A Multi-Omics Network of a Seven-Gene Prognostic Signature for Non-Small Cell Lung Cancer.
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ABSTRACT:
SUBMITTER: Ye Q
PROVIDER: S-EPMC8745553 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundInhibitors targeting immune checkpoints, such as PD-1/PD-L1 and CTLA-4, have prolonged survival in small groups of non-small cell lung cancer (NSCLC) patients, but biomarkers predictive of the response to the immune checkpoint inhibitors (ICIs) remain rare.MethodsThe nonnegative matrix factorization (NMF) was performed for TCGA-NSCLC tumor samples based on the LM22 immune signature to construct subgroups. Characterization of NMF subgroups involved the single sample gene set variation analysis (ssGSVA), and mutation/copy number alteration and methylation analyses. Construction of RNA interaction network was based on the identification of differentially expressed RNAs (DERs). The prognostic predictor was constructed by a LASSO-Cox regression model. Four GEO datasets were used for the validation analysis.ResultsFour immune based NMF subgroups among NSCLC patients were identified. Genetic and epigenetic analyses between subgroups revealed an important role of somatic copy number alterations in determining the immune checkpoint expression on specific immune cells. Seven hub genes were recognized in the regulatory network closely related to the immune phenotype, and a three-gene prognosis predictor was constructed.ConclusionsOur study established an immune-based prognosis predictor, which might have the potential to select subgroups benefiting from the ICI treatment, for NSCLC patients using publicly available databases.
| S-EPMC8662860 | biostudies-literature
Project description:Background: The JBR.10 trial demonstrated significant survival benefit from adjuvant cisplatin/vinorelbine (ACT) in stage IB-II NSCLC (HR 0.69, p=0.04), but stage IB patients did not derive significant benefit (HR: 0.94, p= 0.79). We hypothesized that expression profiling could identify stage-independent subgroups of patients who might benefit from adjuvant chemotherapy. Methods: Gene expression profiling was conducted on mRNA isolated from frozen JBR.10 tumor samples (either from patients under observation [OBS], or treated with ACT). The minimum gene set that selected for the greatest separation of good and poor prognosis patient subgroups in OBS patients was identified and this gene signature was used to classify patients into high and low risk for death after surgery, and predict ACT effect. The prognostic gene signature was additionally tested on ACT patients and publicly available microarray datasets. Results: A 15-gene signature separated OBS patients into equal high and low risk subgroups with significantly different prognoses (HR 15.02, 95% CI 5.12-44.04, p=0.0001). The signature was prognostic in both stage IB and II. It was also predictive of improved survival following ACT treatment in high-risk patients (HR 0.33, 95% CI 0.17-0.63, p=0.0005), but not in low risk patients (HR 3.67, 95% CI 1.22-11.06, p=0.0133; interaction p=0.0001). The prognostic effect of the signature was validated in two independent gene expression datasets of 169 stage I-II adenocarcinoma and 106 squamous cell carcinoma patients. Conclusions: This microarray-based 15-gene prognostic expression signature is stage and histology independent and may select early stage NSCLC patients who are most likely to benefit from adjuvant chemotherapy with cisplatin/vinorelbine. Keywords: Expression profiling by microarray; prognosis prediction 90 samples
| S-ECPF-GEOD-14814 | biostudies-other
Project description:The tumor microenvironment strongly influences cancer development, progression, and metastasis. The role of carcinoma-associated fibroblasts (CAFs) in these processes and their clinical impact has not been studied systematically in non-small cell lung carcinoma (NSCLC). We established primary cultures of CAFs and matched normal fibroblasts (NFs) from 15 resected NSCLC. We demonstrate that CAFs have greater ability than NFs to enhance the tumorigenicity of lung cancer cell lines. Microarray gene-expression analysis of the 15 matched CAF and NF cell lines identified 46 differentially expressed genes, encoding for proteins that are significantly enriched for extracellular proteins regulated by the TGF-? signaling pathway. We have identified a subset of 11 genes (13 probe sets) that formed a prognostic gene-expression signature, which was validated in multiple independent NSCLC microarray datasets. Functional annotation using protein-protein interaction analyses of these and published cancer stroma-associated gene-expression changes revealed prominent involvement of the focal adhesion and MAPK signaling pathways. Fourteen (30%) of the 46 genes also were differentially expressed in laser-capture-microdissected corresponding primary tumor stroma compared with the matched normal lung. Six of these 14 genes could be induced by TGF-?1 in NF. The results establish the prognostic impact of CAF-associated gene-expression changes in NSCLC patients.
| S-EPMC3084093 | biostudies-literature
Project description:Background: The tumor microenvironment (TME) is involved in the development and progression of lung carcinomas. A deeper understanding of TME landscape would offer insight into prognostic biomarkers and potential therapeutic targets investigation. To this end, we aimed to identify the TME components of lung cancer and develop a prognostic signature to predict overall survival (OS). Methods: Expression data was retrieved from The Cancer Genome Atlas (TCGA) database and differentially expressed TME-related genes were calculated between tumor and normal tissues. Then nonnegative matrix factorization (NMF) clustering was used to identify two distinct subtypes. Results: Our analysis yielded a gene panel consisting of seven TME-related genes as candidate signature set. With this panel, our model showed that the high-risk group experienced a shorter survival time. This model was further validated by an independent cohort with data from Gene Expression Omnibus (GEO) database (GSE50081 and GSE13213). Additionally, we integrated the clinical factors and risk score to construct a nomogram for predicting prognosis. Our data suggested less immune cells infiltration but more fibroblasts were found in tumor tissues derived from patients at high-risk and those patients exhibited a worse immunotherapy response. Conclusion: The signature set proposed in this work could be an effective model for estimating OS in lung cancer patients. Hopefully analysis of the TME could have the potential to provide novel diagnostic, prognostic and therapeutic opportunities.
| S-EPMC9400803 | biostudies-literature
Project description:Background: The current staging system is imprecise for prognostic prediction of early-stage non-small cell lung cancer (NSCLC). This study aimed to develop a robust prognostic signature for early-stage NSCLC, allowing classification of patients with a high risk of poor outcome and specific treatment decision. Method: In the present study, a comprehensive genome-wide profiling analysis was conducted using a retrospective pool of early-stage NSCLC patient data from the previous datasets of Gene Expression Omnibus (GEO) including GSE31210, GSE37745, and GSE50081 and The Cancer Genome Atlas (TCGA). Cox proportional hazards models were implemented to determine the association between gene expression levels and overall patient survival in each dataset. The common genes among all datasets were selected as candidate prognostic genes. A risk score model was developed and validated using four independent datasets and the entire cohort. The Kaplan-Meier with log-rank test was used to assess survival difference. Results: A univariate Cox proportional hazards regression analysis for each dataset showed that a total of 2280 genes in GSE31210, 762 genes in GSE37745, 871 genes in GSE50081, and 666 genes in TCGA were identified as candidate protective genes, while overall 2131 genes in GSE31210, 913 in GSE37745, 1107 in GSE50081, and 997 in TCGA were identified as candidate risky genes. There were 8 common genes associated with overall survival, including 7 mRNA and 1 lncRNA. By using the Step-wise multivariate Cox analysis, an 8-gene prognostic signature (CDCP1, HMMR, TPX2, CIRBP, HLF, KBTBD7, SEC24B-AS1, and SH2B1) for early-stage NSCLC was developed. Patients in the high-risk group had shorter overall survival than those in the low-risk group. Multivariate regression and stratified analysis suggested that the prognostic power of the 8-gene signature was independent of other clinical factors. Furthermore, the 8-gene signature achieved AUC values of 0.726, 0.701, 0.725 and 0.650 in GSE31210, GSE37745, GSE50081 and TCGA, respectively. Moreover, the combination of the 8-gene signature and the stage resulted to a better patient classification for survival prediction and treatment decision. Conclusion: This study developed a robust gene signature with great value for prognostic prediction in early-stage NSCLC, which may contribute to patient classification and personalized treatment decisions.
| S-EPMC6684755 | biostudies-literature
Project description:The tumor microenvironment strongly influences cancer development, progression and metastasis. The role of carcinoma-associated fibroblasts (CAFs) in these processes and their clinical impact has not been studied systematically in non-small cell lung carcinoma (NSCLC). We established primary cultures of CAFs and matched normal fibroblasts (NFs) from 15 resected NSCLC. We demonstrate that CAFs have greater ability than NFs to enhance the tumorigenicity of lung cancer cell lines. Microarray gene expression analysis of the 15 matched CAF and NF cell lines identified 46 differentially expressed genes, encoding for proteins that are significantly enriched for extracellular proteins regulated by the TGF-beta signaling pathway. We have identified a subset of 11 genes that formed a prognostic gene expression signature, which was validated in multiple independent NSCLC microarray datasets. Functional annotation using protein-protein interaction analyses of these and published cancer stroma-associated gene expression changes revealed prominent involvement of the focal adhesion and MAPK signalling pathways. Fourteen (30%) of the 46 genes also were differentially expressed in laser-capture micro-dissected corresponding primary tumor stroma compared to the matched normal lung. Six of these 14 genes could be induced by TGF-beta1 in NF. The results establish the prognostic impact of CAF-associated gene expression changes in NSCLC patients. 30 samples: 15 primary NSCLC fibroblast cell lines, 15 normal lung fibroblast cell lines
| S-ECPF-GEOD-22862 | biostudies-other
Project description:Mutations in Kelch-like ECH-associated protein 1 (KEAP1) cause the aberrant activation of nuclear factor erythroid-derived 2-like 2 (NRF2), which leads to oncogenesis and drug resistance in lung cancer cells. Our study was designed to identify the genes involved in lung cancer progression targeted by NRF2. A series of microarray experiments in normal and cancer cells, as well as in animal models, have revealed regulatory genes downstream of NRF2 that are involved in wide variety of pathways. Specifically, we carried out individual and combinatorial microarray analysis of KEAP1 overexpression and NRF2 siRNA-knockdown in a KEAP1 mutant-A549 non-small cell lung cancer (NSCLC) cell line. As a result, we identified a list of genes which were mainly involved in metabolic functions in NSCLC by using functional annotation analysis. In addition, we carried out in silico analysis to characterize the antioxidant responsive element sequences in the promoter regions of known and putative NRF2-regulated metabolic genes. We further identified an NRF2-regulated metabolic gene signature (NRMGS) by correlating the microarray data with lung adenocarcinoma RNA-Seq gene expression data from The Cancer Genome Atlas followed by qRT-PCR validation, and finally showed that higher expression of the signature conferred a poor prognosis in 8 independent NSCLC cohorts. Our findings provide novel prognostic biomarkers for NSCLC.
| S-EPMC5642521 | biostudies-literature
Project description:PurposeThe JBR.10 trial demonstrated benefit from adjuvant cisplatin/vinorelbine (ACT) in early-stage non-small-cell lung cancer (NSCLC). We hypothesized that expression profiling may identify stage-independent subgroups who might benefit from ACT.Patients and methodsGene expression profiling was conducted on mRNA from 133 frozen JBR.10 tumor samples (62 observation [OBS], 71 ACT). The minimum gene set that was selected for the greatest separation of good and poor prognosis patient subgroups in OBS patients was identified. The prognostic value of this gene signature was tested in four independent published microarray data sets and by quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR).ResultsA 15-gene signature separated OBS patients into high-risk and low-risk subgroups with significantly different survival (hazard ratio [HR], 15.02; 95% CI, 5.12 to 44.04; P < .001; stage I HR, 13.31; P < .001; stage II HR, 13.47; P < .001). The prognostic effect was verified in the same 62 OBS patients where gene expression was assessed by qPCR. Furthermore, it was validated consistently in four separate microarray data sets (total 356 stage IB to II patients without adjuvant treatment) and additional JBR.10 OBS patients by qPCR (n = 19). The signature was also predictive of improved survival after ACT in JBR.10 high-risk patients (HR, 0.33; 95% CI, 0.17 to 0.63; P = .0005), but not in low-risk patients (HR, 3.67; 95% CI, 1.22 to 11.06; P = .0133; interaction P < .001). Significant interaction between risk groups and ACT was verified by qPCR.ConclusionThis 15-gene expression signature is an independent prognostic marker in early-stage, completely resected NSCLC, and to our knowledge, is the first signature that has demonstrated the potential to select patients with stage IB to II NSCLC most likely to benefit from adjuvant chemotherapy with cisplatin/vinorelbine.
| S-EPMC2988634 | biostudies-literature
Project description:BackgroundLung adenocarcinoma (LUAD) is one of the most common types in the world with a high mortality rate. Despite advances in treatment strategies, the overall survival (OS) remains short. Our study aims to establish a reliable prognostic signature closely related to the survival of LUAD patients that can better predict prognosis and possibly help with individual monitoring of LUAD patients.MethodsRaw RNA-sequencing data were obtained from Fudan University and used as a training group. Differentially expressed genes (DEGs) for the training group were screened. The univariate, least absolute shrinkage and selection operator (LASSO), and multivariate cox regression analysis were conducted to identify the candidate prognostic genes and construct the risk score model. Kaplan-Meier analysis, time-dependent receiver operating characteristic (ROC) curve were used to evaluate the prognostic power and performance of the signature. Moreover, The Cancer Genome Atlas (TCGA-LUAD) dataset was further used to validate the predictive ability of prognostic signature.ResultsA prognostic signature consisting of seven prognostic-related genes was constructed using the training group. The 7-gene prognostic signature significantly grouped patients in high and low-risk groups in terms of overall survival in the training cohort [hazard ratio, HR = 8.94, 95% confidence interval (95% CI)] [2.041-39.2]; P = 0.0004), and in the validation cohort (HR = 2.41, 95% CI [1.779-3.276]; P < 0.0001). Cox regression analysis (univariate and multivariate) demonstrated that the seven-gene signature is an independent prognostic biomarker for predicting the survival of LUAD patients. ROC curves revealed that the 7-gene prognostic signature achieved a good performance in training and validation groups (AUC = 0.91, AUC = 0.7 respectively) in predicting OS for LUAD patients. Furthermore, the stratified analysis of the signature showed another classification to predict the prognosis.ConclusionOur study suggested a new and reliable prognostic signature that has a significant implication in predicting overall survival for LUAD patients and may help with early diagnosis and making effective clinical decisions regarding potential individual treatment.
| S-EPMC8183047 | biostudies-literature
Project description:The tumor microenvironment strongly influences cancer development, progression and metastasis. The role of carcinoma-associated fibroblasts (CAFs) in these processes and their clinical impact has not been studied systematically in non-small cell lung carcinoma (NSCLC). We established primary cultures of CAFs and matched normal fibroblasts (NFs) from 15 resected NSCLC. We demonstrate that CAFs have greater ability than NFs to enhance the tumorigenicity of lung cancer cell lines. Microarray gene expression analysis of the 15 matched CAF and NF cell lines identified 46 differentially expressed genes, encoding for proteins that are significantly enriched for extracellular proteins regulated by the TGF-beta signaling pathway. We have identified a subset of 11 genes that formed a prognostic gene expression signature, which was validated in multiple independent NSCLC microarray datasets. Functional annotation using protein-protein interaction analyses of these and published cancer stroma-associated gene expression changes revealed prominent involvement of the focal adhesion and MAPK signalling pathways. Fourteen (30%) of the 46 genes also were differentially expressed in laser-capture micro-dissected corresponding primary tumor stroma compared to the matched normal lung. Six of these 14 genes could be induced by TGF-beta1 in NF. The results establish the prognostic impact of CAF-associated gene expression changes in NSCLC patients. 30 samples: 15 primary lung tumor stroma, 15 normal lung parenchyma
| S-ECPF-GEOD-22863 | biostudies-other