scholarly journals Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in Estrogen Receptor (ER) or Progesterone Receptor (PR) Positive and Human Epidermal Growth Factor Receptor 2 (HER2) Negative Breast Cancer

Author(s):  
Wei Wang ◽  
Hongnan Jiang ◽  
Yanrong Gao

Abstract Background: Although intrinsic molecular subtype has been extensively used, the risk stratification have not been fully elucidated in estrogen receptor (ER) or progesterone receptor (PR) positive and human epidermal growth factor receptor 2 (HER2) negative breast cancer. Methods: RNA transcriptional data from The Cancer Genome Atlas (TCGA), METABRIC and GEO were used. Immune-related genes were obtained from the datasets and literature search. Univariate, lasso regression and multivariate cox regression were employed to identify prognostic immune-related genes and establish the risk signature. Relationships between the risk signature and clinical parameters, tumor-infiltrating immune cell abundances and cancer phenotypes were further evaluated.Results: Noted, 102 immune-related prognostic genes were identified in METABRIC dataset by univariate cox analysis. Consecutively, 7 immune genes (SHMT2, AGA, COL17A1, FLT3, SLC7A2, ATP6AP1 and CCL19) were selected as risk signature by lasso regression and multivariate cox analysis. Its performance was further verified in TCGA,GSE20685 and GSE9195 datasets. Multivariate Cox regression indicated that the risk signature was an independent predictor. The prognostic signature showed significant correlation with intrinsic molecular subtypes, 70-gene signature and tamoxifen resistance signature. The CIBERSORT algorithm revealed that CD4+ memory T cells were significant higher in low-risk group. Conversely, M0-type macrophages were significant higher in high-risk group in both TCGA and METABRIC cohorts, which may have effect on the prognosis. Furthermore, we found that low-risk group may be associated with immune-related pathway and high-risk group was with cell cycle-related pathway, which also showed impact on the prognosis.Conclusion: The present study constructed a robust seven immune-related gene signature and established an effective method in risk stratification and prediction of clinical outcome in ER or PR positive and HER2 negative breast cancer.

2021 ◽  
Author(s):  
Menglin He ◽  
Cheng Hu ◽  
Jian Deng ◽  
Hui Ji ◽  
Weiqian Tian

Abstract Background: Breast cancer (BC) is a kind of cancer with high incidence and mortality in female. Conventional clinical characteristics are far from accurate to predict individual outcomes. Therefore, we aimed to develop a novel signature to predict the survival of patients with BC. Methods: We analyzed the data of a training cohort from the TCGA database and a validation cohort from GEO database. After the applications of GSEA and Cox regression analyses, a glycolysis-related signature for predicting the survival of patients with BC was developed. The signature contains AK3, CACNA1H, IL13RA1, NUP43, PGK1, and SDC1. Then, we constructed a risk score formula to classify the patients into high and low-risk groups based on the expression levels of six-gene in patients. The receiver operating characteristic (ROC) curve and the Kaplan-Meier curve were used to assess the predicted capacity of the model. Next, a nomogram was developed to predict the outcomes of patients with risk score and clinical features in 1, 3, and 5 years. We further used Human Protein Atlas (HPA) database to validate the expressions of the six biomarkers in tumor and sample tissues.Results: We constructed a six-gene signature to predict the outcomes of patients with BC. The patients in high-risk group showed poor prognosis than that in low-risk group. The AUC values were 0.719 and 0.702, showing that the prediction performance of the signature is acceptable. Additionally, Cox regression analysis revealed that these biomarkers could independently predict the prognosis of BC patients without being affected by clinical factors. The expression levels of all six biomarkers in BC tissues were higher than that in normal tissues except AK3. Conclusion: We developed a six-gene signature to predict the prognosis of patients with BC. Our signature has been proved to have the ability to make an accurate and obvious prediction and might be used to expand the prediction methods in clinical.


2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xiangxin Zhang ◽  
Liu Yang ◽  
Ming Kong ◽  
Jian Ma ◽  
Yutao Wei

Abstract Background Esophageal adenocarcinoma (EAC) is an aggressive malignancy with a poor prognosis. The immune-related genes (IRGs) are crucial to immunocytes tumor infiltration. This study aimed to construct a IRG-related prediction signature in EAC. Methods The related data of EAC patients and IRGs were obtained from the TCGA and ImmPort database, respectively. The cox regression analysis constructed the prediction signature and explored the transcription factors regulatory network through the Cistrome database. TIMER database and CIBERSORT analytical tool were utilized to explore the immunocytes infiltration analysis. Results The prediction signature with 12 IRGs (ADRM1, CXCL1, SEMG1, CCL26, CCL24, AREG, IL23A, UCN2, FGFR4, IL17RB, TNFRSF11A, and TNFRSF21) was constructed. Overall survival (OS) curves indicate that the survival rate of the high-risk group is significantly shorter than the low-risk group (P = 7.26e−07), and the AUC of 1-, 3- and 5- year survival prediction rates is 0.871, 0.924, and 0.961, respectively. Compared with traditional features, the ROC curve of the risk score in the EAC patients (0.967) is significant than T (0.57), N (0.738), M (0.568), and Stage (0.768). Moreover, multivariate Cox analysis and Nomogram of risk score are indicated that the 1-year and 3-year survival rates of patients are accurate by the combined analysis of the risk score, Sex, M stage, and Stage (The AUC of 1- and 3-years are 0.911, and 0.853). Conclusion The 12 prognosis-related IRGs might be promising therapeutic targets for EAC.


PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e8128 ◽  
Author(s):  
Cheng Yue ◽  
Hongtao Ma ◽  
Yubai Zhou

Background Lung cancer has the highest morbidity and mortality worldwide, and lung adenocarcinoma (LADC) is the most common pathological subtype. Accumulating evidence suggests the tumor microenvironment (TME) is correlated with the tumor progress and the patient’s outcome. As the major components of TME, the tumor-infiltrated immune cells and stromal cells have attracted more and more attention. In this study, differentially expressed immune and stromal signature genes were used to construct a TME-related prognostic model for predicting the outcomes of LADC patients. Methods The expression profiles of LADC samples with clinical information were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) related to the TME of LADC were identified using TCGA dataset by Wilcoxon rank sum test. The prognostic effects of TME-related DEGs were analyzed using univariate Cox regression. Then, the least absolute shrinkage and selection operator (LASSO) regression was performed to reduce the overfit and the number of genes for further analysis. Next, the prognostic model was constructed by step multivariate Cox regression and risk score of each sample was calculated. Then, survival and Receiver Operating Characteristic (ROC) analyses were conducted to validate the model using TCGA and GEO datasets, respectively. The Kyoto Encyclopedia of Genes and Genomes analysis of gene signature was performed using Gene Set Enrichment Analysis (GSEA). Finally, the overall immune status, tumor purity and the expression profiles of HLA genes of high- and low-risk samples was further analyzed to reveal the potential mechanisms of prognostic effects of the model. Results A total of 93 TME-related DEGs were identified, of which 23 DEGs were up-regulated and 70 DEGs were down-regulated. The univariate cox analysis indicated that 23 DEGs has the prognostic effects, the hazard ratio ranged from 0.65 to 1.25 (p < 0.05). Then, seven genes were screened out from the 23 DEGs by LASSO regression method and were further analyzed by step multivariate Cox regression. Finally, a three-gene (ADAM12, Bruton Tyrosine Kinase (BTK), ERG) signature was constructed, and ADAM12, BTK can be used as independent prognostic factors. The three-gene signature well stratified the LADC patients in both training (TCGA) and testing (GEO) datasets as high-risk and low-risk groups, the 3-year area under curve (AUC) of ROC curves of three GEO sets were 0.718 (GSE3141), 0.646 (GSE30219) and 0.643 (GSE50081). The GSEA analysis indicated that highly expressed ADAM12, BTK, ERG mainly correlated with the activation of pathways involving in focal adhesion, immune regulation. The immune analysis indicated that the low-risk group has more immune activities and higher expression of HLA genes than that of the high-risk group. In sum, we identified and constructed a three TME-related DEGs signature, which could be used to predict the prognosis of LADC patients.


2021 ◽  
Author(s):  
Sijia Li ◽  
Hongyang Zhang ◽  
Wei Li

Abstract Background: The purpose of our study is establishing a model based on ferroptosis-related genes predicting the prognosis of patients with head and neck squamous cell carcinoma (HNSCC).Methods: In our study, transcriptome and clinical data of HNSCC patients were from The Cancer Genome Atlas, ferroptosis-related genes and pathways were from Ferroptosis Signatures Database. Differentially expressed genes (DEGs) were screened by comparing tumor and adjacent normal tissues. Functional enrichment analysis of DEGs, protein-protein interaction network and gene mutation examination were applied. Univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression were used to identified DEGs. The model was constructed by multivariate Cox regression analysis and verified by Kaplan-Meier analysis. The relationship between risk scores and other clinical features was also analyzed. Univariate and multivariate Cox analysis was used to verified the independence of our model. The model was evaluated by receiver operating characteristic analysis and calculation of the area under the curve (AUC). A nomogram model based on risk score, age, gender and TNM stages was constructed.Results: We analyzed data including 500 tumor tissues and 44 adjacent normal tissues and 259 ferroptosis-related genes, then obtained 73 DEGs. Univariate Cox regression analysis screened out 16 genes related to overall survival, and LASSO analysis fingered out 12 of them with prognostic value. A risk score model based on these 12 genes was constructed by multivariate Cox regression analysis. According to the median risk score, patients were divided into high-risk group and low-risk group. The survival rate of high-risk group was significantly lower than that of low-risk group in Kaplan-Meier curve. Risk scores were related to T and grade. Univariate and multivariate Cox analysis showed our model was an independent prognostic factor. The AUC was 0.669. The nomogram showed high accuracy predicting the prognosis of HNSCC patients.Conclusion: Our model based on 12 ferroptosis-related genes performed excellently in predicting the prognosis of HNSCC patients. Ferroptosis-related genes may be promising biomarkers for HNSCC treatment and prognosis.


2021 ◽  
Vol 12 ◽  
Author(s):  
Susu Zheng ◽  
Xiaoying Xie ◽  
Xinkun Guo ◽  
Yanfang Wu ◽  
Guobin Chen ◽  
...  

Pyroptosis is a novel kind of cellular necrosis and shown to be involved in cancer progression. However, the diverse expression, prognosis and associations with immune status of pyroptosis-related genes in Hepatocellular carcinoma (HCC) have yet to be analyzed. Herein, the expression profiles and corresponding clinical characteristics of HCC samples were collected from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Then a pyroptosis-related gene signature was built by applying the least absolute shrinkage and selection operator (LASSO) Cox regression model from the TCGA cohort, while the GEO datasets were applied for verification. Twenty-four pyroptosis-related genes were found to be differentially expressed between HCC and normal samples. A five pyroptosis-related gene signature (GSDME, CASP8, SCAF11, NOD2, CASP6) was constructed according to LASSO Cox regression model. Patients in the low-risk group had better survival rates than those in the high-risk group. The risk score was proved to be an independent prognostic factor for overall survival (OS). The risk score correlated with immune infiltrations and immunotherapy responses. GSEA indicated that endocytosis, ubiquitin mediated proteolysis and regulation of autophagy were enriched in the high-risk group, while drug metabolism cytochrome P450 and tryptophan metabolism were enriched in the low-risk group. In conclusion, our pyroptosis-related gene signature can be used for survival prediction and may also predict the response of immunotherapy.


2021 ◽  
Author(s):  
Jianyu Zhao ◽  
Bo Liu ◽  
Xiaoping Li

Abstract Background: Adrenocortical carcinoma (ACC) is a rare endocrine cancer that manifests as abdominal masses and excessive steroid hormone levels. Transcription factors (TFs) deregulation is found to be involved in adrenocortical tumorigenesis and cancer progression. This study aimed to construct a TF-based prognostic signature for prediction of survival of ACC patients.Methods: The gene expression profile for ACC patients were downloaded from TCGA and GEO datasets. The univariate Cox analysis was applied to identify survival-related TFs and the LASSO Cox regression was conducted to construct the TF signature. The multivariate analysis was used to reveal the independent prognostic factors.Results: We identified a 13-TF prognostic signature comprised of CREB3L3, NR0B1, CENPA, FOXM1, E2F2, MYBL2, HOXC11, ZIC2, ZNF282, DNMT1, TCF3, ELK4, and KLF6 using the univariate Cox analysis and LASSO Cox regression. The risk score based on the TF-signature could classify patients into low- and high-risk group. Kaplan-Meier analyses showed that patients in the high-risk group had significantly shorter overall survival compared to the low-risk patients. ROC curves showed that the prognostic signature predicted the overall survival of ACC patients with good sensitivity and specificity. Furthermore, the TF-risk score was an independent prognostic factor.Conclusion: Taken together, we identified a 13-TF prognostic marker to predict overall survival in ACC patients.


2020 ◽  
Author(s):  
Li Liu ◽  
She Tian ◽  
Zhu Li ◽  
Yongjun Gong ◽  
Hao Zhang

Abstract Background : Hepatocellular carcinoma (HCC) is one of the most common clinical malignant tumors, resulting in high mortality and poor prognosis. Studies have found that LncRNA plays an important role in the onset, metastasis and recurrence of hepatocellular carcinoma. The immune system plays a vital role in the development, progression, metastasis and recurrence of cancer. Therefore, immune-related lncRNA can be used as a novel biomarker to predict the prognosis of hepatocellular carcinoma. Methods : The transcriptome data and clinical data of HCC patients were obtained by using The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA‑LIHC), and immune-related genes were extracted from the Molecular Signatures Database (IMMUNE RESPONSE M19817 and IMMUNE SYSTEM PROCESS M13664). By constructing the co-expression network and Cox regression analysis, 13 immune-lncRNAs was identified to predict the prognosis of HCC patients. Patients were divided into high risk group and low risk group by using the risk score formula, and the difference in overall survival (OS) between the two groups was reflected by Kaplan-Meier survival curve. The time - dependent receiver operating characteristics (ROC) analysis and principal component analysis (PCA) were used to evaluate 13 immune -lncRNAs signature. Results : Through TCGA - LIHC extracted from 343 cases of patients with hepatocellular carcinoma RNA - Seq data and clinical data, 331 immune-related genes were extracted from the Molecular Signatures Database , co-expression networks and Cox regression analysis were constructed, 13 immune-lncRNAs signature was identified as biomarkers to predict the prognosis of patients. At the same time using the risk score median divided the patients into high risk and low risk groups, and through the Kaplan-Meier survival curve analysis found that high-risk group of patients' overall survival (OS) less low risk group of patients. The AUC value of the ROC curve is 0.828, and principal component analysis (PCA) results showed that patients could be clearly divided into two parts by immune-lncRNAs, which provided evidence for the use of 13 immune-lncRNAs signature as prognostic markers. Conclusion : Our study identified 13 immune-lncRNAs signature that can effectively predict the prognosis of HCC patients, which may be a new prognostic indicator for predicting clinical outcomes.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jinyuan Shi ◽  
Pu Wu ◽  
Lei Sheng ◽  
Wei Sun ◽  
Hao Zhang

Abstract Background Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer (TC), accounting for more than 80% of all cases. Ferroptosis is a novel iron-dependent and Reactive oxygen species (ROS) reliant type of cell death which is distinct from the apoptosis, necroptosis and pyroptosis. Considerable studies have demonstrated that ferroptosis is involved in the biological process of various cancers. However, the role of ferroptosis in PTC remains unclear. This study aims at exploring the expression of ferroptosis-related genes (FRG) and their prognostic values in PTC. Methods A ferroptosis-related gene signature was constructed using lasso regression analysis through the PTC datasets of the Cancer Genome Atlas (TCGA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate the bioinformatics functions of significantly different genes (SDG) of ferroptosis. Additionally, the correlations of ferroptosis and immune cells were assessed through the single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT database. Finally, SDG were test in clinical PTC specimens and normal thyroid tissues. Results LASSO regression model was utilized to establish a novel FRG signature with 10 genes (ANGPTL7, CDKN2A, DPP4, DRD4, ISCU, PGD, SRXN1, TF, TFRC, TXNRD1) to predicts the prognosis of PTC, and the patients were separated into high-risk and low-risk groups by the risk score. The high-risk group had poorer survival than the low-risk group (p < 0.001). Receiver operating characteristic (ROC) curve analysis confirmed the signature's predictive capacity. Multivariate regression analysis identified the prognostic signature-based risk score was an independent prognostic indicator for PTC. The functional roles of the DEGs in the TGCA PTC cohort were explored using GO enrichment and KEGG pathway analyses. Immune related analysis demonstrated that the most types of immune cells and immunological function in the high-risk group were significant different with those in the low-risk group. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) verified the SDG have differences in expression between tumor tissue and normal thyroid tissue. In addition, cell experiments were conducted to observe the changes in cell morphology and expression of signature’s genes with the influence of ferroptosis induced by sorafenib. Conclusions We identified differently expressed FRG that may involve in PTC. A ferroptosis-related gene signature has significant values in predicting the patients’ prognoses and targeting ferroptosis may be an alternative for PTC’s therapy.


PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9621
Author(s):  
Shanliang Zhong ◽  
Huanwen Chen ◽  
Sujin Yang ◽  
Jifeng Feng ◽  
Siying Zhou

We aimed to identify prognostic signature based on autophagy-related genes (ARGs) for breast cancer patients. The datasets of breast cancer were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Least absolute shrinkage and selection operator (LASSO) Cox regression was conducted to construct multiple-ARG risk signature. In total, 32 ARGs were identified as differentially expressed between tumors and adjacent normal tissues based on TCGA. Six ARGs (IFNG, TP63, PPP1R15A, PTK6, EIF4EBP1 and NKX2-3) with non-zero coefficient were selected from the 32 ARGs using LASSO regression. The 6-ARG signature divided patients into high-and low-risk group. Survival analysis indicated that low-risk group had longer survival time than high-risk group. We further validated the 6-ARG signature using dataset from GEO and found similar results. We analyzed the associations between ARGs and breast cancer survival in TCGA and nine GEO datasets, and obtained 170 ARGs with significant associations. EIF4EBP1, FOS and FAS were the top three ARGs with highest numbers of significant associations. EIF4EBP1 may be a key ARG which had a higher expression level in patients with more malignant molecular subtypes and higher grade breast cancer. In conclusion, our 6-ARG signature was of significance in predicting of overall survival of patients with breast cancer. EIF4EBP1 may be a key ARG associated with breast cancer survival.


Author(s):  
Jindong Xie ◽  
Yutian Zou ◽  
Feng Ye ◽  
Wanzhen Zhao ◽  
Xinhua Xie ◽  
...  

Regarded as the most invasive subtype, triple-negative breast cancer (TNBC) lacks the expression of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2) proteins. Platelets have recently been shown to be associated with metastasis of malignant tumors. Nevertheless, the status of platelet-related genes in TNBC and their correlation with patient prognosis remain unknown. In this study, the expression and variation levels of platelet-related genes were identified and patients with TNBC were divided into three subtypes. We collected cohorts from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. By applying the least absolute shrinkage and selection operator (LASSO) Cox regression method, we constructed a seven-gene signature which classified the two cohorts of patients with TNBC into low- or high-risk groups. Patients in the high-risk group were more likely to have lower survival rates than those in the low-risk group. The risk score, incorporated with the clinical features, was confirmed as an independent factor for predicting the overall survival (OS) time. Functional enrichment analyses revealed the involvement of a variety of vital biological processes and classical cancer-related pathways that could be important to the ultimate prognosis of TNBC. We then built a nomogram that performed well. Moreover, we tested the model in other cohorts and obtained positive outcomes. In conclusion, platelet-related genes were closely related to TNBC, and this novel signature could serve as a tool for the assessment of clinical prognosis.


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