Clinical and Prognostic Implications of an Immune-Related Risk Model Based on TP53 Status in Lung Adenocarcinoma

Abstract Background: TP53 mutation is the most widespread mutation in lung adenocarcinoma (LUAD), meanwhile p53 (encoded by TP53) has recently been implicated in immune responses. However, it is still unknown whether TP53 mutation may remodel tumor microenvironment to influence tumor progression and prognosis in LUAD.Methods: we developed a six-gene immune-related model (IRM) to predict the survival of patients with LUAD in TCGA cohort based on TP53 status using LASSO Cox analysis, which was also confirmed the predictive ability in two independent cohorts.Results: The mutation of TP53 led to a decrease in the immune response in LUAD. Further analysis revealed that patients in the high-index group had observably lower relative infiltration of memory B cells and regulatory T cells, together with significantly higher relative infiltration proportions neutrophils and resting memory CD4+ T cells. Additionally, the IRM index positively correlated with expression of critical immune checkpoint genes including PDCD1 (encoding PD-1) and CD274 (encoding PD-L1), which was validated in Nanjing cohort. Furthermore, the IRM index as an independent prognostic factor was used to establish a nomogram for clinical application.Conclusion: This immune-related model may serve as a powerful prognostic tool to further optimize immunotherapies for LUAD.

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Clinical and prognostic implications of an immune‐related risk model based on TP53 status in lung adenocarcinoma

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.17097 ◽

2021 ◽

Author(s):

Xuming Song ◽

Qiang Chen ◽

Jifan Wang ◽

Qixing Mao ◽

Wenjie Xia ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Risk Model ◽

Model Based ◽

Related Risk ◽

Prognostic Implications ◽

Tp53 Status

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A Five Autophagy-Related Long Non-Coding RNA Prognostic Model for Patients with Lung Adenocarcinoma

10.21203/rs.3.rs-543033/v1 ◽

2021 ◽

Author(s):

Boxuan Liu ◽

Yun Zhao ◽

Shuanying Yang

Keyword(s):

Lung Adenocarcinoma ◽

Risk Score ◽

Prognostic Model ◽

Risk Model ◽

Cox Regression ◽

Predictive Ability ◽

Enrichment Analysis ◽

Pathway Enrichment Analysis ◽

Lasso Regression ◽

Cox Regression Analysis

Abstract Background: Lung adenocarcinoma is the most occurred pathological type among non-small cell lung cancer. Although huge progress has been made in terms of early diagnosis, precision treatment in recent years, the overall 5-year survival rate of a patient remains low. In our study, we try to construct an autophagy-related lncRNA prognostic signature that may guide clinical practice.Methods: The mRNA and lncRNA expression matrix of lung adenocarcinoma patients were retrieved from TCGA database. Next, we constructed a co-expression network of lncRNAs and autophagy-related genes. Lasso regression and multivariate Cox regression were then applied to establish a prognostic risk model. Subsequently, a risk score was generated to differentiate high and low risk group and a ROC curve and Nomogram to visualize the predictive ability of current signature. Finally, gene ontology and pathway enrichment analysis were executed via GSEA.Results: A total of 1,703 autophagy-related lncRNAs were screened and five autophagy-related lncRNAs (LINC01137, AL691432.2, LINC01116, AL606489.1 and HLA-DQB1-AS1) were finally included in our signature. Judging from univariate(HR=1.075, 95% CI: 1.046–1.104) and multivariate(HR =1.088, 95%CI = 1.057 − 1.120) Cox regression analysis, the risk score is an independent factor for LUAD patients. Further, the AUC value based on the risk score for 1-year, 3-year, 5-year, was 0.735, 0.672 and 0.662 respectively. Finally, the lncRNAs included in our signature were primarily enriched in autophagy process, metabolism, p53 pathway and JAK/STAT pathway. Conclusions: Overall, our study indicated that the prognostic model we generated had certain predictability for LUAD patients’ prognosis.

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Independent Prognostic Potential of GNPNAT1 in Lung Adenocarcinoma

BioMed Research International ◽

10.1155/2020/8851437 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16

Author(s):

Xiangyu Zheng ◽

Yongwei Li ◽

Chao Ma ◽

Jinjun Zhang ◽

Yanmin Zhang ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

B Cells ◽

Lung Adenocarcinoma ◽

Cd4 T Cells ◽

Prognostic Value ◽

Marker Genes ◽

Immune Signatures ◽

Cox Analysis

Background. Glucosamine-Phosphate N-Acetyltransferase 1 (GNPNAT1) is a critical enzyme in the biosynthesis of uridine diphosphate-N-acetylglucosamine. It has many important functions, such as protein binding, monosaccharide binding, and embryonic development and growth. However, the role of GNPNAT1 in lung adenocarcinoma (LUAD) remains unclear. Methods. In this study, we explored the expression pattern and prognostic value of GNPNAT1 in LUAD across TCGA and GEO databases and assessed its independent prognostic value via Cox analysis. LinkedOmics and GEPIA2 were applied to investigate coexpression and functional networks associated with GNPNAT1. The TIMER web tool was deployed to assess the correlation between GNPNAT1 and the main six types of tumor-infiltrating immune cells. Besides, the correlations between GNPNAT1 and the LUAD common genetic mutations, TMB, and immune signatures were examined. Results. GNPNAT1 was validated upregulated in tumor tissues in TCGA-LUAD and GEO cohorts. Moreover, in both TCGA and GEO cohorts, high GNPNAT1 expression was found to be associated with poor overall survival. Cox analysis showed that high GNPNAT1 expression was an independent risk factor for LUAD. Functional network analysis suggested that GNPNAT1 regulates cell cycle, ribosome, proteasome, RNA transport, and spliceosome signaling through pathways involving multiple cancer-related kinases and E2F family. In addition, GNPNAT1 correlated with infiltrating levels of B cells, CD4+ T cells, and dendritic cells. B cells and dendritic cells could predict the outcome of LUAD, and B cells and CD4+ T cells were significant independent risk factors. The TMB and mutations of KRAS, EGFR, STK11, and TP53 were correlated with GNPNAT1. At last, the correlation analysis showed GNPNAT1 correlated with most of the immune signatures we performed. Conclusion. Our findings showed that GNPNAT1 was correlated to the prognosis and immune infiltration of LUAD. In particular, the tight relationship between GNPNAT1 and B cell marker genes may be the epicenter of the immune response and one of the key factors affecting the prognosis. Our findings laid the foundation for further research on the immunomodulatory role of GNPNAT1 in LUAD.

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Integrated Dissection of lncRNA-miRNA-mRNA Pairs and Potential Regulatory Role of lncRNA PCAT19 in Lung Adenocarcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.765275 ◽

2022 ◽

Vol 12 ◽

Author(s):

Xiaomei Tang ◽

Xiaoyan Hua ◽

Xujin Peng ◽

Yongyan Pei ◽

Zhigang Chen

Keyword(s):

Lung Adenocarcinoma ◽

Cell Function ◽

Risk Model ◽

Special Functions ◽

Histological Grade ◽

The Cancer Genome Atlas ◽

Regulatory Role ◽

Migration And Invasion ◽

Potential Biomarker ◽

Cox Analysis

Lung adenocarcinoma (LUAD) is the main cause of cancer-related deaths worldwide. Long noncoding RNAs have been reported to play an important role in various cancers due to their special functions. Therefore, identifying the lncRNAs involved in LUAD tumorigenesis and development can help improve therapeutic strategies. The TCGA-LUAD RNA expression profile was downloaded from The Cancer Genome Atlas, and a total of 49 differential lncRNAs, 112 differential miRNAs, and 2,953 differential mRNAs were screened. Through Kaplan–Meier curves, interaction networks, hub RNAs (lncRNAs, miRNAs, and mRNAs) were obtained. These hub genes are mainly involved in cell proliferation, cell cycle, lung development, and tumor-related signaling pathways. Two lncRNAs (SMIM25 and PCAT19) more significantly related to the prognosis of LUAD were screened by univariate Cox analysis, multivariate Cox analysis, and risk model analysis. The qPCR results showed that the expression levels of SMIM25 and PCAT19 were downregulated in clinical tissues, A549 and SPC-A1 cells, which were consistent with the bioinformatics analysis results. Subsequently, the PCAT19/miR-143-3p pairs were screened through the weighted gene co-expression network analysis and miRNA-lncRNA regulatory network. Dual luciferase detection confirmed that miR-143-3p directly targets PCAT19, and qPCR results indicated that the expression of the two is positively correlated. Cell function tests showed that overexpression of PCAT19 could significantly inhibit the proliferation, migration, and invasion of A549 and SPC-A1 cells. In contrast, knockout of PCAT19 can better promote the proliferation and migration of A549 and SPC-A1 cells. The expression of PCAT19 was negatively correlated with tumor grade, histological grade, and tumor mutation load in LUAD. In addition, co-transfection experiments confirmed that the miR-143-3p mimic could partially reverse the effect of PCAT19 knockout on the proliferation of A549 and SPC-A1 cells. In summary, PCAT19 is an independent prognostic factor in patients with LUAD that can regulate the proliferation, migration, and invasion of LUAD cells and may be a potential biomarker for the diagnosis of LUAD. PCAT19/miR-143-3p plays a very important regulatory role in the occurrence and development of LUAD.

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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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SFTPA1 is a potential prognostic biomarker correlated with immune cell infiltration and response to immunotherapy in lung adenocarcinoma

Cancer Immunology Immunotherapy ◽

10.1007/s00262-021-02995-4 ◽

2021 ◽

Author(s):

Lu Yuan ◽

Xixi Wu ◽

Longshan Zhang ◽

Mi Yang ◽

Xiaoqing Wang ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

Lung Adenocarcinoma ◽

Expression Profile ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Regulatory Pathways ◽

Chronic Lung Diseases ◽

Potential Biomarker

AbstractPulmonary surfactant protein A1 (SFTPA1) is a member of the C-type lectin subfamily that plays a critical role in maintaining lung tissue homeostasis and the innate immune response. SFTPA1 disruption can cause several acute or chronic lung diseases, including lung cancer. However, little research has been performed to associate SFTPA1 with immune cell infiltration and the response to immunotherapy in lung cancer. The findings of our study describe the SFTPA1 expression profile in multiple databases and was validated in BALB/c mice, human tumor tissues, and paired normal tissues using an immunohistochemistry assay. High SFTPA1 mRNA expression was associated with a favorable prognosis through a survival analysis in lung adenocarcinoma (LUAD) samples from TCGA. Further GeneOntology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that SFTPA1 was involved in the toll-like receptor signaling pathway. An immune infiltration analysis clarified that high SFTPA1 expression was associated with an increased number of M1 macrophages, CD8+ T cells, memory activated CD4+ T cells, regulatory T cells, as well as a reduced number of M2 macrophages. Our clinical data suggest that SFTPA1 may serve as a biomarker for predicting a favorable response to immunotherapy for patients with LUAD. Collectively, our study extends the expression profile and potential regulatory pathways of SFTPA1 and may provide a potential biomarker for establishing novel preventive and therapeutic strategies for lung adenocarcinoma.

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Immunogenomic Gene Signature of Cell-Death Associated Genes with Prognostic Implications in Lung Cancer

Cancers ◽

10.3390/cancers13010155 ◽

2021 ◽

Vol 13 (1) ◽

pp. 155

Author(s):

Pankaj Ahluwalia ◽

Meenakshi Ahluwalia ◽

Ashis K. Mondal ◽

Nikhil Sahajpal ◽

Vamsi Kota ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

Cell Death ◽

T Cell ◽

High Risk ◽

Lung Adenocarcinoma ◽

Risk Group ◽

High Risk Group ◽

Free Survival ◽

Cell Death Pathways

Lung cancer is one of the leading causes of death worldwide. Cell death pathways such as autophagy, apoptosis, and necrosis can provide useful clinical and immunological insights that can assist in the design of personalized therapeutics. In this study, variations in the expression of genes involved in cell death pathways and resulting infiltration of immune cells were explored in lung adenocarcinoma (The Cancer Genome Atlas: TCGA, lung adenocarcinoma (LUAD), 510 patients). Firstly, genes involved in autophagy (n = 34 genes), apoptosis (n = 66 genes), and necrosis (n = 32 genes) were analyzed to assess the prognostic significance in lung cancer. The significant genes were used to develop the cell death index (CDI) of 21 genes which clustered patients based on high risk (high CDI) and low risk (low CDI). The survival analysis using the Kaplan–Meier curve differentiated patients based on overall survival (40.4 months vs. 76.2 months), progression-free survival (26.2 months vs. 48.6 months), and disease-free survival (62.2 months vs. 158.2 months) (Log-rank test, p < 0.01). Cox proportional hazard model significantly associated patients in high CDI group with a higher risk of mortality (Hazard Ratio: H.R 1.75, 95% CI: 1.28–2.45, p < 0.001). Differential gene expression analysis using principal component analysis (PCA) identified genes with the highest fold change forming distinct clusters. To analyze the immune parameters in two risk groups, cytokines expression (n = 265 genes) analysis revealed the highest association of IL-15RA and IL 15 (> 1.5-fold, p < 0.01) with the high-risk group. The microenvironment cell-population (MCP)-counter algorithm identified the higher infiltration of CD8+ T cells, macrophages, and lower infiltration of neutrophils with the high-risk group. Interestingly, this group also showed a higher expression of immune checkpoint molecules CD-274 (PD-L1), CTLA-4, and T cell exhaustion genes (HAVCR2, TIGIT, LAG3, PDCD1, CXCL13, and LYN) (p < 0.01). Furthermore, functional enrichment analysis identified significant perturbations in immune pathways in the higher risk group. This study highlights the presence of an immunocompromised microenvironment indicated by the higher infiltration of cytotoxic T cells along with the presence of checkpoint molecules and T cell exhaustion genes. These patients at higher risk might be more suitable to benefit from PD-L1 blockade or other checkpoint blockade immunotherapies.

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Identification and development of a novel invasion-related gene signature for prognosis prediction in colon adenocarcinoma

Cancer Cell International ◽

10.1186/s12935-021-01795-1 ◽

2021 ◽

Vol 21 (1) ◽

Cited By ~ 1

Author(s):

Jiahua Liu ◽

Chunhui Jiang ◽

Chunjie Xu ◽

Dongyang Wang ◽

Yuguang Shen ◽

...

Keyword(s):

T Cells ◽

External Validation ◽

Colon Adenocarcinoma ◽

Gene Signature ◽

The Cancer Genome Atlas ◽

Immune Infiltration ◽

Prognosis Prediction ◽

Protein Levels ◽

Limma Package ◽

Cox Analysis

AbstractThe overall survival of metastatic colon adenocarcinoma (COAD) remains poor, so it is important to explore the mechanisms of metastasis and invasion. This study aimed to identify invasion-related genetic markers for prognosis prediction in patients with COAD. Three molecular subtypes (C1, C2, and C3) were obtained based on 97 metastasis-related genes in 365 COAD samples from The Cancer Genome Atlas (TCGA). A total of 983 differentially expressed genes (DEGs) were identified among the different subtypes by using the limma package. A 6-gene signature (ITLN1, HOXD9, TSPAN11, GPRC5B, TIMP1, and CXCL13) was constructed via Lasso-Cox analysis. The signature showed strong robustness and could be used in the training, testing, and external validation (GSE17537) cohorts with stable predictive efficiency. Compared with other published signatures, our model showed better performance in predicting outcomes. Pan-cancer expression analysis results showed that ITLN1, TSPAN11, CXCL13, and GPRC5B were downregulated and TIMP1 was upregulated in most tumor samples, including COAD, which was consistent with the results of the TCGA and GEO cohorts. Western blot analysis and immunohistochemistry were performed to validate protein expression. Tumor immune infiltration analysis results showed that TSPAN11, GPRC5B, TIMP1, and CXCL13 protein levels were significantly positively correlated with CD4+ T cells, macrophages, neutrophils, and dendritic cells. Further, the TIMP1 and CXCL13 proteins were significantly related to the tumor immune infiltration of CD8+ T cells. We recommend using our signature as a molecular prognostic classifier to assess the prognostic risk of patients with COAD.

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