A novel ferroptosis-related gene signature for prognostic prediction of patients with lung adenocarcinoma.
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ABSTRACT: Background
Lung adenocarcinoma (LUAD) is a heterogeneous disease characterized by high mortality and poor prognosis. Ferroptosis, a newly discovered iron-dependent type of cell death, has been found to play a crucial role in the development of cancers. However, little is known about the prognostic value of ferroptosis-related genes (FRGs) in LUAD.Methods
In the present study, RNA-seq transcriptome data of LUAD patients were obtained from The Cancer Genome Atlas (TCGA) database. Cox regression analysis was used to construct a multigene signature. Kaplan-Meier survival and receiver operating characteristic (ROC) curves were utilized to assess the prognostic prediction efficiency of the constructed survival model. LUAD patients from the GSE30219 dataset were used for validation.Results
We found 46 differentially expressed FRGs between LUAD and adjacent normal tissues. Via univariate and multivariate Cox regression analyses, 5 differentially expressed FRGs were identified as being highly correlated with LUAD. Patients were divided into low- and high-risk groups according to the risk score. We found that the overall survival (OS) of patients in the high-risk group was significantly worse than that of their low-risk counterparts. (P < 0.0001 in the TCGA dataset and P = 0.044 in the GSE30219 cohort). In addition, gene set variation analysis (GSVA) of the tumor microenvironment of the two groups may explain the different survival of LUAD patients.Conclusions
Our study identified a novel FRG signature that could be used to evaluate and predict the prognosis of LUAD patients, which might provide a new therapeutic target for the treatment of LUAD patients.
SUBMITTER: Jin J
PROVIDER: S-EPMC8266333 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundLung cancer has been the focus of attention for many researchers in recent years due to its leading contribution to cancer-related death worldwide, with lung adenocarcinoma (LUAD) being the most common histological type. Ferroptosis, a novel iron-dependent form of regulated cell death, can be induced by sorafenib. Emerging evidence shows that triggering ferroptosis has potential as a cancer therapy. This work aimed to build a ferroptosis-related gene signature for predicting the outcome of LUAD.MethodsThe TCGA-LUAD dataset was set as the training cohort, and the GSE72094 and GSE68465 datasets were set as the validation cohorts. Sixty-two ferroptosis-related genes were retrieved from the literature. A univariate Cox regression model was constructed for the training cohort to preliminarily screen for potential prognostic ferroptosis-related genes. A gene signature was generated from a LASSO Cox regression model and assessed with the training and validation cohorts through Kaplan-Meier, Cox, and ROC analyses. In addition, the correlation between the risk score and autophagy-related genes was determined by the Pearson test. Finally, GSEA and immune infiltrating analyses were performed to better study the functional annotation of the signature and the role of each kind of immune cell.ResultsA ten-gene signature was constructed from the training cohort and validated in three cohorts by Kaplan-Meier and Cox regression analyses, revealing its independent prognostic value in LUAD. Moreover, a ROC analysis conducted with all cohort data confirmed the predictive ability of the ten-gene signature for LUAD prognosis. A total of 62.85% (308/490) of autophagy-related genes were found to be significantly correlated with risk scores. GSEA detailed the exact pathways related to the gene signature, and immune-infiltrating analyses identified crucial roles for resting mast cells and resting dendritic cells in the prognosis of LUAD.ConclusionsWe identified a novel ferroptosis-related ten-gene signature (PHKG2, PGD, PEBP1, NCOA4, GLS2, CISD1, ATP5G3, ALOX15, ALOX12B, and ACSL3) that can accurately predict LUAD prognosis and is closely linked to resting mast cells and resting dendritic cells.
| S-EPMC8339871 | biostudies-literature
Project description:Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Most patients are diagnosed at an advanced stage, therefore it is crucial to identify novel prognostic biomarkers for LUAD. As important regulatory cells, inducible regulatory T cells (iTregs) play a vital role in immune suppression and are important for the maintenance of immune homeostasis. This study explored the prognostic value and therapeutic effects of iTreg-related genes in LUAD. Data for LUAD patients, including immune infiltration data, RNA sequencing data, and clinical features, were acquired from The Cancer Genome Atlas, Gene Expression Omnibus, and Tumor Immune Single-cell Hub 2 databases. Immune-related subgroups with different infiltration patterns and iTreg-related genes were identified through univariate and multivariate Cox regression analyses and weighted correlation network analysis. Functional enrichment analyses were performed to explore the underlying mechanisms of iTreg-related genes. A prognostic risk signature was constructed using Cox regression analysis with the least absolute shrinkage and selection operator penalty. The ESTIMATE algorithm was applied to determine the immune status of LUAD patients. We applied the constructed signature to predict chemosensitivity and performed single-cell RNA sequencing analysis. The infiltration of iTregs was identified as an independent factor for predicting patient outcomes. We constructed a prognostic signature based on seven iTreg-related genes (GIMAP5, SLA, MS4A7, ZNF366, POU2AF1, MRPL12, and COL5A1), which was applied to subdivide patients into high- and low-risk subgroups. Our results revealed that patients in the iTreg-related low-risk subgroup had a better prognosis and possibly greater sensitivity to traditional chemotherapy. Our study provides a novel iTreg-related signature to elucidate the mechanisms underlying LUAD prognosis and promote individualized chemotherapy treatment.
| S-EPMC10823293 | biostudies-literature
Project description:Lung adenocarcinoma (LUAD) has been the major cause of tumor-associated mortality in recent years and has a poor prognosis. Pyroptosis is regulated via the activation of inflammasomes and participates in tumorigenesis. However, the effects of pyroptosis-related lncRNAs (PRlncRNAs) on LUAD have not yet been completely elucidated. Therefore, we attempted to systematically explore patterns of cell pyroptosis to establish a novel signature for predicting LUAD survival. Based on TCGA database, we set up a prognostic model by incorporating PRlncRNAs with differential expression using Cox regression and LASSO regression. Kaplan-Meier analysis was conducted to compare the survival of LUAD patients. We further simplified the risk model and created a nomogram to enhance the prediction of LUAD prognosis. Altogether, 84 PRlncRNAs with differential expression were discovered. Subsequently, a new risk model was constructed based on five PRlncRNAs, GSEC, FAM83A-AS1, AL606489.1, AL034397.3 and AC010980.2. The proposed signature exhibited good performance in prognostic prediction and was related to immunocyte infiltration. The nomogram exactly forecasted the overall survival of patients and had excellent clinical utility. In the present study, the five-lncRNA prognostic risk signature and nomogram are trustworthy and effective indicators for predicting the prognosis of LUAD.
| S-EPMC8806662 | biostudies-literature
Project description:Lung adenocarcinoma (LUAD) is the most diagnosed subtype of lung cancer; ferroptosis is widely involved in the pathological cell death associated with various cancers, including lung cancer. However, the comprehensive relationship between ferroptosis and LUAD is little known in molecular levels until now. In the present study, 513 LUAD patients could be aggregated into three clusters by consensus clustering based on RNA sequencing data of 291 ferroptosis-related genes (FRGs) in The Cancer Genome Atlas (TCGA) database; cluster2 had significant survival advantage compared to the other two clusters. A novel prognostic model of 8 differential FRGs was constructed to effectively divide LUAD patients into high- or low-risk group according to the risk scores by the Cox and LASSO regression analyses. The overall survival of LUAD patients in the high-risk group was significantly worse in the TCGA and GEO cohorts. Moreover, patients with radiation therapy or high clinical stage had obviously higher risk scores. We validated the differential mRNA and protein expression of four FRGs in paired tumor and normal samples from our clinical cohort. Our study constructed a novel FRG signature to predict the prognosis of LUAD patients, which might provide a new prognostic tool and potential therapeutic targets for LUAD.
| S-EPMC8928751 | biostudies-literature
Project description:Lung adenocarcinoma is the most common histological subtype of lung cancer which causes the largest number of deaths worldwide. Exploring reliable prognostic biomarkers based on biological behaviors and molecular mechanisms is essential for predicting prognosis and individualized treatment strategies. Ferroptosis is a recently discovered type of regulated cell death. We downloaded ferroptosis-related genes from the literature and collected transcriptome profiles of lung adenocarcinoma from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to construct ferroptosis-related gene-pair matrixes. Then, we performed the least absolute shrinkage and selection operator regression to build our prognostic ferroptosis-related gene-pair index (FRGPI) in TCGA training matrix. Our study validated FRGPI through ROC curves, Kaplan-Meier methods, and Cox hazard analyses in TCGA and GEO cohorts. The optimal cut-off 0.081 stratified patients into low- and high-FRGPI groups. Also, the low-FRGPI group had a significantly better prognosis than the high-FRGPI group. For further study, we analyzed differentially expressed ferroptosis-related genes between high- and low-FRGPI groups. Gene set enrichment analysis (GSEA) enrichment maps indicated that "cell cycle," "DNA replication," "proteasome," and "the p53 signaling pathway" were significantly enriched in the high-FRGPI group. The high-FRGPI group also presented higher infiltration of M1 macrophages. Meanwhile, there were few differences in adaptive immune responses between high- and low-FRGPI groups. In conclusion, FRGPI was an independent prognostic biomarker which might be beneficial for guiding individualized tumor therapy.
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Project description:ObjectiveLung cancer is the most common malignancy worldwide and exhibits both high morbidity and mortality. In recent years, scientists have made substantial breakthroughs in the early diagnosis and treatment of lung adenocarcinoma (LUAD), however, patient prognosis still shows vast individual differences. In this study, bioinformatics methods were used to identify and analyze ferroptosis-related genes to establish an effective signature for predicting prognosis in LUAD patients.MethodsThe gene expression profiles of LUAD patients with complete clinical and follow-up information were downloaded from two public databases, univariate Cox regression and multivariate Cox regression analysis were used to obtain ferroptosis-related genes for constructing the prognos tic risk model, AUC and calibration plot were used to evaluate the predictive accuracy of the FRGS and nomogram.ResultsA total of 74 ferroptosis-related differentially expressed genes (DEGs) were identi fied between LUAD and normal tissues from The Cancer Genome Atlas (TCGA) database. A five-gene panel for prediction of LUAD prognosis was established by multivariate regression and was verified using the GSE68465 cohort from the Gene Expression Omnibus (GEO) database. Patients were divided into two different risk groups according to the median risk score of the five genes. Based on Kaplan-Meier (KM) analysi, the OS rate of the high-risk group was markedly worse than that of the low-risk group. We also found that risk score was an independent prognostic indicator. The receiver operating characteristic ROC curve showed that the proposed model had good prediction ability. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses indicated that risk score was prominently enriched in ferroptosis processes. Moreover, at the score of immune-associated gene sets, significant differences were found between the two risk groups.ConclusionsThis study demonstrated that ferroptosis-related gene signatures can be used as a potential predictor for the prognosis of LUAD, thus providing a novel strategy for individualized treatment in LUAD patients.
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Project description:Lung cancer has been identified as one of the deadliest malignant tumors worldwide. Mounting evidence suggests that ferroptosis is a well-known non-apoptotic cell death process that participates in pathological mechanisms and is a new cancer treatment strategy. Aberrantly expressed long non-coding RNAs (lncRNAs) that drive lung cancer progression have attracted increasing attention. Herein, we explored the prognostic significance of ferroptosis-related lncRNAs in lung cancer patients. LUAD gene expression patterns and clinicopathological data were downloaded from The Cancer Genome Atlas (TCGA) database. Based on LASSO-Cox regression, A 14 ferroptosis-related differentially expressed lncRNAs (FRDELs) signature was constructed. Subsequently, a nomogram model for predicting the prognosis of LUAD patients was constructed based on clinicopathological data and the 14 - FRDELs signature. The signature was shown to be correlated with tumor mutational burden (TMB) and immune cell infiltration within the tumor microenvironment. Furthermore, Gene Set Enrichment Analysis (GSEA) confirmed that the signature was correlated with LUAD-related biological functions such as the P53 signaling pathway, DNA replication, and cell cycle. The roles and mechanisms of PACERR in the signature were explored by si-lncRNA-mediated knockdown and transfection-mediated overexpression via in vitro experiments in A549 and H1299 cells. PACERR was significantly upregulated in A549 and H1299 cells, and higher expression promoted LUAD cell proliferation, migration, and invasion via in vitro experiments, while knockdown of PACERR presented the opposite effects. In conclusion, our study provided information regarding ferroptosis-related lncRNA expression and established a prognostic nomogram based on 14 FRDELs to predict overall survival in LUAD accurately. Additionally, our results in vitro revealed that PACERR played an oncogenic role in LUAD proliferation and metastasis, which provides mechanistic insights into the roles of ferroptosis-related lncRNA in LUAD progression and that it may be a potential biomarker for LUAD treatment.
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Project description:ObjectiveTelomere-related genes (TRGs) play a critical role in various types of tumors. However, there is a lack of comprehensive exploration of their relevance in lung cancer. This research aimed to verify the relationship between TRGs gene expression and the prognosis of patients with lung adenocarcinoma (LUAD), as well as the prediction of drug treatment efficiency.MethodsA total of 2093 TRGs were acquired from TelNet. The clinical information including age, tumor stage, follow up and outcome (death/survival) and TRGs expression profile of LUAD were obtained from the patients in The Cancer Genome Atlas (TCGA) database and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. The two databases were used to construct and verify a prognostic model based on the expression of hubTRGs. The tumor mutation burden, immune infiltration and subtypes, as well as IC50 prediction of multiple targeted drugs were also evaluated in TRGs-divided risk groups.ResultsA total of 335 TRGs were significantly differentially expressed in LUAD as compared with normal control. Among them, 9 TRGs (ABCC2, ABCC8, ALDH2, FOXP3, GNMT, JSRP1, MACF1, PLCD3, SULT4A1) were finally identified as hubGenes and used to construct a TRG risk score. The TRG risk score showed favorable performance in constructing a prognostic nomogram in predicting survival of LUAD, and the ROC curves at 1, 3 and 5 years were plotted and the AUROC values were 0.743, 0.754 and 0.735, respectively. Higher TRGs risk score correlated with worse immune subtypes and higher tumor mutation burden in LUAD tissues. In addition, the patients in TRG high risk group harbored a lower TIDE score which indicated potentially better response to immunotherapy.ConclusionThis study proposed a broad molecular signature of telomere-related genes that can be used in further functional and therapeutic investigations, and also represents an integrated modality for characterizing critical molecules when exploring novel targets for lung cancer immunotherapy.
| S-EPMC10497012 | biostudies-literature
Project description:Background: Ferroptosis is an iron-dependent programmed cell death process. Recent studies have found that ferroptosis inducers hold promising potential in the treatment of lung adenocarcinoma (LUAD). However, the comprehensive analysis about the prognostic value of ferroptosis-related genes in LUAD remains to be elucidated. Methods: The RNA sequencing data and corresponding clinical information were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A total of 259 ferroptosis-related genes were extracted from FerrDb website. The ferroptosis-related prognostic signature was developed by least absolute shrinkage and selection operator (LASSO) Cox regression analysis in TCGA LUAD cohort, and then validated by 5 independent GEO cohorts. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were performed to identify the difference in biological processes and functions between different risk groups. The expression levels of core prognostic genes were then verified in LUAD samples by immunohistochemistry (IHC) and erastin-treated LUAD cell lines by real-time polymerase chain reaction (PCR). The potential roles of GPX2 and DDIT4 as ferroptosis drivers in LUAD cell line were further confirmed by in vitro experiments. Results: A total of 20 intersecting genes between 70 ferroptosis-related DEGs and 45 potential prognostic genes were obtained for LASSO Cox regression analysis. The ferroptosis-related prognostic signature was developed by 7 core prognostic DEGs, and stratified LUAD patients into two risk groups. Kaplan-Meier analysis showed that the overall survival (OS) of LUAD patients in the high-risk group was significantly worse than that of the low-risk group. External validation of 5 independent GEO cohorts further confirmed that the ferroptosis-related prognostic signature was an ideal biomarker for predicting the survival of LUAD patients. Significant enrichment of fatty acid metabolism and cell cycle-related pathways were found in different risk groups. The expression patterns of 7 core prognostic genes in LUAD and adjacent normal lung tissues were validated by IHC, which was almost consistent with the results from public database. Furthermore, the changes related to cell cycle and ferroptosis after erastin treatment were also validated in LUAD cell lines. In addition, silencing GPX2 or DDIT4 could partially reverse the erastin-induced ferroptosis. Conclusion: In summary, the ferroptosis-related prognostic signature based on 7 core prognostic DEGs indicated superior predictive performance of LUAD patients. Targeting ferroptosis holds potential to be a therapeutic alternative for LUAD.
| S-EPMC8294813 | biostudies-literature
Project description:Ferroptosis is a newly discovered, iron-dependent, nonapoptotic form of programmed cell death that plays an important role in the development of lung adenocarcinoma (LUAD). In this study, ferroptosis-related genes (FRGs) were identified from the FerrDb dataset, and the mRNA expression profiles and corresponding clinical data of LUAD patients were downloaded from the University of California, Santa Cruz (UCSC) databases. Data from LUAD patients from the Gene Expression Omnibus (GEO) dataset were used as the verification set. Cox and Lasso regression analyses were used to screen the FRGs with prognostic value, and six prognostic-related FRGs were selected to construct prognostic risk score signatures. Immunohistochemistry was utilized to manifest the differential expression of six FRGs in tumor and normal tissues at the protein level. Functional enrichment analysis indicated that FRGs were mainly enriched in ferroptosis-related pathways. Patients were divided into high- and low-risk groups based on the median risk score. The Kaplan-Meier survival curves confirmed that patients with a high score had significantly worse overall survival. Receiver operating characteristic (ROC) curves proved that the prognostic signature has good sensitivity and specificity for predicting the prognosis of LUAD patients. Nomogram analysis showed that the prognostic signature has potential independent prognostic value. Moreover, the prognostic signature has been shown to be significantly associated with some clinical features (T stage, N stage, tumor stage, and survival status) as well as many immune-activity-related genes and immune-checkpoint-related genes. In conclusion, we constructed a prognostic signature consisting of six FGRs, which can provide a reference for predicting the prognosis of LUAD patients.
| S-EPMC8564102 | biostudies-literature