scholarly journals Model based on five tumour immune microenvironment-related genes for predicting hepatocellular carcinoma immunotherapy outcomes

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xinyu Gu ◽  
Jun Guan ◽  
Jia Xu ◽  
Qiuxian Zheng ◽  
Chao Chen ◽  
...  

Abstract Background Although the tumour immune microenvironment is known to significantly influence immunotherapy outcomes, its association with changes in gene expression patterns in hepatocellular carcinoma (HCC) during immunotherapy and its effect on prognosis have not been clarified. Methods A total of 365 HCC samples from The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset were stratified into training datasets and verification datasets. In the training datasets, immune-related genes were analysed through univariate Cox regression analyses and least absolute shrinkage and selection operator (LASSO)-Cox analyses to build a prognostic model. The TCGA-LIHC, GSE14520, and Imvigor210 cohorts were subjected to time-dependent receiver operating characteristic (ROC) and Kaplan–Meier survival curve analyses to verify the reliability of the developed model. Finally, single-sample gene set enrichment analysis (ssGSEA) was used to study the underlying molecular mechanisms. Results Five immune-related genes (LDHA, PPAT, BFSP1, NR0B1, and PFKFB4) were identified and used to establish the prognostic model for patient response to HCC treatment. ROC curve analysis of the TCGA (training and validation sets) and GSE14520 cohorts confirmed the predictive ability of the five-gene-based model (AUC > 0.6). In addition, ROC and Kaplan–Meier analyses indicated that the model could stratify patients into a low-risk and a high-risk group, wherein the high-risk group exhibited worse prognosis and was less sensitive to immunotherapy than the low-risk group. Functional enrichment analysis predicted potential associations of the five genes with several metabolic processes and oncological signatures. Conclusions We established a novel five-gene-based prognostic model based on the tumour immune microenvironment that can predict immunotherapy efficacy in HCC 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 ◽  
Author(s):  
Shenglan Huang ◽  
Jian Zhang ◽  
Dan Li ◽  
Xiaolan Lai ◽  
Lingling Zhuang ◽  
...  

Abstract Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with poor prognosis. Tumor microenvironment (TME) plays a vital role in the tumor progression of HCC. Thus, we aimed to analyze the association of TME with HCC prognosis, and construct an TME-related lncRNAs signature for predicting the prognosis of HCC patients.Methods: We firstly assessed the stromal/immune /Estimate scores within the HCC microenvironment using the ESTIMATE algorithm based on TCGA database, and its associations with survival and clinicopathological parameters were also analyzed. Then, different expression lncRNAs were filtered out according to immune/stromal scores. Cox regression was performed to built an TME-related lncRNAs risk signature. Kaplan–Meier analysis was carried out to explored the prognostic values of the risk signature. Furthermore, we explored the biological functions and immune microenvironment feathers in high- and low risk groups. Lastly, we probed the association of the risk signature with the treatment responses to immune checkpoint inhibitors (ICIs) in HCC by comparing the immunophenoscore (IPS).Results: Stromal/immune /Estimate scores of HCC patients were obtained based on the ESTIMATE algorithm. The Kaplan-Meier curve analysis showed the high stromal/immune/ Estimate scores were significantly associated with better prognosis of the HCC patients. Then, six TME-related lncRNAs were screened for constructing the prognosis model. Kaplan-Meier survival curves suggested that HCC patients in high-risk group had worse prognosis than those with low-risk. ROC curve and Cox regression analyses demonstrated the signature could predict HCC survival exactly and independently. Function enrichment analysis revealed that some tumor- and immune-related pathways associated with HCC tumorigenesis and progression might be activated in high-risk group. We also discovered that some immune cells, which were beneficial to enhance immune responses towards cancer, were remarkably upregulated in low-risk group. Besides, there was closely correlation of immune checkmate inhibitors (ICIs) with the risk signature and the signature can be used to predict treatment response of ICIs.Conclusions: We analyzed the impact of the tumor microenvironment scores on the prognosis of patients with HCC. A novel TME-related prognostic risk signature was established, which may improve prognostic predictive accuracy and guide individualized immunotherapy for HCC patients.


2021 ◽  
Vol 12 ◽  
Author(s):  
Zhijie Xu ◽  
Bi Peng ◽  
Qiuju Liang ◽  
Xi Chen ◽  
Yuan Cai ◽  
...  

Ferroptosis is an iron-dependent cell death process that plays important regulatory roles in the occurrence and development of cancers, including hepatocellular carcinoma (HCC). Moreover, the molecular events surrounding aberrantly expressed long non-coding RNAs (lncRNAs) that drive HCC initiation and progression have attracted increasing attention. However, research on ferroptosis-related lncRNA prognostic signature in patients with HCC is still lacking. In this study, the association between differentially expressed lncRNAs and ferroptosis-related genes, in 374 HCC and 50 normal hepatic samples obtained from The Cancer Genome Atlas (TCGA), was evaluated using Pearson’s test, thereby identifying 24 ferroptosis-related differentially expressed lncRNAs. The least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression model were used to construct and validate a prognostic risk score model from both TCGA training dataset and GEO testing dataset (GSE40144). A nine-lncRNA-based signature (CTD-2033A16.3, CTD-2116N20.1, CTD-2510F5.4, DDX11-AS1, LINC00942, LINC01224, LINC01231, LINC01508, and ZFPM2-AS1) was identified as the ferroptosis-related prognostic model for HCC, independent of multiple clinicopathological parameters. In addition, the HCC patients were divided into high-risk and low-risk groups according to the nine-lncRNA prognostic signature. The gene set enrichment analysis enrichment analysis revealed that the lncRNA-based signature might regulate the HCC immune microenvironment by interfering with tumor necrosis factor α/nuclear factor kappa-B, interleukin 2/signal transducers and activators of transcription 5, and cytokine/cytokine receptor signaling pathways. The infiltrating immune cell subtypes, such as resting memory CD4(+) T cells, follicular helper T cells, regulatory T cells, and M0 macrophages, were all significantly different between the high-risk group and the low-risk group as indicated in Spearman’s correlation analysis. Moreover, a substantial increase in the expression of B7H3 immune checkpoint molecule was found in the high-risk group. Our findings provided a promising insight into ferroptosis-related lncRNAs in HCC and a personalized prediction tool for prognosis and immune responses in patients.


2020 ◽  
Author(s):  
Bo Hu ◽  
Xiao-Bo Yang ◽  
Xinting Sang

Abstract Background: Hepatocellular carcinoma (HCC) is one of the deadliest malignancies. Currently, there is still a lack of effective treatment. Our purpose was to develop an immune-related prognosis lncRNA signature with regard to HCC.Methods: A total of 14,142 lncRNAs and 331 immune genes were obtained from The Cancer Genome Atlas (TCGA) and the Molecular Signatures Database to construct the immune-related lncRNAs co-expression networks. Moreover, the tumor samples collected from TCGA were randomized as training set and testing set, among which, the testing set and the entire set were used for verification. Subsequently, gene set enrichment analysis (GSEA) and principal component analysis (PCA) were employed for functional annotation.Results: An immune-related signature consisting of AC015908.3, AC068987.4 and AL365203.2 was identified among HCC patients. Under different conditions, patients in low-risk group exhibited longer overall survival (OS) than those in high-risk group (P < 0.001). Moreover, the as-constructed signature was an independent factor, which showed marked association with patient OS (P < 0.001, hazard ratio (HR) = 1.407). These findings were further validated in testing set and the entire set. Additionally, GSEA results revealed the different immune states between low-risk and high-risk groups. On the other hand, lncRNA-related mRNAs were also extracted to depict the networks.Conclusion: Our findings indicate that the three-lncRNA immune-related signature shows prognostic value for HCC.


2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Qian Yan ◽  
Wenjiang Zheng ◽  
Boqing Wang ◽  
Baoqian Ye ◽  
Huiyan Luo ◽  
...  

Abstract Background Hepatocellular carcinoma (HCC) is a disease with a high incidence and a poor prognosis. Growing amounts of evidence have shown that the immune system plays a critical role in the biological processes of HCC such as progression, recurrence, and metastasis, and some have discussed using it as a weapon against a variety of cancers. However, the impact of immune-related genes (IRGs) on the prognosis of HCC remains unclear. Methods Based on The Cancer Gene Atlas (TCGA) and Immunology Database and Analysis Portal (ImmPort) datasets, we integrated the ribonucleic acid (RNA) sequencing profiles of 424 HCC patients with IRGs to calculate immune-related differentially expressed genes (DEGs). Survival analysis was used to establish a prognostic model of survival- and immune-related DEGs. Based on genomic and clinicopathological data, we constructed a nomogram to predict the prognosis of HCC patients. Gene set enrichment analysis further clarified the signalling pathways of the high-risk and low-risk groups constructed based on the IRGs in HCC. Next, we evaluated the correlation between the risk score and the infiltration of immune cells, and finally, we validated the prognostic performance of this model in the GSE14520 dataset. Results A total of 100 immune-related DEGs were significantly associated with the clinical outcomes of patients with HCC. We performed univariate and multivariate least absolute shrinkage and selection operator (Lasso) regression analyses on these genes to construct a prognostic model of seven IRGs (Fatty Acid Binding Protein 6 (FABP6), Microtubule-Associated Protein Tau (MAPT), Baculoviral IAP Repeat Containing 5 (BIRC5), Plexin-A1 (PLXNA1), Secreted Phosphoprotein 1 (SPP1), Stanniocalcin 2 (STC2) and Chondroitin Sulfate Proteoglycan 5 (CSPG5)), which showed better prognostic performance than the tumour/node/metastasis (TNM) staging system. Moreover, we constructed a regulatory network related to transcription factors (TFs) that further unravelled the regulatory mechanisms of these genes. According to the median value of the risk score, the entire TCGA cohort was divided into high-risk and low-risk groups, and the low-risk group had a better overall survival (OS) rate. To predict the OS rate of HCC, we established a gene- and clinical factor-related nomogram. The receiver operating characteristic (ROC) curve, concordance index (C-index) and calibration curve showed that this model had moderate accuracy. The correlation analysis between the risk score and the infiltration of six common types of immune cells showed that the model could reflect the state of the immune microenvironment in HCC tumours. Conclusion Our IRG prognostic model was shown to have value in the monitoring, treatment, and prognostic assessment of HCC patients and could be used as a survival prediction tool in the near future.


Author(s):  
Hui Huang ◽  
Si-min Ruan ◽  
Meng-fei Xian ◽  
Ming-de Li ◽  
Mei-qing Cheng ◽  
...  

Objectives: This study aimed to construct a prediction model based on contrast-enhanced ultrasound (CEUS) ultrasomics features and investigate its efficacy in predicting early recurrence (ER) of primary hepatocellular carcinoma (HCC) after resection or ablation. Methods: This study retrospectively included 215 patients with primary HCC, who were divided into a developmental cohort (n = 139) and a test cohort (n = 76). Four representative images—grayscale ultrasound, arterial phase, portal venous phase and delayed phase —were extracted from each CEUS video. Ultrasomics features were extracted from tumoral and peritumoral area inside the region of interest. Logistic-regression was used to establish models, including a tumoral model, a peritumoral model and a combined model with additional clinical risk factors. The performance of the three models in predicting recurrence within 2 years was verified. Results: The combined model performed best in predicting recurrence within 2 years, with an area under the curve (AUC) of 0.845, while the tumoral model had an AUC of 0.810 and the peritumoral model one of 0.808. For prediction of recurrence-free survival, the 2 year cumulative recurrence rate was significant higher in the high-risk group (76.5%) than in the low-risk group (9.5%; p < 0.0001). Conclusion: These CEUS ultrasomics models, especially the combined model, had good efficacy in predicting early recurrence of HCC. The combined model has potential for individual survival assessment for HCC patients undergoing resection or ablation. Advances in knowledge: CEUS ultrasomics had high sensitivity, specificity and PPV in diagnosing early recurrence of HCC, and high efficacy in predicting early recurrence of HCC (AUC > 0.8). The combined model performed better than the tumoral ultrasomics model and peritumoral ultrasomics model in predicting recurrence within 2 years. Recurrence was more likely to occur in the high-risk group than in the low-risk group, with 2-year cumulative recurrence rates respectively 76.5% and 9.5% (p < 0.0001).


2020 ◽  
Author(s):  
FengLing Shao ◽  
Zhenni Wang ◽  
Shan Wang

Abstract BackgroundDue to the extremely high mortality rate of children with high-risk Neuroblastoma (NB), there is an urgent need for new indicators to further classify children in the high-risk group for more precise treatment. The purpose of our research is to explore the immune-related genes in NB in the high-risk group, and to further identify and develop a prognostic nomogram based on immune IRG signatures. MethodsThrough bioinformatics analysis to explore the abnormal expression of immune-related genes in the high-risk group. Cox regression and the least absolute shrinkage and selection operator (LASSO) analysis were conducted to identify the immune and overall survival (OS) related mRNA. The accuracy of the risk score is evaluated by Kaplan-Meier method and receiver operating characteristics (ROC) analysis, which is used to build a nomogram in combination with other clinical characteristics.. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the accuracy of our results. ResultsA total of 127 common differentially expressed immune genes were found between the high-risk group and the non-high-risk group of the two data sets. Four immune-related genes (IRG) related to prognosis were identified and a risk score was established. Kaplan–Meier survival analysis and time-dependent ROC analysis showed that the 4-IRG risk score has satisfactory predictive potential and achieved consistency in the verification of external data sets. Subsequently, the risk score combined with clinical characteristics draws a nomogram. The reliability of the results was verified on 29 cases of NB tissues by qRT-PCR. ConclusionsOverall, we have developed a powerful multi-gene classifier that can effectively classify NB patients into low- and high-risk groups with poor prognosis, and draw a nomogram for children in the high-risk group. This feature can help select high-risk patients who need more aggressive adjuvant target therapy or immunotherapy.


2020 ◽  
Author(s):  
Qinqin Liu ◽  
Jing Li ◽  
Fei Liu ◽  
Weilin Yang ◽  
Jingjing Ding ◽  
...  

Abstract Background Hepatocellular carcinoma (HCC) is associated with dismal prognosis, and prediction of the prognosis of HCC can assist the therapeutic decisions. More and more studies showed that the texture parameters of images can reflect the heterogeneity of the tumor, and may have the potential to predict the prognosis of patients with HCC after surgical resection. The aim of the study was to investigate the prognostic value of computed tomography (CT) texture parameters for patients with HCC after hepatectomy, and try to develop a radiomics nomograms by combining clinicopathological factors with radiomics signature.Methods 544 eligible patients were enrolled in the retrospective study and randomly divided into training cohort (n=381) and validation cohort (n=163). The regions of interest (ROIs) of tumor is delineated, then the corresponding texture parameters are extracted. The texture parameters were selected by using the least absolute shrinkage and selection operator (LASSO) Cox model in training cohort, and the radiomics score (Rad-score) was generated. According to the cut-off value of the Rad-score calculated by the receiver operating characteristic (ROC) curve, the patients were divided into high-risk group and low-risk group. The prognosis of the two groups was compared and validated in the validation cohort. Univariate and multivariable analyses by COX proportional hazard regression model were used to select the prognostic factors of overall survival (OS). The radiomics nomogram for OS were established based on the radiomics signature and clinicopathological factors. The Concordance index (C-index), calibration plot and decision curve analysis (DCA) were used to evaluate the performance of the radiomics nomogram.Result 7 texture parameters associated with OS were selected in the training, and the radiomics signature was formulated based on the texture parameters. The patients were divided into high-risk group and low-risk group by the cut-off values of the Rad-score of OS. The 1-, 3- and 5-year OS rate was 71.0%, 45.5% and 35.5% in the high-risk group, respectively, and 91.7%, 82.1% and 78.7%, in the low-risk group, respectively, with significant difference (P <0.001). COX regression model found that Rad-score was an independent prognostic factor of OS. In addition, the radiomics nomogram was developed based on five variables: α‐fetoprotein (AFP), platelet lymphocyte ratio (PLR), largest tumor size, microvascular invasion (MVI) and Rad-score. The nomograms displayed good accuracy in predicting OS (C-index=0.747) in the training cohort and was confirmed in the validation cohort (C-index=0.777). The calibration plots also showed an excellent agreement between the actual and predicted survival probabilities. The DAC indicated that the radiomics nomogram showed better clinical usefulness than the clinicopathologic nomogram.Conclusion The radiomics signature is potential biomarkers of the prognosis of HCC after hepatectomy. Radiomics nomogram that integrated radiomics signature can provide more accurate estimate of OS for patients with HCC after hepatectomy.


2021 ◽  
Author(s):  
Jing Liu ◽  
Ting Ye ◽  
Xue fang Zhang ◽  
Yong jian Dong ◽  
Wen feng Zhang ◽  
...  

Abstract Most of the malignant melanomas are already in the middle and advanced stages when they are diagnosed, which is often accompanied by the metastasis and spread of other organs.Besides, the prognosis of patients is bleak. The characteristics of the local immune microenvironment in metastatic melanoma have important implications for both tumor progression and tumor treatment. In this study, data on patients with metastatic melanoma from the TCGA and GEO datasets were selected for immune, stromal, and estimate scores, and overlapping differentially expressed genes (DEGs) were screened. A nine-IRGs prognostic model (ALOX5AP, ARHGAP15, CCL8, FCER1G, GBP4, HCK, MMP9, RARRES2 and TRIM22) was established by univariate COX regression, LASSO and multivariate COX regression. Receiver operating characteristic (ROC) curves were used to test the predictive accuracy of the model. Immune infiltration was analyzed by using CIBERSORT, Xcell and ssGSEA in high-risk and low-risk groups. The immune infiltration of the high-risk group was significantly lower than that of the low-risk group. Immune checkpoint analysis revealed that the expression of PDCD1, CTLA4, TIGIT, CD274, HAVR2 and LAG3 were significantly different in groups with different levels of risk scores. WGCNA analysis found that the yellow-green module contained seven genes (ALOX5AP, FCER1G, GBP4, HCK, MMP9, RARRES2 and TRIM22) from the nine-IRG prognostic model, of which the yellow-green module had the highest correlation with risk scores. The results of GO and KEGG suggested that the genes in the yellow-green module were mainly enriched in immune-related biological processes. Finally, we analyzed the prognostic ability and expression characteristics of ALOX5AP, ARHGAP15, CCL8, FCER1G, GBP4, HCK, MMP9, RARRES2 and TRIM22 in metastatic melanoma. Overall, a prognostic model for metastatic melanoma based on the characteristics of the tumor immune microenvironment was established, which was helpful for further studies.It could function well in helping people to understand the characteristics of the immune microenvironment in metastatic melanoma and to find possible therapeutic targets.


2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Yifang Hu ◽  
Jiahang Song ◽  
Zhen Wang ◽  
Jingbao Kan ◽  
Yaoqi Ge ◽  
...  

Background. Glioma is the most common central nervous system (CNS) cancer with a short survival period and a poor prognosis. The S100 family gene, comprising 25 members, relates to diverse biological processes of human malignancies. Nonetheless, the significance of S100 genes in predicting the prognosis of glioma remains largely unclear. We aimed to build an S100 family-based signature for glioma prognosis. Methods. We downloaded 665 and 313 glioma patients, respectively, from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) database with RNAseq data and clinical information. This study established a prognostic signature based on the S100 family genes through multivariate COX and LASSO regression. The Kaplan–Meier curve was plotted to compare overall survival (OS) among groups, whereas Receiver Operating Characteristic (ROC) analysis was performed to evaluate model accuracy. A representative gene S100B was further verified by in vitro experiments. Results. An S100 family-based signature comprising 5 genes was constructed to predict the glioma that stratified TCGA-derived cases as a low- or high-risk group, whereas the significance of prognosis was verified based on CGGA-derived cases. Kaplan–Meier analysis revealed that the high-risk group was associated with the dismal prognosis. Furthermore, the S100 family-based signature was proved to be closely related to immune microenvironment. In vitro analysis showed S100B gene in the signature promoted glioblastoma (GBM) cell proliferation and migration. Conclusions. We constructed and verified a novel S100 family-based signature associated with tumor immune microenvironment (TIME), which may shed novel light on the glioma diagnosis and treatment.


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