to measure and evaluate the specific immune responses and relative mechanisms. Moreover, an immunoscore model based on the percent of immune cells was constructed via the univariate and multivariate Cox regression models, which provided an in-depth overview of the LUAD immune microenvironment and shed light on the immune regulatory mechanism. The differential expression genes (DEGs) were acquired based on the immunoscore model, and prognostic immune-related genes were further identified. GSEA and the protein–protein interaction network (PPI) further revealed that these genes were mostly enriched in many immune-related biological processes. It is hoped that this immune landscape could provide a more accurate understanding for LUAD development and tumor immune therapy.

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A Glycolysis-Based Long Non-coding RNA Signature Accurately Predicts Prognosis in Renal Carcinoma Patients

Frontiers in Genetics ◽

10.3389/fgene.2021.638980 ◽

2021 ◽

Vol 12 ◽

Author(s):

Honghao Cao ◽

Hang Tong ◽

Junlong Zhu ◽

Chenchen Xie ◽

Zijia Qin ◽

...

Keyword(s):

Clinical Significance ◽

Risk Score ◽

Cox Regression ◽

Risk Group ◽

Enrichment Analysis ◽

Roc Curves ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Survival Prediction ◽

Kaplan Meier

BackgroundThe prognosis of renal cell carcinoma (RCC) varies greatly among different risk groups, and the traditional indicators have limited effect in the identification of risk grade in patients with RCC. The purpose of our study is to explore a glycolysis-based long non-coding RNAs (lncRNAs) signature and verify its potential clinical significance in prognostic prediction of RCC patients.MethodsIn this study, RNA data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate cox regression displayed six significantly related lncRNAs (AC124854.1, AC078778.1, EMX2OS, DLGAP1-AS2, AC084876.1, and AC026401.3) which were utilized in construction of risk score by a formula. The accuracy of risk score was verified by a series of statistical methods such as receiver operating characteristic (ROC) curves, nomogram and Kaplan-Meier curves. Its potential clinical significance was excavated by gene enrichment analysis.ResultsKaplan-Meier curves and ROC curves showed reliability of the risk score to predict the prognosis of RCC patients. Stratification analysis indicated that the risk score was independent predictor compare to other traditional clinical parameters. The clinical nomogram showed highly rigorous with index of 0.73 and precisely predicted 1-, 3-, and 5-year survival time of RCC patients. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene set enrichment analysis (GSEA) depicted the top ten correlated pathways in both high-risk group and low-risk group. There are 6 lncRNAs and 25 related mRNAs including 36 lncRNA-mRNA links in lncRNA-mRNA co-expression network.ConclusionThis research demonstrated that glycolysis-based lncRNAs possessed an important value in survival prediction of RCC patients, which would be a potential target for future treatment.

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Abnormal Expression and Prognostic Significance of Bone Morphogenetic Proteins and Their Receptors in Lung Adenocarcinoma

BioMed Research International ◽

10.1155/2021/6663990 ◽

2021 ◽

Vol 2021 ◽

pp. 1-23

Author(s):

Zhixiao Xu ◽

Chengshui Chen

Keyword(s):

Lung Adenocarcinoma ◽

Mrna Expression ◽

Risk Score ◽

Prognostic Model ◽

Cox Regression ◽

Roc Curves ◽

Gene Set Enrichment Analysis ◽

Normal Lung ◽

Regression Analyses ◽

Bmp Receptors

Background. Lung adenocarcinoma (LUAD) is one of the most life-threatening malignancies. The crucial role of bone morphogenetic protein (BMP)/BMP receptors reveals the significance of exploring BMP protein-related prognostic predictors in LUAD. Methods. The mRNA expression of BMPs/BMP receptors was investigated in LUAD and normal lung tissues. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed, and the prognostic values were assessed by Kaplan-Meier Plotter. Univariate and multivariate Cox regression analyses were executed to ascertain the correlation between overall survival (OS) and the mRNA expression of BMPs/BMP receptors. The receiver operating characteristic (ROC) curves were implemented to evaluate the predictive power of the prognostic model. Then, the prognostic model was validated in the GEO cohort. Furthermore, a nomogram comprising the prognostic model was established. Results. The mRNA expression of BMP2/5/6/R2, ACVRL1, and TGFBR2/3 was lower in LUAD tissues than in normal lung tissues. High expression of BMP2/4/5/R1A/R2, ACVR1/2A/L1, and TGFBR1/3 was associated with better OS, while BMP7 and ACVR1C/2B were associated with poorer OS. Three genes (BMP5, BMP7, and ACVR2A) were screened by univariate and multivariate Cox regression analyses to develop the prognostic model in TCGA. Significantly better survival was observed in LUAD patients with a low-risk score than those with a high-risk score. The ROC curves confirmed the good performance of the prognostic model, then, the prognostic model was validated in the GSE31210 dataset. A nomogram was constructed (AUCs>0.7). And hub genes were further evaluated, including gene set enrichment analysis and immune cell infiltration. Conclusions. BMP5, BMP7, and ACVR2A are potential therapeutic targets in LUAD. The three-gene prognostic model and the nomogram are reliable tools for predicting the OS of LUAD patients.

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NRAS Expression is Associated With Prognosis and Tumor Immune Microenvironment in Lung Adenocarcinoma

10.21203/rs.3.rs-862652/v1 ◽

2021 ◽

Author(s):

Yueren Yan ◽

Zhendong Gao ◽

Han Han ◽

Yue Zhao ◽

Yang Zhang ◽

...

Keyword(s):

T Cells ◽

Lung Adenocarcinoma ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Expression Level ◽

Immune Microenvironment ◽

Kaplan Meier ◽

Tumor Immune Microenvironment ◽

Cox Analysis

Abstract Purpose: NRAS plays a pivotal role in progression of various kinds of somatic malignancies; however, the correlation between NRAS and lung adenocarcinoma is less known. We aim to analyze the prognostic value of NRAS expression in lung adenocarcinoma, and explore the relationship between NRAS and tumor immune microenvironment. Methods: We obtained the transcriptome pofiles and clinical data of LUAD from The Cancer Genome Atlas database and three Genome Expression Omnibus datasets. Specimens from 325 patients with completely resected lung adenocarcinoma were collected for immunohistochemical assays of NRAS, PD-L1, PD-1 and TIM-3. Then we performed gene set enrichment analysis to investigate cancer-related and immune-related signaling pathways. TIMER algorithms were performed to evaluate tumor immune infiltrating cells and immune-related biomarkers.Results: Compared with adjacent non-tumor tissue, NRAS expression was significantly upregulated in LUAD tissue. NRAS expression was significantly correlated with more advanced stage and positive lymph nodes. Kaplan-Meier curves and Cox analysis suggested that high NRAS expression led to a poor prognosis, and could be an independent prognostic factor in LUAD patients. Besides, NRAS expression was positively correlated with CD8+ T cells, macrophages, and neutrophils, and negatively correlated with B cells and CD4+ T cells. The expression level of NRAS was positively correlated with PD-L1, PD-1, and TIM-3 both at RNA and protein level. Conclusions: To conclude, we found NRAS a novel prognostic biomarker in LUAD. Besides, the expression level of NRAS may influence the prognosis of LUAD via various kinds of cancer-related pathways and remodeling TIM.

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High CTHRC1 expression may be closely associated with angiogenesis and indicates poor prognosis in lung adenocarcinoma patients

Cancer Cell International ◽

10.1186/s12935-019-1041-5 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Yangshan Chen ◽

Yu Sun ◽

Yongmei Cui ◽

Yiyan Lei ◽

Neng Jiang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Predictive Model ◽

Tumor Angiogenesis ◽

Poor Prognosis ◽

Cox Regression ◽

Enrichment Analysis ◽

Progression Free Survival ◽

Gene Set Enrichment Analysis ◽

Cox Regression Analysis ◽

Potential Biomarker

Abstract Background This study aimed to investigate the prognostic value of the potential biomarker collagen triple helix repeat containing 1 (CTHRC1) in lung adenocarcinoma (LUAD) patients. Methods A total of 210 LUAD patients diagnosed between 2003 and 2016 in the Department of Pathology of the First Affiliated Hospital of Sun Yat-sen University were included in this study. The expression of CTHRC1 and vascular endothelial growth factor (VEGF), and microvessel density (MVD, determined by CD34 immunostaining) were evaluated by immunohistochemistry in LUAD tissues. The association between the expression of these proteins and clinicopathological features or clinical outcomes was analyzed. Results Here, we confirmed that CTHRC1 expression was associated with prognosis and can serve as a significant predictor for overall survival (OS) and progression-free survival (PFS) in LUAD. Additionally, we observed that CTHRC1 expression was positively associated with tumor angiogenesis markers, such as VEGF expression (P < 0.001) and MVD (P < 0.01). Then, we performed gene set enrichment analysis (GESA) and cell experiments to confirm that enhanced CTHRC1 expression can promote VEGF levels. Based on and cox regression analysis, a predictive model that included CTHRC1, VEGF and MVD was constructed and confirmed as a more accurate independent predictor for OS (P = 0.001) and PFS (P < 0.001) in LUAD than other parameters. Conclusions These results demonstrated that high CTHRC1 expression may be closely related to tumor angiogenesis and poor prognosis in LUAD. The predictive model based on the CTHRC1 level and tumor angiogenesis markers can be used to predict LUAD patient prognosis more accurately.

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Identification prognosis-associated immune genes in colon adenocarcinoma

Bioscience Reports ◽

10.1042/bsr20201734 ◽

2020 ◽

Vol 40 (11) ◽

Author(s):

Yandong Miao ◽

Jiangtao Wang ◽

Xueping Ma ◽

Yuan Yang ◽

Denghai Mi

Keyword(s):

Risk Score ◽

Hormone Secretion ◽

Colon Adenocarcinoma ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Functional Enrichment ◽

Receptor Interaction ◽

Signal Pathways ◽

Immune Genes ◽

Prognosis Model

Abstract Colon adenocarcinoma (COAD) is one of the most prevalent malignant tumors worldwide. Immune genes (IGs) have a considerable correlation with tumor initiation and prognosis. The present paper aims to identify the prognosis value of IGs in COAD and conduct a prognosis model for clinical utility. Gene expression data of COAD were downloaded from The Cancer Genome Atlas (TCGA), screening and analyzing differentially expressed IGs by bioinformatics. Core genes were screened by univariate and multivariate Cox regression analyses. Survival analysis was appraised by the Kaplan–Meier method and the log-rank test. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis (GSEA) were used to identify IGs’ relevant signal pathways. We predicted the overall survival (OS) by nomogram. Finally, a prognosis model was conducted based on 12 IGs (SLC10A2, CXCL3, NOX4, FABP4, ADIPOQ, IGKV1-33, IGLV6-57, INHBA, UCN, VIP, NGFR, and TRDC). The risk score was an independent prognostic factor, and a nomogram could accurately predict the OS of individual COAD patients. These results were validated in GSE39582, GSE12945, and GSE103479 cohorts. Functional enrichment analysis demonstrated that these IGs are mainly enriched in hormone secretion, hormone transport, lipid transport, cytokine–cytokine receptor interaction, and peroxisome proliferators-activated receptor signaling pathway. In summary, the risk score is an independent prognostic biomarker. We also excavated several IGs related to COAD’s survival and maybe potential biomarkers for COAD diagnosis and treatment.

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Two predicted models based on ceRNAs and immune cells in lung adenocarcinoma

PeerJ ◽

10.7717/peerj.11029 ◽

2021 ◽

Vol 9 ◽

pp. e11029

Author(s):

Miaomiao Zhang ◽

Peiyan Zheng ◽

Yuan Wang ◽

Baoqing Sun

Keyword(s):

Lung Adenocarcinoma ◽

Immune Cells ◽

Cox Regression ◽

Expression Profiles ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Prognostic Models ◽

Risk Scores ◽

Immune Microenvironment

Background It is well accepted that both competitive endogenous RNAs (ceRNAs) and immune microenvironment exert crucial roles in the tumor prognosis. The present study aimed to find prognostic ceRNAs and immune cells in lung adenocarcinoma (LUAD). Materials and Methods More specifically, we explored the associations of crucial ceRNAs with the immune microenvironment. The Cancer Genome Atlas (TCGA) database was employed to obtain expression profiles of ceRNAs and clinical data. CIBERSORT was utilized to quantify the proportion of 22 immune cells in LUAD. Results We constructed two cox regression models based on crucial ceRNAs and immune cells to predict prognosis in LUAD. Subsequently, seven ceRNAs and seven immune cells were involved in prognostic models. We validated both predicted models via an independent cohort GSE72094. Interestingly, both predicted models proved that the longer patients were smoking, the higher risk scores would be obtained. We further investigated the relationships between seven genes and immune/stromal scores via the ESTIMATE algorithm. The results indicated that CDC14A and H1F0 expression were significantly related to stromal scores/immune scores in LUAD. Moreover, based on the result of the ceRNA model, single-sample gene set enrichment analysis (ssGSEA) suggested that differences in immune status were evident between high- and low-risk groups.

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P02.07 Characterization of the tumor immune microenvironment of pediatric posterior fossa A ependymomas

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-itoc8.19 ◽

2021 ◽

Vol 9 (Suppl 1) ◽

pp. A10.1-A10

Author(s):

J Lammers ◽

F Calkoen ◽

M Kranendonk ◽

A Federico ◽

M Kool ◽

...

Keyword(s):

Rna Sequencing ◽

Posterior Fossa ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Rna Expression ◽

Sequencing Data ◽

Immune Microenvironment ◽

Gene Set Enrichment ◽

Tumor Immune Microenvironment ◽

Immune Related Genes

BackgroundEpendymoma is the third most common brain tumor in children. At the moment, surgery and radiotherapy are the only effective treatments that can be offered, and despite this, a significant part of the patients relapse with no therapeutic salvage options. Therefore, new treatment modalities are needed. To develop immunotherapies for these children, knowledge of the tumor microenvironment is crucial. The current study aims to unravel the tumor immune microenvironment (TIME) of pediatric posterior fossa A (PFA) ependymomas.Materials and MethodsWe used bulk RNA sequencing data of 22 pediatric ependymomas. We defined two groups, hereafter called PFA immune+ (PFAI+) and PFAI-, based on the RNA expression levels of the NanoString panel of Human PanCancer Immune Profiling genes. We performed gene set enrichment analysis and deconvoluted the bulk RNA samples with ependymoma-specific single-cell RNA sequencing datasets. To validate our findings on a protein level, we applied immunohistochemistry with antibodies recognizing tumor-infiltrating lymphocytes, tumor-associated macrophages and microglia.ResultsUnsupervised hierarchical clustering of RNA expression of immune-related genes revealed two distinct PFA groups. Differential gene expression analysis showed that PFAI+ have a significantly higher expression of genes associated with immune functions, such as CD3E, CCR2, GZMA, CXCL9 and TRBC2. Accordingly, gene set enrichment analysis demonstrated that several immune pathways, including T-cell signalling, interferon-gamma response and TNFα signalling are enriched in PFAI+ ependymomas. RNA expression of immune checkpoints was also higher in PFAI+ tumors, indicating that these tumors might be more responsive to combinational therapies including immune checkpoint inhibitors. While immunohistochemistry showed low amounts of infiltrating CD3+, CD8+ and CD20+ cells, high numbers of CD163+ and HLA-DRA+ cells were detected. These cells were mainly located in regions of tumor necrosis. Increased amounts of CD4+ and CD8+ lymphocytes were present in PFAI+ tumors compared to PFAI- tumors. Deconvolution of the bulk RNA samples based on single-cell RNA sequencing data revealed an enrichment of myeloid cell populations, especially microglia and macrophages. Furthermore, PFAI+ tumors were found to contain significantly higher relative proportions of T-cells compared to PFAI- tumors (median of 3.76% for PFAI+ compared to 0.03% for PFAI-).ConclusionsWe suggest that pediatric posterior fossa A ependymomas can be divided into two groups based on the expression of immune-related genes, in which PFAI+ ependymomas are characterized by higher RNA expression levels of these genes and greater amounts of tumor-infiltrating immune cells. Several techniques showed an enrichment of T-lymphocytes in the PFAI+ ependymomas relative to the PFAI- ependymomas.Disclosure InformationJ. Lammers: None. F. Calkoen: None. M. Kranendonk: None. A. Federico: None. M. Kool: None. L. Kester: None. J. van der Lugt: None.

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Co-Mutation of FAT3 and LRP1B in Lung Adenocarcinoma Defines a Unique Subset Correlated With the Efficacy of Immunotherapy

Frontiers in Immunology ◽

10.3389/fimmu.2021.800951 ◽

2022 ◽

Vol 12 ◽

Author(s):

Mingyu Zhu ◽

Lu Zhang ◽

Haiyan Cui ◽

Qiang Zhao ◽

Hao Wang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Age Of Onset ◽

Checkpoint Inhibitors ◽

Enrichment Analysis ◽

Progression Free Survival ◽

Gene Set Enrichment Analysis ◽

Black African ◽

Tumor Mutational Burden ◽

Tumor Immunogenicity ◽

Nsclc Patients

Immunotherapy based on immune checkpoint inhibitors (ICIs) have demonstrated remarkable survival benefits and gained regulatory approval in non-small cell lung cancer (NSCLC) patients without an actionable driver mutation, but currently there is no well-established standard for how to screen the most suitable population for ICIs treatment. Here, we conducted a comprehensive analysis of the somatic mutation landscape of lung adenocarcinoma (LUAD) samples. After the stepwise screening of high-frequency mutated genes, two genes with prominent significance, FAT3 and LRP1B, were finally screened out. Through further analysis, we discovered that the co-mutation of FAT3 and LRP1B was associated with an earlier age of onset and occurred more frequently in Black/African American. Furthermore, co-mutation defines a unique subgroup of lung adenocarcinoma that can increase tumor mutational burden (TMB), boost cytotoxicity and tumor immunogenicity, and facilitate lymphocyte infiltration. The results of gene set enrichment analysis (GSEA) indicated that co-mutation can influence tumorigenesis through a variety of mechanisms. More strikingly, the subset of LUAD with co-mutation of FAT3 and LRP1B exhibited significantly prolonged immunotherapy progression free survival (PFS). In summary, co-mutation of FAT3 and LRP1B is a promising useful biomarker for predicting the efficacy of immunotherapy, which can improve the clinical efficiency of practicing precision medicine in lung adenocarcinoma patients.

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Increased VEGF-A in solid type of lung adenocarcinoma reduces the patients’ survival

Scientific Reports ◽

10.1038/s41598-020-79907-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Woon Yong Jung ◽

Kyueng-Whan Min ◽

Young Ha Oh

Keyword(s):

Immune Response ◽

Survival Analysis ◽

Lung Adenocarcinoma ◽

Survival Rates ◽

Treatment Strategies ◽

Enrichment Analysis ◽

Genetic Alterations ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Solid Type

AbstractThe histological classification of lung adenocarcinoma includes 5 types: lepidic, acinar, papillary, micropapillary and solid. The complex gene interactions and anticancer immune response of these types are not well known. The aim of this study was to reveal the survival rates, genetic alterations and immune activities of the five histological types and provide treatment strategies. This study reviewed the histological findings of 517 patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA) database and classified them into five types. We performed gene set enrichment analysis (GSEA) and survival analysis according to the different types. We found six oncogenic gene sets that were higher in lung adenocarcinoma than in normal tissues. In the survival analysis of each type, the acinar type had a favorable prognosis, and the solid subtype had an unfavorable prognosis; however, the survival differences between the other types were not significant. Our study focused on the solid type, which had the poorest prognosis. The solid type was related to adaptive immune resistance associated with elevated CD8 T cells and high CD274 (encoding PD-L1) expression. In the pathway analyses, the solid type was significantly related to high vascular endothelial growth factor (VEGF)-A expression, reflecting tumor angiogenesis. Non-necrosis/low immune response affected by high VEGF-A was associated with worse prognosis. The solid type associated with high VEGF-A expression may contribute to the development of therapeutic strategies for lung adenocarcinoma.

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