Development and Validation of a Prognostic Autophagy-Related Gene Pair Index Related to Tumor-Infiltrating Lymphocytes in Early-Stage Lung Adenocarcinoma.
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ABSTRACT:
SUBMITTER: Wang ZH
PROVIDER: S-EPMC8488280 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hepatoid adenocarcinoma of the stomach (HAS) is a particular subtype of Gastric cancer (GC) with distinct pathological characteristics and genetic profile, but most HAS patients were received identical regimens as common GC. To date, only a few studies has been conducted to investigate the molecular characteristics of HAS, which may prevent the rational application of new anticancer strategies. To further obtain the genetic features and potential predictive and prognostic biomarkers of HAS, our current study evaluated the clinical implications of spectrum molecular markers in 36 surgical resection specimens. None Epstein-Barr virus (EBV) positive and/or micro-satellite instable high (MSI-h) tumors occurred in our study implies that the molecular classification of HAS should be mainly categorized into genomic stable (GS) and chromosomal instability (CIN) phenotypes, and wild type P53 status predicts better prognosis. More importantly, although the prognosis and clinical characteristics were independent of programmed cell death-ligand 1 (PD-L1), the presence of tumor infiltrating lymphocytes (TILs) still suggested that a portion of the enrolled HAS patients are potentially appropriate candidates for immune checkpoint blockade therapy. Additionally, the immune prognostic index (IPI) and derived neutrophil to lymphocyte ratio (dNLR) demonstrated their potential as reliable and economic indicators for predicting prognosis of HAS. We hope this first systematic evaluation will help in deciphering the molecular characterization and potential individualized regimens for this particular subtype of GC.
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Project description:Lung adenocarcinoma (LUAD) has become the main histologic type, which account for nearly 40% of lung cancer. The present study aimed to investigate the gene expression signature in smoking related LUAD. A total of 45 smoking related DEGs in LUAD were identified and functional enrichment analysis was also performed. Then Cox's regression model and Kaplan-Meier analysis were used to screen potential prognostic genes. Finally, AURKA and FAM83A were left for further immune-related mechanism exploration. Kaplan-Meier analysis indicated survival rates are related to different immune cell (B cell and Dendritic cell) infiltration levels. Mechanistically, we further explore the correlation between AURKA and FAM83A gene expression levels and tumor-infiltrating lymphocytes (TILs) level as well as their response to immunomodulators. The results suggested that AURKA and FAM83A are highly expressed in smoking related LUAD, and negatively correlated to B cell and Dendritic cell infiltration levels. At the same time, B cell and Dendritic cell infiltration levels also related to the prognosis of LUAD. We further revealed AURKA and FAM83A could be novel targets to improve the prognosis of LUAD through regulated the response to immunomodulators.
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Project description:BackgroundLung cancer is the most common malignant tumor in the world, and its prognosis is still not optimistic. The aim of this study was to establish an immune-related gene (IRG) prognostic index (IRGPI) for lung adenocarcinoma (LUAD) based on IRGs, and to explore the prognosis, molecular and immune features, and response to immune checkpoint inhibitor (ICI) therapy in IRGPI-classified different subgroups of LUAD.MethodsBased on the LUAD transcriptome RNA-sequencing data in TCGA database, the differentially expressed genes (DEGs) were selected. Subsequently, DEGs were intersected with IRGs to obtain differentially expressed immune-related genes (DEIRGs). Weighted gene co-expression network analysis (WGCNA) identified hub genes in DEIRGs. Finally, univariate and multivariate Cox regression analyses were used to build an IRGPI model. Subsequently, TCGA patients were divided into high- and low-risk groups, and the survival of patients in different groups was further analyzed. Besides, we validated the molecular and immune characteristics, relationship with immune checkpoints, angiogenesis-related genes, and immune subtypes distribution in different subgroups. Meanwhile, we further validated the response to ICI therapy in different subgroups.ResultsThe IRGPI was constructed based on 13 DEIRGs. Compared with the low-risk group, overall survival (OS) was lower in the high-risk group, and the high-risk score was independently associated with poorer OS. Besides, the high-risk score was associated with cell cycle pathway, high mutation rate of TP53 and KRAS, high infiltration of M0 macrophages, and immunosuppressive state, and these patients had poorer prognosis but the TIDE score of the high-risk group was lower than that of the other group, which means that the high-risk group could benefit more from ICI treatment. In contrast, the low-risk score was related to low mutation rate of TP53 and KRAS, high infiltration of plasma cells, and immunoactive state, and these patients had better prognosis but the low-risk group less benefit from ICI treatment based on the results of TIDE score.ConclusionsIRGPI is a prospective biomarker based on IRGs that can distinguish high- and low-risk groups to predict patient prognosis, help characterize the tumor immune microenvironment, and evaluate the benefit of ICI therapy in LUAD.
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Project description:BackgroundThe immunosuppressive tumor microenvironment produced by cancer cells is a key mechanisms of cancer immune escape. In this study, we investigated the relationship between the metabolic patterns and tumor immune environment in the TME of lung adenocarcinoma (LUAD) with the p53 mutation.MethodsThe clinical data of 495 LUAD patients was obtained from The Cancer Genome Atlas as transcriptomic and somatic mutation data. Using differential analysis, survival analysis, and a LASSO regression model based on metabolic unigenes from KEGG pathways, a tumor metabolic model was constructed to predict the prognosis of LUAD patients. Subsequently, nomogram, receiver operating characteristic, and decision curve analyses were conducted to assess the predictive ability of the model. In addition, the ESTIMATE and CIBERSORT algorithms were used to detect tumor purity and estimate the fractions of 22 immune cell types in each patient, respectively. We found a correlation between the composition of immune cells and the tumor metabolic model. The results were validated using an independent GSE72094 dataset with 442 patients, as well as an immunohistochemistry assay, RT-qPCR, and western blot.ResultsThe tumor metabolic model reassigned the risk score of every patient, and a tumor metabolic risk score (TMRS) was generated to show the predictive ability for patient prognoses (hazard ratio =0.39; 95% confidence interval: 0.18-0.85). Using a combination of TMRS and clinical features, a nomogram was produced with a predictive accuracy of 0.72. Further analysis showed that CD4 memory resting T cells and M1 macrophages may by correlated with the TMRS, which corresponded to immunoediting in p53 mutant patients. Additionally, the similar expression of ALDH3A1 and MGAT5B were also verified by wetlab experiments.ConclusionsBased on the identified tumor metabolism-immune landscape, we were able to predict a metabolism risk score for patient prognosis and identify a correlation with two types of infiltrating lymphocytes in the TME of p53-mutated LUAD. This landscape provides insights that will help identify the molecular mechanisms of immune-editing tumor metabolism.
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Project description:BackgroundAutophagy related genes (ARGs) regulate lysosomal degradation to induce autophagy, and are involved in the occurrence and development of a variety of cancers. The expression of ARGs in tumor tissues has a great prospect in predicting the survival of patients. The aim of this study was to construct a prognostic risk score model for lung adenocarcinoma (LUAD) based on ARGs.Methods5,786 ARGs were obtained from GeneCards database. Gene expression profiles and clinical data of 395 LUAD patients were collected from The Cancer Genome Atlas (TCGA) database. All ARGs expression data were extracted, and The ARGs differentially expressed were identified by R software. Survival analysis of differentially expressed ARGs was performed to screen for ARGs with prognostic value, and functional enrichment analysis was performed. The least absolute selection operator (LASSO) regression and Cox regression model were used to construct a prognostic risk scoring model for ARGs. The receiver operating characteristic (ROC) curve was drawn to obtain the optimal cut-off value of risk score. According to the cut-off value, the patients were divided into high-risk group and low-risk group. The area under curve (AUC) and the Kaplan-Meier survival curve was plotted to evaluate the model performance, which was verified in external data sets. Finally, univariate and multivariate Cox regression analysis was applied to evaluate the independent prognostic value of the model, and its clinical relevance was analyzed.ResultsSurvival analysis, Lasso regression and Cox regression analysis were used to construct a LUAD prognostic risk score model with five ARGs (ADAM12, CAMP, DKK1, STRIP2 and TFAP2A). The survival time of patients with low-risk score in this model was significantly better than that of patients with high-risk score (P<0.001). The model showed good prediction performance for LUAD in both the training set (AUCmax=0.78) and two external validation sets (AUCmax=0.88). Risk score was significantly associated with the prognosis of LUAD patients in univariate and multivariate Cox regression analyses, suggested that risk score could be a potential independent prognostic factor for LUAD. Correlation analysis of clinical characteristic showed that high risk score was closely associated with high T stage, high tumor stage and poor prognosis.ConclusionsWe constructed a LUAD risk score model consisting of five ARGs, which can provide a reference for predicting the prognosis of LUAD patients, and may be used in combination with tumor node metastasis (TNM) staging for prognosis prediction of LUAD patients in the future.
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Project description:BackgroundLung adenocarcinoma (LUAD) is a deadly respiratory system malignancy with poor prognosis. Autophagy is essential for the beginning, development, and therapy resistance of cancer. However, the expression of genes participating in autophagy in LUAD and their associations with prognosis remain unclear.MethodsPredictive genes participating in autophagy in LUAD samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were investigated. TCGA and GEO cohorts were divided into two risk groups, while the low-risk group having a longer overall survival (OS) time. This article aims to point out the interaction between genes participating in autophagy and immune function, immune checkpoints, and m6a in LUAD. The prediction model was designed for exploring least absolute shrinkage and selection operator (LASSO) regression. It has been revealed that gene expression and autophagy are inextricably connected.ResultsGenes participating in autophagy were shown to be somewhat overexpressed in the high-risk group even though no different clinical symptoms were present, indicating that they might be used in a model to predict LUAD prognosis. The majority of genes participating in autophagy prognostic signatures controlled immunological and tumor-related pathways, according to gene set enrichment analysis (GSEA). KRT6A, KYNU, IGFBP1, DKK1, PKP2, PLEK2, GAPDH, FLNC, and NTSR1 might be related to the oncology process for LUAD patients. CERS4, CMAHP, and PLEKHB1 have been identified as being associated with low risk in patients with LUAD. Furthermore, the immune function and m6a gene expression differed significantly between the two groups.ConclusionsGenes participating in autophagy are connected to the development and progression of LUAD. LUAD patients' prognoses are often foreseen utilizing matched prognostic models. Genes participating in autophagy in LUAD may be therapeutic targets that ought to be investigated more.
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Project description:BackgroundThe incidence of stage I and stage II lung adenocarcinoma (LUAD) is likely to increase with the introduction of annual screening programs for high-risk individuals. We aimed to identify a reliable prognostic signature with immune-related genes that can predict prognosis and help making individualized management for patients with early-stage LUAD.MethodsThe public LUAD cohorts were obtained from the large-scale databases including 4 microarray data sets from the Gene Expression Omnibus (GEO) and 1 RNA-seq data set from The Cancer Genome Atlas (TCGA) LUAD cohort. Only early-stage patients with clinical information were included. Cox proportional hazards regression model was performed to identify the candidate prognostic genes in GSE30219, GSE31210 and GSE50081 (training set). The prognostic signature was developed using the overlapped prognostic genes based on a risk score method. Kaplan-Meier curve with log-rank test and time-dependent receiver operating characteristic (ROC) curve were used to evaluate the prognostic value and performance of this signature, respectively. Furthermore, the robustness of this prognostic signature was further validated in TCGA-LUAD and GSE72094 cohorts.ResultsA prognostic immune signature consisting of 21 immune-related genes was constructed using the training set. The prognostic signature significantly stratified patients into high- and low-risk groups in terms of overall survival (OS) in training data set, including GSE30219 (HR = 4.31, 95% CI 2.29-8.11; P = 6.16E-06), GSE31210 (HR = 11.91, 95% CI 4.15-34.19; P = 4.10E-06), GSE50081 (HR = 3.63, 95% CI 1.90-6.95; P = 9.95E-05), the combined data set (HR = 3.15, 95% CI 1.98-5.02; P = 1.26E-06) and the validation data set, including TCGA-LUAD (HR = 2.16, 95% CI 1.49-3.13; P = 4.54E-05) and GSE72094 (HR = 2.95, 95% CI 1.86-4.70; P = 4.79E-06). Multivariate cox regression analysis demonstrated that the 21-gene signature could serve as an independent prognostic factor for OS after adjusting for other clinical factors. ROC curves revealed that the immune signature achieved good performance in predicting OS for early-stage LUAD. Several biological processes, including regulation of immune effector process, were enriched in the immune signature. Moreover, the combination of the signature with tumor stage showed more precise classification for prognosis prediction and treatment design.ConclusionsOur study proposed a robust immune-related prognostic signature for estimating overall survival in early-stage LUAD, which may be contributed to make more accurate survival risk stratification and individualized clinical management for patients with early-stage LUAD.
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Project description:BackgroundWe investigated the correlation between pancreatic ductal adenocarcinoma patient prognosis and the presence of tumour infiltrating lymphocytes and expression of 521 immune system genes.MethodsIntratumoural CD3+, CD8+, and CD20+ lymphocytes were examined by immunohistochemistry in 12 PDAC patients with different outcomes who underwent pancreaticoduodenectomy. The results were correlated with gene expression profile using the digital multiplexed NanoString nCounter analysis system (NanoString Technologies, Seattle, WA, USA).ResultsTwenty immune system genes were significantly differentially expressed in patients with a good prognosis relative to patients with a worse prognosis: TLR2 and TLR7 (Toll-like receptor superfamily); CD4, CD37, FOXP3, PTPRC (B cell and T cell signalling); IRF5, IRF8, STAT1, TFE3 (transcription factors); ANP32B, CCND3 (cell cycle); BTK (B cell development); TNF, TNFRF1A (TNF superfamily); HCK (leukocyte function); C1QA (complement system); BAX, PNMA1 (apoptosis); IKBKE (NFκB pathway). Differential expression was more than twice log 2 for TLR7, TNF, C1QA, FOXP3, and CD37.DiscussionTumour infiltrating lymphocytes were present at higher levels in samples from patients with better prognosis. Our findings indicate that tumour infiltrating lymphocyte levels and expression level of the immune system genes listed above influence pancreatic ductal adenocarcinoma prognosis. This information could be used to improve selection of best responders to immune inhibitors.
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Project description:ObjectiveOur goal is to construct an immune-related gene prognostic risk index (IRGPRI) for pancreatic adenocarcinoma (PAAD), and to clarify the immune and molecular features in IRGPRI-defined PAAD subgroups and the benefit of immune checkpoint inhibitors (ICIs) therapy.MethodThrough differential gene expression analysis, weighted gene co-expression network analysis (WGCNA), and univariate Cox regression analysis, 16 immune-related hub genes were identified using the Cancer Genome Atlas (TCGA) PAAD dataset (n = 182) and immune gene set. From these genes, we constructed an IRGPRI with the Cox regression method and the IRGPRI was verified based on the Gene Expression Omnibus (GEO) dataset (n = 45). Then, we analyzed the immune and molecular features and the benefit of ICI therapy in IRGPRI-defined subgroups.ResultsFive genes, including S100A16, CD40, VCAM1, TNFRSF4 and TRAF1 were used to construct IRGPRI. As with the results of the GEO cohort, the overall survival (OS) was more favorable in low IRGPRI patients versus high IRGPRI patients. The composite results pointed out that low IRGPRI was associated with immune response-related pathways, high level of CTLA4, low KRAS and TP53 mutation rate, more infiltration of activated memory CD4+ T cells, CD8+ T cells, and more benefits from ICIs therapy. In comparison, high IRGPRI was associated with cancer-related pathways, low expression of CTLA4, high KRAS and TP53 mutation rate, more infiltration of M2 macrophages, and less benefit from ICIs therapies.ConclusionThis IRGPRI is an encouraging biomarker to define the prognosis, immune and molecular features, and benefits from ICIs treatments in PAAD.
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Project description:Long non-coding RNAs (lncRNAs) have been reported to be prognostic factors for cancer. Ferroptosis is an iron-dependent process of programmed cell death. Here, we established a ferroptosis-related lncRNA (frlncRNA) pair signature and revealed its prognostic value in colon adenocarcinoma (COAD) by analyzing the data from The Cancer Genome Atlas (TCGA). FrlncRNAs were identified based on co-expression analysis using the Pearson correlation. Differentially expressed frlncRNAs (DEfrlncRNAs) were recognized and paired, followed by prognostic assessment using univariate Cox regression analysis. The least absolute shrinkage and selection operator (LASSO) penalized Cox analysis was used to determine and construct a risk score prognostic model, by which the receiver operating characteristic (ROC) curves for predicting the overall survival (OS) were conducted. Following the evaluation of whether it was an independent prognostic factor, correlations between the risk score model and clinicopathological characteristics, hypoxia- and immune-related factors, and somatic variants were investigated. In total, 148 DEfrlncRNA pairs were identified, 25 of which were involved in a risk score prognostic signature. The area under ROC curves (AUCs) representing the predictive effect for 1-, 3-, and 5-year survival rates were 0.860, 0.885, and 0.934, respectively. The risk score model was confirmed as an independent prognostic factor and was significantly superior to the clinicopathological characteristics. Correlation analyses showed disparities in clinicopathological characteristics, hypoxia- and immune-related factors, and somatic variants, as well as specific signaling pathways between high- and low-risk groups. The novel risk score prognostic model constructed by pairing DEfrlncRNAs showed promising clinical prediction value in COAD.
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