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Identification and validation of tumor microenvironment-related genes of prognostic value in lung adenocarcinoma.

ABSTRACT: Lung adenocarcinoma (LUAD) is a major subtype of non-small cell lung cancer. Despite significant progress in its diagnosis and treatment, the mortality and morbidity rate of LUAD remains high worldwide. The aim of the present study was to perform a systematic investigation of the tumor microenvironment (TME) and identify TME-related genes of prognostic value in patients with LUAD. Firstly, the immune scores and stromal scores of patients with LUAD from The Cancer Genome Atlas were calculated using the Estimation of STromal and Immune cells in MAlignant Tumors using Expression data algorithm, and a total of 281 prognostic TME-related genes were identified. Subsequently, functional analysis and protein-protein interaction network analysis revealed that these genes were mainly related to immune response, inflammatory response and chemotaxis. Finally, two independent LUAD cohorts from the Gene Expression Omnibus database were used to validate these genes, and 4 genes (GTPase IMAP family member 1, T-cell surface glycoprotein CD1b, integrin alpha-L and leukocyte surface antigen CD53) were identified, and downregulation of these genes was indicated to be associated with poor overall survival rate in patients with LUAD. In conclusion, a comprehensive analysis of TME was performed and 4 prognostic TME-related genes in patients with LUAD were identified.

SUBMITTER: Yuan J

PROVIDER: S-EPMC7377199 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Identification and validation of tumor microenvironment-related genes of prognostic value in lung adenocarcinoma.

Yuan Jingyan J Yuan Bo B Zeng Lizhong L Liu Boxuan B Chen Yang Y Meng Xia X Sun Ruiying R Lv Xin X Wang Wei W Yang Shuanying S

Oncology letters 20200616 2

Lung adenocarcinoma (LUAD) is a major subtype of non-small cell lung cancer. Despite significant progress in its diagnosis and treatment, the mortality and morbidity rate of LUAD remains high worldwide. The aim of the present study was to perform a systematic investigation of the tumor microenvironment (TME) and identify TME-related genes of prognostic value in patients with LUAD. Firstly, the immune scores and stromal scores of patients with LUAD from The Cancer Genome Atlas were calculated usi ...[more]

PMID: 32724420

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Project description:Background:Prognostic genes in the tumor microenvironment play an important role in immune biological processes and the response of cancer to immunotherapy. Thus, we aimed to assess new biomarkers that are associated with immune/stromal cells in lung adenocarcinomas (LUAD) using the ESTIMATE algorithm, which also significantly affects the prognosis of cancer. Methods:The RNA sequencing (RNA-Seq) and clinical data of LUAD were downloaded from the the Cancer Genome Atlas (TCGA ). The immune and stromal scores were calculated for each sample using the ESTIMATE algorithm. The LUAD gene chip expression profile data and the clinical data (GSE37745, GSE11969, and GSE50081) were downloaded from the Gene Expression Omnibus (GEO) for subsequent validation analysis. Differentially expressed genes were calculated between high and low score groups. Univariate Cox regression analysis was performed on differentially expressed genes (DEGs) between the two groups to obtain initial prognosis genes. These were verified by three independent LUAD cohorts from the GEO database. Multivariate Cox regression was used to identify overall survival-related DEGs. UALCAN and the Human Protein Atlas were used to analyze the mRNA /protein expression levels of the target genes. Immune cell infiltration was evaluated using the Tumor Immune Estimation Resource (TIMER) and CIBERSORT methods, and stromal cell infiltration was assessed using xCell. Results:In this study, immune scores and stromal scores are significantly associated with the clinical characteristics of LUAD, including T stage, M stage, pathological stage, and overall survival time. 530 DEGs (18 upregulated and 512 downregulated) were found to coexist in the difference analysis with the immune scores and stromal scores subgroup. Univariate Cox regression analysis showed that 286 of the 530 DEGs were survival-related genes (p < 0.05). Of the 286 genes initially identified, nine prognosis-related genes (CSF2RB, ITK, FLT3, CD79A, CCR4, CCR6, DOK2, AMPD1, and IGJ) were validated from three separate LUAD cohorts. In addition, functional analysis of DEGs also showed that various immunoregulatory molecular pathways, including regulation of immune response and the chemokine signaling pathways, were involved. Five genes (CCR6, ITK, CCR4, DOK2, and AMPD1) were identified as independent prognostic indicators of LUAD in specific data sets. The relationship between the expression levels of these genes and immune genes was assessed. We found that CCR6 mRNA and protein expression levels of LUAD were greater than in normal tissues. We evaluated the infiltration of immune cells and stromal cells in groups with high and low levels of expression of CCR6 in the TCGA LUAD cohort. In summary, we found a series of prognosis-related genes that were associated with the LUAD tumor microenvironment.

Project description:AimImmune cells that infiltrate the tumor microenvironment (TME) are associated with cancer prognosis. The aim of the current study was to identify TME related gene signatures related to the prognosis of sarcoma (SARC) by using the data from The Cancer Genome Atlas (TCGA).MethodsImmune and stromal scores were calculated by estimation of stromal and immune cells in malignant tumor tissues using expression data algorithms. The least absolute shrinkage and selection operator (lasso) based cox model was then used to select hub survival genes. A risk score model and nomogram were used to predict the overall survival of patients with SARC.ResultsWe selected 255 patients with SARC for our analysis. The Kaplan-Meier method found that higher immune (p = 0.0018) or stromal scores (p = 0.0022) were associated with better prognosis of SARC. The estimated levels of CD4+ (p = 0.0012) and CD8+ T cells (p = 0.017) via the tumor immune estimation resource were higher in patients with SARC with better overall survival. We identified 393 upregulated genes and 108 downregulated genes (p < 0.05, fold change >4) intersecting between the immune and stromal scores based on differentially expressed gene (DEG) analysis. The univariate Cox analysis of each intersecting DEG and subsequent lasso-based Cox model identified 11 hub survival genes (MYOC, NNAT, MEDAG, TNFSF14, MYH11, NRXN1, P2RY13, CXCR3, IGLV3-25, IGHV1-46, and IGLV2-8). Then, a hub survival gene-based risk score gene signature was constructed; higher risk scores predicted worse SARC prognosis (p < 0.0001). A nomogram including the risk scores, immune/stromal scores and clinical factors showed a good prediction value for SARC overall survival (C-index = 0.716). Finally, connectivity mapping analysis identified that the histone deacetylase inhibitors trichostatin A and vorinostat might have the potential to reverse the harmful TME for patients with SARC.ConclusionThe current study provided new indications for the association between the TME and SARC. Lists of TME related survival genes and potential therapeutic drugs were identified for SARC.

Dataset Information

Identification and validation of tumor microenvironment-related genes of prognostic value in lung adenocarcinoma.

Publications

Identification and validation of tumor microenvironment-related genes of prognostic value in lung adenocarcinoma.

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