A Nomogram Integrating Ferroptosis- and Immune-Related Biomarkers for Prediction of Overall Survival in Lung Adenocarcinoma.
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ABSTRACT:
SUBMITTER: Chai M
PROVIDER: S-EPMC8441018 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The immunoscore, which is used to quantify immune infiltrates, has greater relative prognostic value than tumor, node, and metastasis (TNM) stage and might serve as a new system for classification of colorectal cancer. However, a comparable immunoscore for predicting lung adenocarcinoma (LUAD) prognosis is currently lacking. We analyzed the expression of 18 immune features by immunohistochemistry in 171 specimens. The relationship of immune marker expression and clinicopathologic factors to the overall survival (OS) was analyzed with the Kaplan-Meier method. A nomogram was developed by using the optimal features selected by least absolute shrinkage and selection operator (LASSO) regression in the training cohort (n = 111) and evaluated in the validation cohort (n = 60). The indicators integrated in the nomogram were TNM stage, neuron-specific enolase, carcino-embryonic antigen, CD8center of tumor (CT), CD8invasive margin (IM), FoxP3CT, and CD45ROCT. The calibration curve showed prominent agreement between the observed 2- and 5-year OS and that predicted by the nomogram. To simplify the nomogram, we developed a new immune-serum scoring system (I-SSS) based on the points awarded for each factor in the nomogram. Our I-SSS was able to stratify same-stage patients into different risk subgroups. The combination of I-SSS and TNM stage had better prognostic value than the TNM stage alone. Our new I-SSS can accurately and individually predict LUAD prognosis and may be used to supplement prognostication based on the TNM stage.
| S-EPMC8185867 | 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:BackgroundThis study aimed to develop a prognostic model for lung adenocarcinoma (LUAD) associated with mitotic cell cycle. The model will predict the probability of survival at different time points and serve as a reference tool to evaluate the effectiveness of LUAD treatment.MethodsA cohort of 442 patients with LUAD from the gene expression omnibus (GEO) database was randomly divided into a training group (n = 299) and a validation group (n = 99). The least absolute shrinkage and selection operator (LASSO)-COX algorithm was used to reduce the number of predictors based on the clinicopathological and RNA sequencing data to establish mutant characteristics that could predict patient survival. Additionally, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set variation analysis (GSVA), and gene set enrichment analysis (GSEA) analyses were conducted on the mutant characteristics. The performance of the developed nomogram was evaluated using calibration curves and the C-index.ResultsThe mutant characteristics had prognostic value for LUAD and acted as an independent prognostic factor. The mutant characteristics profile derived from the LASSO-COX algorithm demonstrated a significant association with overall survival in patients with LUAD. Functional annotation based on the mutant score, its involvement in the phase transition of the mitotic cell cycle, and its regulatory processes. The nomogram, which combined the mutant score with clinical factors associated with prognosis, showed robust accuracy in both the training and validation groups.ConclusionThis study presents the first individualized model that establishes a mutant score for predicting survival in LUAD. This model can be used as a predictive tool for determining 1-, 2-, 3-, and 5-year survival probabilities in patients with LUAD.
| S-EPMC10726878 | biostudies-literature
Project description:Objective: The interaction between immunity and hypoxia in tumor microenvironment (TME) has clinical significance, and this study aims to explore immune-hypoxia related biomarkers in LUAD to guide accurate prognosis of patients. Methods: The LUAD gene expression dataset was downloaded from GEO and TCGA databases. The immune-related genes and hypoxia-related genes were acquired from ImmPort and MSigDB databases, respectively. Genes related to immune and hypoxia in LUAD were obtained by intersection. The significantly prognostic genes in LUAD were obtained by LASSO and Cox regression analyses and a prognostic model was constructed. Kaplan-Meier and receiver operating characteristic curves were generated to evaluate and validate model reliability. Single-sample gene set enrichment analysis (ssGSEA) and gene set variation analysis (GSVA) were employed to analyze immune cell infiltration and pathway differences between high- and low-risk groups. Nomogram and calibration curves for survival curve and clinical features were drawn to measure prognostic value of the model. Results: The prognosis model of LUAD was constructed based on seven immune-hypoxia related genes: S100P, S100A16, PGK1, TNFSF11, ARRB1, NCR3, and TSLP. Survival analysis revealed a poor prognosis in high-risk group. ssGSEA result suggested that activities of immune cells in high-risk group was remarkably lower than in low-risk group, and GSVA result showed that immune-related pathway was notably activated in low-risk group. Conclusion: Immune-hypoxia related genes were found to be prognostic biomarkers for LUAD patients, based on which a 7-immune-hypoxia related gene-signature was constructed. This model can assess immune status of LUAD patients, and provide clinical reference for individualized prognosis, treatment and follow-up of LUAD patients.
| S-EPMC9573950 | biostudies-literature
Project description:BackgroundFerroptosis is associated with cancer initiation and progression. However, the molecular mechanism and prognostic value of ferroptosis-related genes in lung squamous cell carcinoma (LUSC) are poorly understood.MethodsThe mRNA expression profiles, methylation data, and clinical information of patients with LUSC were downloaded from TCGA and GEO database. Ferroptosis-related differentially expressed genes (DEGs) were identified between cancerous and non-cancerous tissues, and their prognostic value was systemically investigated by bioinformatic analyses.ResultsA ferroptosis-related gene signature (ALOX5, TFRC, PHKG2, FADS2, NOX1) was constructed using multivariate Cox regression analysis and represented as a risk score. Overall survival (OS) probability was significantly lower in the high-risk group than in the low-risk group (P<0.001), and receiver operating characteristic curve showed a good predictive capacity (AUC = 0.739). The risk score was an independent prognostic factor for LUSC. A nomogram was constructed to predict the OS probabilities at 1, 3, and 5 years. High-risk score was associated with increased immune infiltration, lower methylation levels, higher immune checkpoint genes expression levels, and better chemotherapy response. Cell adhesion molecules, focal adhesion, and extracellular matrix receptor interaction were the main pathways in the high-risk group. The signature was validated using the TCGA test cohort, entire TCGA cohort, GSE30219, GSE157010, GSE73403, and GSE4573 datasets. The gene disorders in patients with LUSC were validated using real-time PCR and single-cell RNA sequencing analysis.ConclusionsA ferroptosis-related gene signature was constructed to predict OS probability in LUSC. This could facilitate novel therapeutic methods and guide individualized therapy.
| S-EPMC9434561 | biostudies-literature
Project description:Background: Lung adenocarcinoma (LUAD) is a malignant tumor with high heterogeneity and poor prognosis. Ferroptosis, a form of regulated cell-death-related iron, has been proven to trigger inflammation-associated immunosuppression in the tumor microenvironment, which promotes tumor growth. Therefore, the clinical prognostic value of ferroptosis-related genes in LUAD needs to be further explored. Method: In this study, we downloaded the mRNA expression profiles and corresponding clinical data of LUAD patients from the Cancer Genome Atlas database. The least absolute shrinkage and selection operator (LASSO) Cox regression model was utilized to construct ferroptosis-related gene signature. Based on these, we established the nomograms for prognosis prediction and validated the model in the GSE72094 dataset. The cell type was identified using the CIBERSORT algorithm for estimating relative subsets of RNA transcripts, which was then used to screen significant tumor immune-infiltrating cells associated with the LUAD prognosis prediction model. Subsequently, we applied co-expression analysis to reveal the relationship between ferroptosis-related genes and significant immune cells. Results: The univariate COX regression analysis showed that 20 genes were associated with the overall survival (OS) as prognostic differentially expressed genes (DEGs) (FDR <0.05). Patients were divided into two risk groups using a 13-gene signature, with the high-risk group having a significantly worse OS than their low-risk counterparts (p < 0.001). We used receiver operating characteristic (ROC) curve analysis to confirm the predictive capacity of the signature. Besides, we identified seven pairs of ferroptosis-related genes and tumor-infiltrating immune cells associated with the prognosis of LUAD patients. Conclusion: In this study, we construct a ferroptosis-related gene signature that can be used for prognostic prediction in LUAD. In addition, we reveal a potential connection between ferroptosis and tumor-infiltrating immune cells.
| S-EPMC8360867 | biostudies-literature
Project description:BACKGROUND: Nomograms are predictive tools that are widely used for estimating cancer prognosis. The aim of this study was to develop a nomogram for the prediction of overall survival (OS) in patients diagnosed with cervical cancer. METHODS: Cervical cancer databases of two large institutions were analysed. Overall survival was defined as the clinical endpoint and OS probabilities were estimated using the Kaplan-Meier method. Based on the results of survival analyses and previous studies, relevant covariates were identified, a nomogram was constructed and validated using bootstrap cross-validation. Discrimination of the nomogram was quantified with the concordance probability. RESULTS: In total, 528 consecutive patients with invasive cervical cancer, who had all nomogram variables available, were identified. Mean 5-year OS rates for patients with International Federation of Gynecologists and Obstetricians (FIGO) stage IA, IB, II, III, and IV were 99.0%, 88.6%, 65.8%, 58.7%, and 41.5%, respectively. Seventy-six cancer-related deaths were observed during the follow-up period. FIGO stage, tumour size, age, histologic subtype, lymph node ratio, and parametrial involvement were selected as nomogram covariates. The prognostic performance of the model exceeded that of FIGO stage alone and the model's estimated optimism-corrected concordance probability was 0.723, indicating accurate prediction of OS. We present the prediction model as nomogram and provide a web-based risk calculator (http://www.ccc.ac.at/gcu). CONCLUSION: Based on six easily available parameters, a novel statistical model to predict OS of patients diagnosed with cervical cancer was constructed and validated. The model was implemented in a nomogram and provides accurate prediction of individual patients' prognosis useful for patient counselling and deciding on follow-up strategies.
| S-EPMC3464766 | biostudies-other
Project description:BackgroundWith the development of research, the importance of microRNAs (miRNAs) in the occurrence, metastasis, and prognosis of lung adenocarcinoma (LUAD) has attracted extensive attention. This study is aimed at predicting overall survival (OS) results through bioinformatics to identify novel miRNA biomarkers and hub genes.Materials and methodsThe data of LUAD-related miRNA and mRNA samples was downloaded from The Cancer Genome Atlas (TCGA) database. Upon screening and pretreatment of initial data, TCGA data were analyzed using R platform and a series of analytical tools to identify biomarkers with high specificity and sensitivity.Results7 miRNAs and 13 hub genes that had strong relation to the overall surviving status were identified in patients with LUAD. The expression of seven miRNAs (hsa-miR-19a-3p, hsa-miR-126-5p, hsa-miR-556-3p, hsa-miR-671-5p, hsa-miR-937-3p, hsa-miR-4664-3p, and hsa-miR-4746-5p) could apparently improve the OS rate of patient with LUAD. The 13 hub genes, namely, CCT6A, CDK5R1, CEP55, DNAJB4, EGLN3, HDGF, HOXC8, LIMD1, MKI67, PCP4L1, PPIL1, SCAI, and STK32A, showed a correlation with the OS status.Conclusion7 miRNAs were identified as novel biomarkers for the prognosis of patients with LUAD. This study offered a deeper comprehension of LUAD treatment and prognosis from the molecular level and helped enhance the understanding of the pathogenesis and potential molecular events of LUAD.
| S-EPMC9485713 | biostudies-literature
Project description:BackgroundLung adenocarcinoma (LUAD) is a set of heterogeneous diseases with distinct genetic and transcriptomic characteristics. Since the introduction of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society histologic classification, increasing evidence has provided insights into genomic mutations and rearrangements among individual histologic subtypes of LUAD. However, how genotypic and phenotypic features of LUAD are interconnected is not well understood.MethodsWe obtained the genomic, transcriptomic, and clinical data sets of 488 LUAD patients from The Cancer Genome Atlas database. Advanced statistical models were used to disentangle the interactions between genetic mutations and expression profiles, and to assess the alterations and changes in expression of each histologic subtype. The prognostic impacts of genetic mutations, expression profiles, and clinicopathological features were integrated to predict the outcomes of LUAD patients.ResultsFrom our data, one or more genetic mutations correlate with expression levels of 6054/18175 (33.3%) genes and explain 8-40% of observed variability in LUAD. The genetic mutations and expression profiles varied remarkably among the histologic subtypes of LUAD, which helped to explain the different prognostic impact based on subtype classification. Genomic, transcriptomic, and clinical data were all shown to have utility for predicting overall and recurrence-free survival, with the largest contribution from the transcriptome.ConclusionOur prediction model integrating genetic mutations, expression profiles, and clinicopathological features exhibited superior accuracy over the current tumor node metastasis staging system to prognosticate outcomes of patients with LUAD (overall survival 67% vs. 55%, recurrence-free survival 57% vs. 49%; P?<?0.01).
| S-EPMC6501026 | biostudies-literature
Project description:BackgroundLung adenocarcinoma (LUAD) is the most common type of Non-small-cell lung cancer (NSCLC). Distant metastasis of lung adenocarcinoma reduces the survival rate. we aim to develop a nomogram in order to predict the survival of patients with metastatic lung adenocarcinoma.MethodsWe retrospectively collected patients who were initially diagnosed as metastatic LUAD from 2010 to 2015 from SEER database. Based on the multivariate and univariate Cox regression analysis of the training cohorts, independent prognostic factors were assessed. The nomogram prediction model was then constructed based on these prognostic factors to predict the overall survival at 12, 24 and 36 months after surgery. Nomogram were identified and calibrated by c-index, time-dependent receiver operating characteristic curve (time-dependent AUC) and calibration curve. Decision curve analysis (DCA) was used to quantify the net benefit of the nomogram at different threshold probabilities, and to better compare with the TNM staging system, we calculated the c-index of this nomogram as well as the net reclassification improvement (NRI) and the integrated discrimination improvement (IDI).ResultA total of 1102 patients with metastatic LUAD who met the requirements were included for analysis. They were randomly divided into 774 in the training cohorts and 328 in the validation cohorts. As can be seen from the calibration plots, the predicted nomogram and the actual observations in both of the training and validation cohorts were generally consistent. The time dependent AUC values of 12 months, 24 months and 36 months were 0.707, 0.674 and 0.686 in the training cohorts and 0.690, 0.680 and 0.688 in the verification cohorts, respectively. C-indexes for the training and validation cohorts were 0.653 (95%CI 0.626-0.68)and 0.663 (95%CI 0.626-1), respectively. NRI and IDI show that the model is more clinical applicable than the existing staging system. In addition, our risk scoring system based on Kaplan Meier (K-M) survival curve can accurately divide patients into three hierarchy risk groups.ConclusionThis has led to the development and validation of a prognostic nomogram to assist clinicians in determining the prognosis of patients with metastatic lung adenocarcinoma after primary site surgery.
| S-EPMC9413074 | biostudies-literature