Identification of a Novel Tumor Microenvironment Prognostic Signature for Advanced-Stage Serous Ovarian Cancer.
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ABSTRACT:
SUBMITTER: Zheng M
PROVIDER: S-EPMC8268985 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe tumor microenvironment (TME) regulates the proliferation and metastasis of solid tumors and the effectiveness of immunotherapy against them. We investigated the prognostic role of TME-related genes based on transcriptomic data of bladder urothelial carcinoma (BLCA) and formulated a prediction model of TME-related signatures.MethodsMolecular subtypes were identified using the non-negative matrix factorization (NMF) algorithm based on TME-related genes from the TCGA database. TME-related genes with prognostic significance were screened with univariate Cox regression analysis and lasso regression. Nomogram was developed based on risk genes. Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used for inner and outer validation of the model. Risk scores (RS) of patients were calculated and divided into high-risk group (HRG) and low-risk group (LRG) to compare the differences in clinical characteristics and PD-L1 treatment responsiveness between HRG and LRG.ResultsWe identified two molecular subtypes (C1 and C2) according to the NMF algorithm. There were significant differences in overall survival (OS) (p<0.05), progression-free survival (PFS) (p<0.05), and immune cell infiltration between the two subtypes. A total of eight TME-associated genes (CABP4, ZNF432, BLOC1S3, CXCL11, ANO9, OAS1, FBN2, CEMIP) with independent prognostic significance were screened to build prognostic risk models. Age (p<0.001), grade (p<0.001), and RS (p<0.001) were independent predictors of survival in BLCA patients. The developed RS nomogram was able to predict the prognosis of BLCA patients at 1, 3, and 5 years more potentially than the models of other investigators according to ROC and DCA. RS showed significantly higher values (p = 0.047) in patients with stable disease (SD)/progressive disease (PD) compared to patients with complete response (CR)/partial response (PR).ConclusionsWe successfully clustered and constructed predictive models for TME-associated genes and helped guide immunotherapy strategies.
| S-EPMC8921452 | biostudies-literature
Project description:The development of immunotherapy has greatly changed the advanced-stage non-small-cell lung cancer (NSCLC) treatment landscape. The complexity and heterogeneity of tumor microenvironment (TME) lead to discrepant immunotherapy effects among patients at the same pathologic stages. This study is aimed at exploring potential biomarkers of immunotherapy and accurately predicting the prognosis for advanced NSCLC patients. RNA-seq data and clinical information on stage III/IV NSCLC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). In TCGA-NSCLC with stage III/IV (n = 192), immune scores and stromal scores were calculated by using the ESTIMATE algorithms. Univariate, LASSO, and multivariate Cox regression analyses were performed to screen prognostic TME-related genes (TMERGs) and constructed a gene signature risk score model. It was validated in external dataset including GSE41271 (n = 91) and GSE81089 (n = 36). Additionally, a nomogram incorporating TMERG signature risk score and clinical characteristics was established. Further, we accessed the proportion of 22 types of tumor-infiltrating immune cells (TIIC) from the CIBERSORT website and analyzed the difference between two risk groups. OS of patients with high immune/stromal scores were higher (log-rank P = 0.044/log-rank P = 0.048). Multivariate Cox regression identified six prognostic TMERGs, including CD200, CHI3L2, CNTN1, CTSL, FYB1, and SLC52A1. We developed a six-gene risk score model, which was validated as an independent prognostic factor for OS (HR: 3.32, 95% CI: 2.16-5.09). Time-ROC curves showed useful discrimination for TCGA-NSCLC cohort (1-, 2-, and 3-year AUCs were 0.718, 0.761, and 0.750). The predictive robustness was validated in the external dataset. The C-index and 1-, 2-, and 3-year AUCs of nomogram were the largest, which demonstrated the nomogram had the greatest predictive accuracy and effectiveness and could be used for clinical guidance. Besides, the increased infiltration of T cells regulatory (Tregs) and macrophages M2 in the high-risk group suggested that chronic inflammation may reduce survival probability in patients with advanced NSCLC. We conducted a comprehensive analysis of the tumor microenvironment and identified the TMERG signature, which could predict prognosis accurately and provide a reference for the personalized immunotherapy for advanced NSCLC patients.
| S-EPMC8028741 | biostudies-literature
Project description:Purpose: Considerable evidence suggests that autophagy plays a crucial role in the biological processes of ovarian cancer. The aim of this study was to develop a novel autophagy-related prognostic signature for serous ovarian cancer. Methods: A univariate Cox proportional regression model was used to analyze mRNA microarray and clinical data in The Cancer Genome Atlas (TCGA) for the purpose of selecting autophagy-related prognostic genes. A multivariate Cox proportional regression model and the survival analysis were used to develop an eight-gene prognostic signature. The multivariate Cox and stratification analysis suggested that this signature was an independent prognostic factor for serous ovarian cancer patients. Bioinformatics functions were investigated by a principal components analysis and gene set enrichment analysis (GSEA). Finally, the correlation between the prognostic signature and gene mutation status was further analyzed in serous ovarian cancer, and especially with regard to the mutation status of BRCA1 and BRCA2 (BRCA1/2) genes. Results: Distinctly different autophagy-related gene expression profiles were identified in normal ovarian tissues and serous ovarian cancer tissues. We profiled an autophagy-related gene set and identified eight genes with significant prognostic values for serous ovarian cancer. Subsequently, an autophagy-related ovarian cancer risk signature was constructed, and patients at a high-risk or low-risk for poor prognosis were identified based on their signature. High-risk patients had significantly shorter overall survival (OS) and disease-free survival (DFS) times than low-risk patients. GSEA results suggested an enhanced intensity of autophagy regulation in high-risk patients when compared with low-risk patients. When studied as an independent prognostic factor for serous ovarian cancer, the significant prognostic value of this signature could be seen in the stratified cohorts. For clinical use, we developed a nomogram that included the prognostic classifier and seven clinical risk factors. Additionally, we identified the 10 most frequently mutated genes found in serous ovarian cancer patients, and analyzed them for their differences in high-risk and low-risk patients. Among 293 patients, 62 had BRCA1/2 gene mutations, and this result was significantly correlated with the autophagy-related prognostic signature. Conclusions: Our findings suggest that the eight-gene autophagy-related signature could serve as an independent prognostic indicator for cases of serous ovarian cancer.
| S-EPMC6218776 | biostudies-literature
Project description:Growing evidence suggest that transcription factors (TFs) play vital roles in serous ovarian cancer (SOC). In the present study, TFs mRNA expression profiles of 564 SOC subjects in the TCGA database, and 70 SOC subjects in the GEO database were screened. A 17-TFs related prognostic signature was constructed using lasso cox regression and validated in the TCGA and GEO cohorts. Consensus clustering analysis was applied to establish a cluster model. The 17-TFs related prognostic signature, risk score and cluster models were effective at accurately distinguishing the overall survival of SOC. Analysis of genomic alterations were used to elaborate on the association between the 17-TFs related prognostic signature and genomic aberrations. The GSEA assay results suggested that there was a significant difference in the inflammatory and immune response pathways between the high-risk and low-risk score groups. The potential immune infiltration, immunotherapy, and chemotherapy responses were analyzed due to the significant difference in the regulation of lymphocyte migration and T cell-mediated cytotoxicity between the two groups. The results indicated that patients with low-risk score were more likely to respond anti-PD-1, etoposide, paclitaxel, and veliparib but not to gemcitabine, doxorubicin, docetaxel, and cisplatin. Also, the prognostic nomogram model revealed that the risk score was a good prognostic indicator for SOC patients. In conclusion, we explored the prognostic values of TFs in SOC and developed a 17-TFs related prognostic signature to predict the survival of SOC patients.
| S-EPMC8010122 | biostudies-literature
Project description:BackgroundOvarian cancer is one of the lethal gynecological diseases in women. However, using tumor microenvironment related genes to identify prognostic signature of ovarian cancer has not been discussed in detail.MethodsThe mRNA profiles of 386 ovarian cancer patients were retrieved from The Cancer Genome Atlas. Univariate Cox regression and LASSO Cox regression analyses were performed and 14 optimized prognostic genes related to tumor microenvironment were identified.ResultsThe multivariate Cox hazards regression showed risk score was an independent prognostic signature for ovarian cancer. Nomogram model could reliably predict the patients' survival. Furthermore, M1 macrophages, M2 macrophages, and follicular helper T cells, differentially expressed between the high- and low-risk groups, were found to be associated with the risk score.ConclusionCTL-associated antigen 4 (CTLA4) and indoleamine 2,3-Dioxygenase 1 (IDO1), which were previously shown to be important immune checkpoints, probably contribute to the immunosuppressive microenvironment aberration. This study may shed light on the prognosis of ovarian cancer.
| S-EPMC8284754 | biostudies-literature
Project description:Ovarian cancer is one of the leading causes of deaths among patients with gynecological malignancies worldwide. In order to identify prognostic markers for ovarian cancer, we performed RNA-sequencing and analyzed the transcriptome data from 51 patients who received conventional therapies for high-grade serous ovarian carcinoma (HGSC). Patients with early-stage (I or II) HGSC exhibited higher immune gene expression than patients with advanced stage (III or IV) HGSC. In order to predict the prognosis of patients with HGSC, we created machine learning-based models and identified USP19 and RPL23 as candidate prognostic markers. Specifically, patients with lower USP19 mRNA levels and those with higher RPL23 mRNA levels had worse prognoses. This model was then used to analyze the data of patients with HGSC hosted on The Cancer Genome Atlas; this analysis validated the prognostic abilities of these two genes with respect to patient survival. Taken together, the transcriptome profiles of USP19 and RPL23 determined using a machine-learning model could serve as prognostic markers for patients with HGSC receiving conventional therapy.
| S-EPMC8391231 | biostudies-literature
Project description:Ovarian cancer is one of the leading causes of death among patients with gynecological malignancies worldwide. To identify prognostic markers for ovarian cancer, we performed RNA-sequencing and analyzed the transcriptome data from 51 patients who received conventional therapies for high-grade serous ovarian carcinoma (HGSC). Patients with early-stage (I or II) HGSC exhibited higher immune gene expression than patients with advanced stage (III or IV) HGSC. To predict the prognosis of HGSC patients, we created machine learning-based models and identified RPL23 and USP19 as candidate prognostic markers. Specifically, patients with higher RPL23 mRNA levels had a worse prognosis and patients with higher USP19 mRNA levels had a better prognosis. This model was then used to analyze HGSC patient data hosted on The Cancer Genome Atlas; this exercise validated the prognostic abilities of these two genes with respect to patient survival. Taken together, the transcriptome profiles of RPL23 and USP19 determined using a machine-learning model could serve as prognostic markers in HGSC patients receiving conventional therapy.
2021-08-09 | GSE165808 | GEO
Project description:Background: In recent years, immunotherapy has changed the therapeutic landscape of hepatocellular carcinoma (HCC). Since the efficacy of immunotherapy is closely related to the tumor microenvironment (TME), in this study, we constructed a prognostic model based on TME to predict the prognosis and immunotherapy effect of HCC patients. Methods: Transcriptome and follow-up data of 374 HCC patients were acquired from the TCGA Cancer Genome Atlas (TCGA) database. The immune/stromal/estimate scores (TME scores) and tumor purity were calculated using the ESTIMATE algorithm and the module most associated with TME scores were screened by the weighted gene co-expression network analysis (WGCNA). A TME score-related prognostic model was constructed and patients were divided into a high-risk group and a low-risk group. Kaplan-Meier survival curves and receiver operator characteristic curve (ROC) were used to evaluate the performance of the TME risk prognostic model and validated with the external database International Cancer Genome Consortium (ICGC) cohort. Combined with clinicopathologic factors, a prognostic nomogram was established. The nomogram's ability to predict prognosis was assessed by ROC, calibration curve, and the decision curve analysis (DCA). Gene Set Enrichment Analyses (GSEA) were conducted to explore the underlying biological functions and pathways of this risk signature. Moreover, the possible correlation of risk signature with TME immune cell infiltration, immune checkpoint inhibitor (ICI) treatment response, single-nucleotide polymorphisms (SNPs), and drug sensitivity were assessed. Finally, real-time PCR was used to verify the gene expression levels in normal liver cells and cancer cells. Results: KM survival analysis results indicated that high immune/stromal/estimate score groups were closely associated with a better prognosis, while the tumor purity showed a reverse trend (p < 0.01). WGCNA demonstrated that the yellow module was significantly correlated with the TME score. The 5-genes TME risk signature was built to predict the prognosis of patients with HCC including DAB2, IL18RAP, RAMP3, FCER1G, and LHFPL2. Patients with a low-risk score have higher levels of tumor-infiltrating immune cells and higher expression of immune checkpoints, which may be more sensitive to immunotherapy. Conclusion: It provided a theoretical basis for predicting the prognosis and personalized treatment of patients with HCC.
| S-EPMC9280086 | biostudies-literature
Project description:Background: Ovarian cancer is highly malignant and has a poor prognosis in the advanced stage. Studies have shown that infiltration of tumor microenvironment cells, immune cells and stromal cells has an important impact on the prognosis of cancers. However, the relationship between tumor microenvironment genes and the prognosis of ovarian cancer has not been studied. Methods: Gene expression profiles and SNP data of ovarian cancer were downloaded from the TCGA database. Cluster analysis, WGCNA analysis and univariate survival analysis were used to identify immune microenvironment genes as prognostic signatures for predicting the survival of ovarian cancer patients. External data were used to evaluate the signature. Moreover, the top five significantly correlated genes were evaluated by immunohistochemical staining of ovarian cancer tissues. Results: We systematically analyzed the relationship between ovarian cancer and immune metagenes. Immune metagenes expression were associated with prognosis. In total, we identified 10 genes related to both immunity and prognosis in ovarian cancer according to the expression of immune metagenes. These data reveal that high expression of ETV7 (OS, HR = 1.540, 95% CI 1.023-2.390, p = 0.041), GBP4 (OS, HR = 1.834, 95% CI 1.242-3.055, p = 0.004), CXCL9 (OS, HR = 1.613, 95% CI 1.080 -2.471, p = 0.021), CD3E (OS, HR = 1.590, 95% CI 1.049 -2.459, p = 0.031), and TAP1 (OS, HR = 1.766, 95% CI 1.163 -2.723, p = 0.009) are associated with better prognosis in patients with ovarian cancer. Conclusion: Our study identified 10 immune microenvironment genes related to the prognosis of ovarian cancer. The list of tumor microenvironment-related genes provides new insights into the underlying biological mechanisms driving the tumorigenesis of ovarian cancer.
| S-EPMC8155613 | biostudies-literature
Project description:Identification of gene expression profiles of cancer stem cells may have significant implications in the understanding of tumor biology and for the design of novel treatments targeted toward these cells. Here we report a potential ovarian cancer stem cell gene expression profile from isolated side population of fresh ascites obtained from women with high-grade advanced stage papillary serous ovarian adenocarcinoma. Affymetrix U133 Plus 2.0 microarrays were used to interrogate the differentially expressed genes between side population (SP) and main population (MP), and the results were analyzed by paired T-test using BRB-ArrayTools. We identified 138 up-regulated and 302 down-regulated genes that were differentially expressed between all 10 SP/MP pairs. Microarray data was validated using qRT-PCR and17/19 (89.5%) genes showed robust correlations between microarray and qRT-PCR expression data. The Pathway Studio analysis identified several genes involved in cell survival, differentiation, proliferation, and apoptosis which are unique to SP cells and a mechanism for the activation of Notch signaling is identified. To validate these findings, we have identified and isolated SP cells enriched for cancer stem cells from human ovarian cancer cell lines. The SP populations were having a higher colony forming efficiency in comparison to its MP counterpart and also capable of sustained expansion and differentiation in to SP and MP phenotypes. 50,000 SP cells produced tumor in nude mice whereas the same number of MP cells failed to give any tumor at 8 weeks after injection. The SP cells demonstrated a dose dependent sensitivity to specific γ-secretase inhibitors implicating the role of Notch signaling pathway in SP cell survival. Further the generated SP gene list was found to be enriched in recurrent ovarian cancer tumors.
| S-EPMC3260150 | biostudies-literature