scholarly journals A Novel Framework to Predict Breast Cancer Prognosis Using Immune-Associated LncRNAs

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhijian Huang ◽  
Chen Xiao ◽  
Fushou Zhang ◽  
Zhifeng Zhou ◽  
Liang Yu ◽  
...  

Background: Breast cancer (BC) is one of the most frequently diagnosed malignancies among females. As a huge heterogeneity of malignant tumor, it is important to seek reliable molecular biomarkers to carry out the stratification for patients with BC. We surveyed immune- associated lncRNAs that may be used as potential therapeutic targets in BC.Methods: LncRNA expression data and clinical information of BC patients were downloaded from the TCGA database for a comprehensive analysis of candidate genes. A model consisting of immune-related lncRNAs enriched in BC cancerous tissues was established using the univariate Cox regression analysis and the iterative Lasso Cox regression analysis. The prognostic performance of this model was validated in two independent cohorts (GSE21653 and BC-KR), and compared with known prognostic biomarkers. A nomogram that integrated the immune-related lncRNA signature and clinicopathological factors was constructed to accurately assess the prognostic value of this signature. The correlation between the signature and immune cell infiltration in BC was also analyzed.Results: The Kaplan-Meier analysis showed that the OS of Patients in the low-risk group had significantly better survival than those in the high-risk group, Clinical subgroup analysis showed that the predictive ability was independent of clinicopathological factors. Univariate/multivariate Cox regression analysis showed immune lncRNA signature is an important prognostic factor and an independent prognostic marker. In addition, GSEA and GSVA analysis as well as comprehensive analysis of immune cells showed that the signature was significantly correlated with the infiltration of immune cells.Conclusion: We successfully constructed an immune-associated lncRNA signature that can accurately predict BC prognosis.

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1419
Author(s):  
Justina Bekampytė ◽  
Agnė Bartnykaitė ◽  
Aistė Savukaitytė ◽  
Rasa Ugenskienė ◽  
Erika Korobeinikova ◽  
...  

Breast cancer is one of the most common oncological diseases among women worldwide. Cell cycle and apoptosis—related genes TP53, BBC3, CCND1 and EGFR play an important role in the pathogenesis of breast cancer. However, the roles of single nucleotide polymorphisms (SNPs) in these genes have not been fully defined. Therefore, this study aimed to analyze the association between TP53 rs1042522, BBC3 rs2032809, CCND1 rs9344 and EGFR rs2227983 polymorphisms and breast cancer phenotype and prognosis. For the purpose of the analysis, 171 Lithuanian women were enrolled. Genomic DNA was extracted from peripheral blood; PCR-RFLP was used for SNPs analysis. The results showed that BBC3 rs2032809 was associated with age at the time of diagnosis, disease progression, metastasis and death. CCND1 rs9344 was associated with tumor size, however an association resulted in loss of significance after Bonferroni correction. In survival analysis, significant associations were observed between BBC3 rs2032809 and OS, PFS and MFS. EGFR rs2227983 also showed some associations with OS and PFS (univariate Cox regression analysis). However, the results were in loss of significance (multivariate Cox regression analysis). In conclusion, BBC3 rs2032809 polymorphism was associated with breast cancer phenotype and prognosis. Therefore, it could be applied as potential markers for breast cancer prognosis.


2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Junyu Huo ◽  
Ge Guan ◽  
Jinzhen Cai ◽  
Liqun Wu

Abstract Background Stromal cells in tumor microenvironment could promote immune escape through a variety of mechanisms, but there are lacking research in the field of gastric cancer (GC). Methods We identified differential expressed immune-related genes (DEIRGs) between the high- and low-stromal cell abundance GC samples in The Cancer Genome Atlas and GSE84437 datasets. A risk score was constructed basing on univariate cox regression analysis, LASSO regression analysis, and multivariate cox regression analysis in the training cohort (n=772). The median value of the risk score was used to classify patients into groups with high and low risk. We conducted external validation of the prognostic signature in four independent cohorts (GSE26253, n=432; GSE62254, n=300; GSE15459, n=191; GSE26901, n=109) from the Gene Expression Omnibus (GEO) database. The immune cell infiltration was quantified by the CIBERSORT method. Results The risk score contained 6 genes (AKT3, APOD, FAM19A5, LTBP3, NOV, and NOX4) showed good performance in predicting 5-year overall survival (OS) rate and 5-year recurrence-free survival (RFS) rate of GC patients. The risk death and recurrence of GC patients growing with the increasing risk score. The patients were clustered into three subtypes according to the infiltration of 22 kinds of immune cells quantified by the CIBERSORT method. The proportion of cluster A with the worst prognosis in the high-risk group was significantly higher than that in the low-risk group; the risk score of cluster C subtype with the best prognosis was significantly lower than that of the other two subtypes. Conclusion This study established and validated a robust prognostic model for gastric cancer by integrated analysis 1804 samples of six centers, and its mechanism was explored in combination with immune cell infiltration characterization.


2021 ◽  
Author(s):  
BO SONG ◽  
Lijun Tian ◽  
Fan Zhang ◽  
Zheyu Lin ◽  
Boshen Gong ◽  
...  

Abstract Background: Thyroid cancer (TC) is the most common endocrine malignancy worldwide. The incidence of TC is high and increasing worldwide due to continuous improvements in diagnostic technology. TC is still often overtreated due to a lack of reliable diagnostic biomarkers. Therefore, determining accurate prognostic predictions to stratify TC patients is important.Methods: Raw data were downloaded from the TCGA database, and pairwise comparisons were applied to identify differentially expressed immune-related lncRNA (DEirlncRNA) pairs. Then, we used univariate Cox regression analysis and a modified Lasso algorithm on these pairs to construct a risk assessment model for TC. Next, TC patients were assigned to high- and low-risk groups based on the optimal cutoff score of the model for the 1-year ROC curve. We evaluated the signature in terms of prognostic independence, predictive value, immune cell infiltration, ICI-related molecules and small-molecule inhibitor efficacy. Results: We identified 30 DEirlncRNA pairs through Lasso regression, and 14 pairs served as the novel predictive signature. The high-risk group had a significantly poorer prognosis than the low-risk group. Cox regression analysis revealed that this immune-related signature can predict prognosis independently and reliably for TC. With the CIBERSORT algorithm, we found an association between the signature and immune cell infiltration. Additionally, several immune checkpoint inhibitor (ICI)-related molecules, such as PD-1 and PD-L1, showed a negative correlation with the high-risk group. We further found that some commonly used small-molecule inhibitors, such as sunitinib, were related to this new signature. Conclusions: We constructed a prognostic immune-related lncRNA signature that can predict TC patient survival without considering the technical bias of different platforms, and this signature also sheds light on TC overall prognosis and novel clinical treatments, such as ICB therapy and small molecular inhibitors.


2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Wei Ma ◽  
Fangkun Zhao ◽  
Xinmiao Yu ◽  
Shu Guan ◽  
Huandan Suo ◽  
...  

Abstract Background Breast cancer is a highly heterogeneous disease, this poses challenges for classification and management. Long non-coding RNAs play acrucial role in the breast cancersdevelopment and progression, especially in tumor-related immune processes which have become the most rapidly investigated area. Therefore, we aimed at developing an immune-related lncRNA signature to improve the prognosis prediction of breast cancer. Methods We obtained breast cancer patient samples and corresponding clinical data from The Cancer Genome Atlas (TCGA) database. Immune-related lncRNAs were screened by co-expression analysis of immune-related genes which were downloaded from the Immunology Database and Analysis Portal (ImmPort). Clinical patient samples were randomly separated into training and testing sets. In the training set, univariate Cox regression analysis and LASSO regression were utilized to build a prognostic immune-related lncRNA signature. The signature was validated in the training set, testing set, and whole cohorts by the Kaplan–Meier log-rank test, time-dependent ROC curve analysis, principal component analysis, univariate andmultivariate Cox regression analyses. Results A total of 937 immune- related lncRNAs were identified, 15 candidate immune-related lncRNAs were significantly associated with overall survival (OS). Eight of these lncRNAs (OTUD6B-AS1, AL122010.1, AC136475.2, AL161646.1, AC245297.3, LINC00578, LINC01871, AP000442.2) were selected for establishment of the risk prediction model. The OS of patients in the low-risk group was higher than that of patients in the high-risk group (p = 1.215e − 06 in the training set; p = 0.0069 in the validation set; p = 1.233e − 07 in whole cohort). The time-dependent ROC curve analysis revealed that the AUCs for OS in the first, eighth, and tenth year were 0.812, 0.81, and 0.857, respectively, in the training set, 0.615, 0.68, 0.655 in the validation set, and 0.725, 0.742, 0.741 in the total cohort. Multivariate Cox regression analysis indicated the model was a reliable and independent indicator for the prognosis of breast cancer in the training set (HR = 1.432; 95% CI 1.204–1.702, p < 0.001), validation set (HR = 1.162; 95% CI 1.004–1.345, p = 0.044), and whole set (HR = 1.240; 95% CI 1.128–1.362, p < 0.001). GSEA analysis revealed a strong connection between the signature and immune-related biological processes and pathways. Conclusions We constructed and verified a robust signature of 8 immune-related lncRNAs for the prediction of breast cancer patient survival.


BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jinzhi Lai ◽  
Hainan Yang ◽  
Tianwen Xu

Abstract Background Malignant mesothelioma (MM) is a relatively rare and highly lethal tumor with few treatment options. Thus, it is important to identify prognostic markers that can help clinicians diagnose mesothelioma earlier and assess disease activity more accurately. Alternative splicing (AS) events have been recognized as critical signatures for tumor diagnosis and treatment in multiple cancers, including MM. Methods We systematically examined the AS events and clinical information of 83 MM samples from TCGA database. Univariate Cox regression analysis was used to identify AS events associated with overall survival. LASSO analyses followed by multivariate Cox regression analyses were conducted to construct the prognostic signatures and assess the accuracy of these prognostic signatures by receiver operating characteristic (ROC) curve and Kaplan–Meier survival analyses. The ImmuCellAI and ssGSEA algorithms were used to assess the degrees of immune cell infiltration in MM samples. The survival-related splicing regulatory network was established based on the correlation between survival-related AS events and splicing factors (SFs). Results A total of 3976 AS events associated with overall survival were identified by univariate Cox regression analysis, and ES events accounted for the greatest proportion. We constructed prognostic signatures based on survival-related AS events. The prognostic signatures proved to be an efficient predictor with an area under the curve (AUC) greater than 0.9. Additionally, the risk score based on 6 key AS events proved to be an independent prognostic factor, and a nomogram composed of 6 key AS events was established. We found that the risk score was significantly decreased in patients with the epithelioid subtype. In addition, unsupervised clustering clearly showed that the risk score was associated with immune cell infiltration. The abundances of cytotoxic T (Tc) cells, natural killer (NK) cells and T-helper 17 (Th17) cells were higher in the high-risk group, whereas the abundances of induced regulatory T (iTreg) cells were lower in the high-risk group. Finally, we identified 3 SFs (HSPB1, INTS1 and LUC7L2) that were significantly associated with MM patient survival and then constructed a regulatory network between the 3 SFs and survival-related AS to reveal potential regulatory mechanisms in MM. Conclusion Our study provided a prognostic signature based on 6 key events, representing a better effective tumor-specific diagnostic and prognostic marker than the TNM staging system. AS events that are correlated with the immune system may be potential therapeutic targets for MM.


2021 ◽  
Vol 12 ◽  
Author(s):  
Tao Han ◽  
Zhifan Zuo ◽  
Meilin Qu ◽  
Yinghui Zhou ◽  
Qing Li ◽  
...  

Background: Although low-grade glioma (LGG) has a good prognosis, it is prone to malignant transformation into high-grade glioma. It has been confirmed that the characteristics of inflammatory factors and immune microenvironment are closely related to the occurrence and development of tumors. It is necessary to clarify the role of inflammatory genes and immune infiltration in LGG.Methods: We downloaded the transcriptome gene expression data and corresponding clinical data of LGG patients from the TCGA and GTEX databases to screen prognosis-related differentially expressed inflammatory genes with the difference analysis and single-factor Cox regression analysis. The prognostic risk model was constructed by LASSO Cox regression analysis, which enables us to compare the overall survival rate of high- and low-risk groups in the model by Kaplan–Meier analysis and subsequently draw the risk curve and survival status diagram. We analyzed the accuracy of the prediction model via ROC curves and performed GSEA enrichment analysis. The ssGSEA algorithm was used to calculate the score of immune cell infiltration and the activity of immune-related pathways. The CellMiner database was used to study drug sensitivity.Results: In this study, 3 genes (CALCRL, MMP14, and SELL) were selected from 9 prognosis-related differential inflammation genes through LASSO Cox regression analysis to construct a prognostic risk model. Further analysis showed that the risk score was negatively correlated with the prognosis, and the ROC curve showed that the accuracy of the model was better. The age, grade, and risk score can be used as independent prognostic factors (p &lt; 0.001). GSEA analysis confirmed that 6 immune-related pathways were enriched in the high-risk group. We found that the degree of infiltration of 12 immune cell subpopulations and the scores of 13 immune functions and pathways in the high-risk group were significantly increased by applying the ssGSEA method (p &lt; 0.05). Finally, we explored the relationship between the genes in the model and the susceptibility of drugs.Conclusion: This study analyzed the correlation between the inflammation-related risk model and the immune microenvironment. It is expected to provide a reference for the screening of LGG prognostic markers and the evaluation of immune response.


2021 ◽  
Author(s):  
Cheng Yan ◽  
Qingling Liu ◽  
Ruoling Jia

Abstract Background: Autophagy plays an important role in triple negative breast cancer (TNBC). However, the prognostic value of autophagy-related genes (ARGs) in TNBC remains unknown. In this study, we established a survival model to evaluate the prognosis of TNBC patients using ARGs signature.Methods: A total of 222 autophagy-related genes were downloaded from The Human Autophagy Database. The RNA-sequencing data and corresponding clinical data of TNBC were obtained from the TCGA database. Differential gene expression of ARGs (DE-ARGs) between normal samples and TNBC samples was determined by the EdgeR software package. Then, univariate Cox, Lasso, and multivariate Cox regression analyses were performed. According to the Lasso regression results based on univariate Cox, we identified a prognostic signature for overall-survival (OS), which was further validated by using GEO cohort. We also found an independent prognostic marker that can predict the clinicopathological features of TNBC. Furthermore, a nomogram was drawn to predict the survival probability of TNBC patients, which could help in clinical decision for TNBC treatment. Finally, we validated the requirement of a ARG in our model for TNBC cell survival and metastasis.Results: There are 43 differentially expressed ARGs (DE-ARGs) were identified between normal and tumor samples. A risk model for OS using CDKN1A, CTSD, CTSL, EIF4EBP1, TMEM74 and VAMP3 by Lasso regression analysis was established based on univariate Cox regression analysis. Overall survival of TNBC patients was significantly shorter in the high-risk group than in the low-risk group for both the training and validation cohorts. Using the Kaplan-Meier curves and ROC curves, we demonstrated the accuracy of the prognostic model. Multivariate Cox regression analysis was used to verify risk score as independent predictor. Then a nomogram was proposed to predict 1-, 3-, and 5-year survival for TNBC patients. The calibration curves showed great accuracy of the model for survival prediction. Finally, we found that depletion of EIF4EBP1, one of ARGs in our model, significantly reduced cell proliferation and metastasis of TNBC cells. Conclusion: An autophagy-related prognosis model in TNBCs was constructed using ARGs signature containing CDKN1A, CTSD, CTSL, EIF4EBP1, TMEM74 and VAMP3. It could serve as an independent prognostic biomarker in TNBC.


2021 ◽  
Vol 8 ◽  
Author(s):  
Zhengjie Xu ◽  
Suxiao Jiang ◽  
Juan Ma ◽  
Desheng Tang ◽  
Changsheng Yan ◽  
...  

Background: Breast cancer (BC) is a heterogeneous malignant tumor, leading to the second major cause of female mortality. This study aimed to establish an in-depth relationship between ferroptosis-related LncRNA (FRlncRNA) and the prognosis as well as immune microenvironment of the patients with BC.Methods: We downloaded and integrated the gene expression data and the clinical information of the patients with BC from The Cancer Genome Atlas (TCGA) database. The co-expression network analysis and univariate Cox regression analysis were performed to screen out the FRlncRNAs related to prognosis. A cluster analysis was adopted to explore the difference of immune microenvironment between the clusters. Furthermore, we determined the optimal survival-related FRLncRNAs for final signature by LASSO Cox regression analysis. Afterward, we constructed and validated the prediction models, which were further tested in different subgroups.Results: A total of 31 FRLncRNAs were filtrated as prognostic biomarkers. Two clusters were determined, and C1 showed better prognosis and higher infiltration level of immune cells, such as B cells naive, plasma cells, T cells CD8, and T cells CD4 memory activated. However, there were no significantly different clinical characters between the clusters. Gene Set Enrichment Analysis (GSEA) revealed that some metabolism-related pathways and immune-associated pathways were exposed. In addition, 12 FRLncRNAs were determined by LASSO analysis and used to construct a prognostic signature. In both the training and testing sets, patients in the high-risk group had a worse survival than the low-risk patients. The area under the curves (AUCs) of receiver operator characteristic (ROC) curves were about 0.700, showing positive prognostic capacity. More notably, through the comprehensive analysis of heatmap, we regarded LINC01871, LINC02384, LIPE-AS1, and HSD11B1-AS1 as protective LncRNAs, while LINC00393, AC121247.2, AC010655.2, LINC01419, PTPRD-AS1, AC099329.2, OTUD6B-AS1, and LINC02266 were classified as risk LncRNAs. At the same time, the patients in the low-risk groups were more likely to be assigned to C1 and had a higher immune score, which were consistent with a better prognosis.Conclusion: Our research indicated that the ferroptosis-related prognostic signature could be used as novel biomarkers for predicting the prognosis of BC. The differences in the immune microenvironment exhibited by BC patients with different risks and clusters suggested that there may be a complementary synergistic effect between ferroptosis and immunotherapy.


2020 ◽  
Author(s):  
Hongli Yin ◽  
Weiwei Song ◽  
Chenguang Han ◽  
Qiantai Mao ◽  
Zhaoshuai Ji ◽  
...  

Abstract Background: In the past few years, tumor microenvironment (TME) has gradually become a hot topic in tumor research, which has important significance in the diagnosis, prevention and prognosis of tumors. Importantly, the immune system is a major contributing factor in TME, and studies have shown that tumors are partially infiltrated with various immune cell subsets. The immune characteristics of the TME play an essential role in evaluating the prognosis of patients. The immune scoring system based on the distribution of tumor local immune cell subsets and cell density has been an essential indicator in the evaluation of patient prognosis and has been verified in various tumor studies. TME is indispensable in the occurrence and development of Colorectal cancer (CRC). However, understanding the dynamic regulation of immunity and matrix components in TME of CRC is still a challenge and should be investigated further.Methods: In this study, we collected transcriptome RNA-seq data of 521 Colon adenocarcinoma (COAD) patients from The Cancer Genome Atlas (TCGA) data portal. We then estimate the fraction of stromal and immune cells in COAD cases by ESTIMATE algorithms [1]. A total of 1109 stromal-immune score-related differentially expressed genes (DEGs) were identified and used to generate a high-confidence protein–protein intersection (PPI) network and univariate COX regression analysis. Intersection analysis of the data from PPI network and univariate COX regression analysis showed the core gene. Then we performed Gene set enrichment analysis (GSEA), survival analysis and clinical analysis for CXCL10, and applied CIBERSORT algorithms to estimate the tumor-infiltrating immune cells (TICs) proportion in COAD cases.Results: The proportion of immune and stromal components in TME are associated with the progression of COAD. For example, tumor metastasis is inversely proportional to immune score. A total of 1109 DEGs were obtained by analyzing the low-score shared genes and the high-score shared genes by intersection analysis which might be the determinant of TME status. The GO enrichment analysis indicated that DEGs are associated with immune-related terms. KEGG pathway enrichment analysis showed that these DEGs are mainly enriched in cytokine cytokine receptor signaling pathway etc. Therefore, DEGs are related to immune regulation, which indicates that the participation of immune factors is the main characteristic of TME in COAD. Moreover, the expression level of CXCL10 has significantly connection with the prognosis of patients and the progression of COAD. Conclusion: Taken together, we conducted a comprehensive analysis of the TME in COAD, and predicted a prognostic indicator for COAD, which provided a novel insight for therapeutics of COAD.


2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Rui Wang ◽  
Wenxuan Bu ◽  
Yang Yang

Multiple myeloma (MM) is the second most commonly diagnosed hematological malignancy. Understanding the basic mechanisms of the metabolism in MM may lead to new therapies that benefit patients. We collected the gene expression profile data of GSE39754 and performed differential analysis. Furthermore, identify the candidate genes that affect the prognosis of the differentially expressed genes (DEGs) related to the metabolism. Enrichment analysis is used to identify the biological effects of candidate genes. Perform coexpression analysis on the verified DEGs. In addition, the candidate genes are used to cluster MM into different subtypes through consistent clustering. Use LASSO regression analysis to identify key genes, and use Cox regression analysis to evaluate the prognostic effects of key genes. Evaluation of immune cell infiltration in MM is by CIBERSORT. We identified 2821 DEGs, of which 348 genes were metabolic-related prognostic genes and were considered candidate genes. Enrichment analysis revealed that the candidate genes are mainly related to the proteasome, purine metabolism, and cysteine and methionine metabolism signaling pathways. According to the consensus clustering method, we identified the two subtypes of group 1 and group 2 that affect the prognosis of MM patients. Using the LASSO model, we have identified 10 key genes. The prognosis of the high-risk group identified by Cox regression analysis is worse than that of the low-risk group. Among them, PKLR has a greater impact on the prognosis of MM, and the prognosis of MM patients is poor when the expression is high. In addition, the level of immune cell infiltration in the high-risk group is higher than that in the low-risk group. In the summary, metabolism-related genes significantly affect the prognosis of MM patients through the metabolic process of MM patients. PKLR may be a prognostic risk factor for MM patients.


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