scholarly journals Identification and validation of an immune-related prognostic signature for hepatocellular carcinoma

2020 ◽  
Author(s):  
Xinxin Xia ◽  
Hui Liu ◽  
Yuejun Li

Abstract Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality. The immune system plays vital roles in HCC initiation and progression. The present study aimed to construct an immune-gene related prognostic signature (IRPS) for predicting the prognosis of HCC patients. Methods: Gene expression data were retrieved from The Cancer Genome Atlas database. Univariate Cox regression analysis was carried out to identify differentially expressed genes that associated with overall survival. The IRPS was established via Lasso and multivariate Cox regression analysis. Both Cox regression analyses were conducted to determine the independent prognostic factors for HCC. Next, the association between the IRPS and clinical-related factors were evaluated. The prognostic values of the IRPS were further validated using the International Cancer Genome Consortium (ICGC) dataset. Gene set enrichment analyses (GSEA) were conducted to understand the biological mechanisms of the IRPS. Results: A total of 62 genes were identified to be candidate immune-related prognostic genes. Transcription factors-immunogenes network was generated to explore the interactions among these candidate genes. According to the results of Lasso and multivariate Cox regression analysis, we established an IRPS and confirmed its stability and reliability in ICGC dataset. The IRPS was significantly associated with advanced clinicopathological characteristics. Both Cox regression analyses revealed that the IRPS could be an independent risk factor influencing the prognosis of HCC patients. The relationships between the IRPS and infiltration immune cells demonstrated that the IRPS was associated with immune cell infiltration. GSEA identified significantly enriched pathways, which might assist in elucidating the biological mechanisms of the IRPS. Furthermore, a nomogram was constructed to estimate the survival probability of HCC patients. Conclusions: The IRPS was effective for predicting prognosis of HCC patients, which might serve as novel prognostic and therapeutic biomarkers for HCC.

2020 ◽  
Author(s):  
Xinxin Xia ◽  
Hui Liu ◽  
Yuejun Li

Abstract Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality. The immune system plays vital roles in HCC initiation and progression. The present study aimed to construct an immune-gene related prognostic signature (IRPS) for predicting the prognosis of HCC patients. Methods: Gene expression data were retrieved from The Cancer Genome Atlas database. Univariate Cox regression analysis was carried out to identify differentially expressed genes that associated with overall survival. The IRPS was established via Lasso and multivariate Cox regression analysis. Both Cox regression analyses were conducted to determine the independent prognostic factors for HCC. Next, the association between the IRPS and clinical-related factors were evaluated. The prognostic values of the IRPS were further validated using the International Cancer Genome Consortium (ICGC) dataset. Gene set enrichment analyses (GSEA) were conducted to understand the biological mechanisms of the IRPS. Results: A total of 62 genes were identified to be candidate immune-related prognostic genes. Transcription factors-immunogenes network was generated to explore the interactions among these candidate genes. According to the results of Lasso and multivariate Cox regression analysis, we established an IRPS and confirmed its stability and reliability in ICGC dataset. The IRPS was significantly associated with advanced clinicopathological characteristics. Both Cox regression analyses revealed that the IRPS could be an independent risk factor influencing the prognosis of HCC patients. The relationships between the IRPS and infiltration immune cells demonstrated that the IRPS was associated with immune cell infiltration. GSEA identified significantly enriched pathways, which might assist in elucidating the biological mechanisms of the IRPS. Furthermore, a nomogram was constructed to estimate the survival probability of HCC patients.Conclusions: The IRPS was effective for predicting prognosis of HCC patients, which might serve as novel prognostic and therapeutic biomarkers for HCC.


2020 ◽  
Author(s):  
Xinxin Xia ◽  
Hui Liu ◽  
Yuejun Li

Abstract Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality. The immune system plays vital roles in HCC initiation and progression. The present study aimed to construct an immune-gene related prognostic signature (IRPS) for predicting the prognosis of HCC patients. Methods: Gene expression data were retrieved from The Cancer Genome Atlas database. Univariate Cox regression analysis was carried out to identify differentially expressed genes that associated with overall survival. The IRPS was established via Lasso and multivariate Cox regression analysis. Both Cox regression analyses were conducted to determine the independent prognostic factors for HCC. Next, the association between the IRPS and clinical-related factors were evaluated. The prognostic values of the IRPS were further validated using the International Cancer Genome Consortium (ICGC) dataset. Gene set enrichment analyses (GSEA) were conducted to understand the biological mechanisms of the IRPS.Results: A total of 62 genes were identified to be candidate immune-related prognostic genes. Transcription factors-immunogenes network was generated to explore the interactions among these candidate genes. According to the results of Lasso and multivariate Cox regression analysis, we established an IRPS and confirmed its stability and reliability in ICGC dataset. The IRPS was significantly associated with advanced clinicopathological characteristics. Both Cox regression analyses revealed that the IRPS could be an independent risk factor influencing the prognosis of HCC patients. The relationships between the IRPS and infiltration immune cells demonstrated that the IRPS was associated with immune cell infiltration. GSEA identified significantly enriched pathways, which might assist in elucidating the biological mechanisms of the IRPS. Furthermore, a nomogram was constructed to estimate the survival probability of HCC patients. Conclusions: The IRPS was effective for predicting prognosis of HCC patients, which might serve as novel prognostic and therapeutic biomarkers for HCC.


2020 ◽  
Author(s):  
Zhihao Wang ◽  
Kidane Siele Embaye ◽  
Qing Yang ◽  
Lingzhi Qin ◽  
Chao Zhang ◽  
...  

Abstract Background: Given that metabolic reprogramming has been recognized as an essential hallmark of cancer cells, this study sought to investigate the potential prognostic values of metabolism-related genes(MRGs) for hepatocellular carcinoma (HCC) diagnosis and treatment. Methods: The metabolism-related genes sequencing data of HCC samples with clinical information were obtained from the International Cancer Genome Consortium(ICGC) and The Cancer Genome Atlas (TCGA). The differentially expressed MRGs were identified by Wilcoxon rank sum test. Then, univariate Cox regression analysis were performed to identify metabolism-related DEGs that related to overall survival(OS). A novel metabolism-related prognostic signature was developed using the least absolute shrinkage and selection operator (Lasso) and multivariate Cox regression analyses . Furthermore, the signature was validated in the TCGA dataset. Finally, cox regression analysis was applied to identify the prognostic value and clinical relationship of the signature in HCC. Results: A total of 178 differentially expressed MRGs were detected between the ICGA dataset and the TCGA dataset. We found that 17 MRGs were most significantly associated with OS by using the univariate Cox proportional hazards regression analysis in HCC. Then, the Lasso and multivariate Cox regression analyses were applied to construct the novel metabolism-relevant prognostic signature, which consisted of six MRGs. The prognostic value of this prognostic model was further successfully validated in the TCGA dataset. Further analysis indicated that this signature could be an independent prognostic indicator after adjusting to other clinical factors. Six MRGs (FLVCR1, MOGAT2, SLC5A11, RRM2, COX7B2, and SCN4A) showed high prognostic performance in predicting HCC outcomes, and were further associated with tumor TNM stage, gender, age, and pathological stage. Finally, the signature was found to be associated with various clinicopathological features. Conclusions: In summary, our data provided evidence that the metabolism-based signature could serve as a reliable prognostic and predictive tool for overall survival in patients with HCC.


2020 ◽  
Author(s):  
Ze-bing Song ◽  
Guo-pei Zhang ◽  
shaoqiang li

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumor in the world which prognosis is poor. Therefore, a precise biomarker is needed to guide treatment and improve prognosis. More and more studies have shown that lncRNAs and immune response are closely related to the prognosis of hepatocellular carcinoma. The aim of this study was to establish a prognostic signature based on immune related lncRNAs for HCC.Methods: Univariate cox regression analysis was performed to identify immune related lncRNAs, which had negative correlation with overall survival (OS) of 370 HCC patients from The Cancer Genome Atlas (TCGA). A prognostic signature based on OS related lncRNAs was identified by using multivariate cox regression analysis. Gene set enrichment analysis (GSEA) and a competing endogenous RNA (ceRNA) network were performed to clarify the potential mechanism of lncRNAs included in prognostic signature. Results: A prognostic signature based on OS related lncRNAs (AC145207.5, AL365203.2, AC009779.2, ZFPM2-AS1, PCAT6, LINC00942) showed moderately in prognosis prediction, and related with pathologic stage (Stage I&II VS Stage III&IV), distant metastasis status (M0 VS M1) and tumor stage (T1-2 VS T3-4). CeRNA network constructed 15 aixs among differentially expressed immune related genes, lncRNAs included in prognostic signature and differentially expressed miRNA. GSEA indicated that these lncRNAs were involved in cancer-related pathways. Conclusion: We constructed a prognostic signature based on immune related lncRNAs which can predict prognosis and guide therapies for HCC.


BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yajuan Du ◽  
Ying Gao

Abstract Background There is growing evidence that pseudogenes may serve as prognostic biomarkers in several cancers. The present study was designed to develop and validate an accurate and robust pseudogene pairs-based signature for the prognosis of hepatocellular carcinoma (HCC). Methods RNA-sequencing data from 374 HCC patients with clinical follow-up information were obtained from the Cancer Genome Atlas (TCGA) database and used in this study. Survival-related pseudogene pairs were identified, and a signature model was constructed by Cox regression analysis (univariate and least absolute shrinkage and selection operator). All individuals were classified into high- and low-risk groups based on the optimal cutoff. Subgroups analysis of the novel signature was conducted and validated in an independent cohort. Pearson correlation analyses were carried out between the included pseudogenes and the protein-coding genes based on their expression levels. Enrichment analysis was performed to predict the possible role of the pseudogenes identified in the signature. Results A 19-pseudogene pair signature, which included 21 pseudogenes, was established. Patients in high-risk group demonstrated an increased the risk of adverse prognosis in the TCGA cohort and the external cohort (all P < 0.001). The novel pseudogene signature was independent of other conventional clinical variables used for survival prediction in HCC patients in the two cohorts revealed by the multivariate Cox regression analysis (all P < 0.001). Subgroup analysis further demonstrated the diagnostic value of the signature across different stages, grades, sexes, and age groups. The C-index of the prognostic signature was 0.761, which was not only higher than that of several previous risk models but was also much higher than that of a single age, sex, grade, and stage risk model. Furthermore, functional analysis revealed that the potential biological mechanisms mediated by these pseudogenes are primarily involved in cytokine receptor activity, T cell receptor signaling, chemokine signaling, NF-κB signaling, PD-L1 expression, and the PD-1 checkpoint pathway in cancer. Conclusion The novel proposed and validated pseudogene pair-based signature may serve as a valuable independent prognostic predictor for predicting survival of patients with HCC.


2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Xiaomin Wu ◽  
Xiaojing Zhang ◽  
Leilei Tao ◽  
Xichao Dai ◽  
Ping Chen

Purposes. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Recent researches have demonstrated that m6A methylation regulators play a key role in various cancers, such as gastric cancer and colon adenocarcinoma. Several m6A methylation regulators are reported to predict the prognosis of HCC. Therefore, there is a need to further identify the predictive value of m6A methylation regulators in HCC. Methods. We utilized The Cancer Genome Atlas (TCGA) database to obtain the gene expression profile of m6A RNA methylation regulators and clinical information for patients with HCC. Besides, we identified two clusters of HCC with various clinical factors by consensus clustering analysis. Then the least absolute shrinkage and selection operator (LASSO) and the Cox regression analysis were applied to construct a prognostic signature. Results. Except for ZC3H13 and METTL14, a majority of the thirteen m6A RNA methylation regulators were significantly overexpressed in HCC specimens. HCC patients were classified into two groups (cluster 1 and cluster 2). The cluster 1 was with a significantly worse prognosis than cluster 2, and most of the 13 known m6A RNA methylation regulators were upregulated in cluster 1. Besides, we developed a prognostic signature consisting of YTHDF2, YTHDF1, METTL3, KIAA1429, and ZC3H13, which could successfully differentiate high-risk patients. More importantly, univariate and multivariate Cox regression analysis indicated that the signature-based risk score was an independent prognostic factor for patients with HCC. Conclusions. Our study showed these five m6A RNA methylation regulators can be used as practical and reliable prognostic tools of HCC, which might have potential value for therapeutic strategies.


2020 ◽  
Author(s):  
Wen Ye ◽  
Zhehao Shi ◽  
Zhongjing Zhang ◽  
Yi Zhou ◽  
Bicheng Chen ◽  
...  

Abstract Background Hepatocellular carcinoma (HCC) is the most common and deadly type of liver cancer. Autophagy is the process of transporting damaged or aging cellular components into lysosomes for digestion and degradation. There is an accumulative evidence implies that autophagy is a key factor of the progression of cancer. The aim of this study was to determine a panel of a novel autophagy-related prognostic marker for liver cancer. Methods We conducted a comprehensive analysis of ARGs expression profiles and corresponding clinical information based on The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database. The univariate Cox proportional regression model was used to screen candidate autophagy-related prognostic genes. In addition, the multivariate Cox proportional regression model were helped to prove five key prognostic autophagy-related genes (ATIC, BAX, BIRC5, CAPNS1 and FKBP1A), which were used to construct prognostic signature. Results Based on the prognostic signature, liver cancer patients were significantly divided into high-risk and low-risk groups in terms of overall survival (OS). Further multivariate Cox regression analysis indicated that the prognostic signature remained as an independent prognostic factor for OS. The prognostic signature in possession of a better Area Under Curves (AUC) has a better performance in predicting the survival of patients with HCC, compared with other clinical parameters. Conclusion This study provides a prospective biomarker for monitoring the outcomes in the patients with HCC.


2020 ◽  
Author(s):  
Zhihao Wang ◽  
Kidane Siele Embaye ◽  
Qing Yang ◽  
Lingzhi Qin Qin ◽  
Chao Zhang ◽  
...  

Abstract BackgroundGiven that metabolic reprogramming has been recognized as an essential hallmark of cancer cells, this study sought to investigate the potential prognostic values of metabolism-related genes(MRGs) for hepatocellular carcinoma (HCC) diagnosis and treatment.MethodsThe metabolism-related genes sequencing data of HCC samples with clinical information were obtained from the International Cancer Genome Consortium(ICGC) and The Cancer Genome Atlas (TCGA). The differentially expressed MRGs were identified by Wilcoxon rank sum test. Then, univariate Cox regression analysis were performed to identify metabolism-related DEGs that related to overall survival(OS) . A novel metabolism-related prognostic signature was developed using the least absolute shrinkage and selection operator (Lasso) and multivariate Cox regression analyses . Furthermore, the signature was validated in the TCGA dataset. Finally, the expression levels of hub genes were validated in cell lines by Western blotting (WB) and quantitative real-timePCR (qRT-PCR).ResultsA total of 178 differentially expressed MRGs were detected between the ICGA dataset and the TCGA dataset. We found that 17 MRGs were most significantly associated with OS by using the univariate Cox proportional hazards regression analysis in HCC. Then, the Lasso and multivariate Cox regression analyses were applied to construct the novel metabolism-relevant prognostic signature, which consisted of six MRGs. The prognostic value of this prognostic model was further successfully validated in the TCGA dataset. Further analysis indicated that this signature could be an independent prognostic indicator after adjusting to other clinical factors. Six MRGs (FLVCR1, MOGAT2, SLC5A11, RRM2, COX7B2, and SCN4A) showed high prognostic performance in predicting HCC outcomes. Finally, hub genes were chosen for validation and the expression of FLVCR1, SLC5A11, and RRM2 were significantly increased in human hepatocellular carcinoma cell lines when compared to normal human hepatic cell line, which were in agreement with the results of differential expression analysis.ConclusionsIn summary, our data provided evidence that the metabolism-based signature could serve as a reliable prognostic and predictive tool for overall survival in patients with HCC.


2021 ◽  
Vol 20 ◽  
pp. 153303382110414
Author(s):  
Xiaoyong Li ◽  
Jiaqong Lin ◽  
Yuguo pan ◽  
Peng Cui ◽  
Jintang Xia

Background: Liver progenitor cells (LPCs) play significant roles in the development and progression of hepatocellular carcinoma (HCC). However, no studies on the value of LPC-related genes for evaluating HCC prognosis exist. We developed a gene signature of LPC-related genes for prognostication in HCC. Methods: To identify LPC-related genes, we analyzed mRNA expression arrays from a dataset (GSE57812 & GSE 37071) containing LPCs, mature hepatocytes, and embryonic stem cell samples. HCC RNA-Seq data from The Cancer Genome Atlas (TCGA) were used to explore the differentially expressed genes (DEGs) related to prognosis through DEG analysis and univariate Cox regression analysis. Lasso and multivariate Cox regression analyses were performed to construct the LPC-related gene prognostic model in the TCGA training dataset. This model was validated in the TCGA testing set and an external dataset (International Cancer Genome Consortium [ICGC] dataset). Finally, we investigated the relationship between this prognostic model with tumor-node-metastasis stage, tumor grade, and vascular invasion of HCC. Results: Overall, 1770 genes were identified as LPC-related genes, of which 92 genes were identified as DEGs in HCC tissues compared with normal tissues. Furthermore, we randomly assigned patients from the TCGA dataset to the training and testing cohorts. Twenty-six DEGs correlated with overall survival (OS) in the univariate Cox regression analysis. Lasso and multivariate Cox regression analyses were performed in the TCGA training set, and a 3-gene signature was constructed to stratify patients into 2 risk groups: high-risk and low-risk. Patients in the high-risk group had significantly lower OS than those in the low-risk group. Receiver operating characteristic curve analysis confirmed the signature's predictive capacity. Moreover, the risk score was confirmed to be an independent predictor for patients with HCC. Conclusion: We demonstrated that the LPC-related gene signature can be used for prognostication in HCC. Thus, targeting LPCs may serve as a therapeutic alternative for HCC.


2021 ◽  
Vol 11 ◽  
Author(s):  
Peng Liu ◽  
Jinhong Wei ◽  
Feiyu Mao ◽  
Zechang Xin ◽  
Heng Duan ◽  
...  

Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide and its incidence continues to increase year by year. Endoplasmic reticulum stress (ERS) caused by protein misfolding within the secretory pathway in cells and has an extensive and deep impact on cancer cell progression and survival. Growing evidence suggests that the genes related to ERS are closely associated with the occurrence and progression of HCC. This study aimed to identify an ERS-related signature for the prospective evaluation of prognosis in HCC patients. RNA sequencing data and clinical data of patients from HCC patients were obtained from The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC). Using data from TCGA as a training cohort (n=424) and data from ICGC as an independent external testing cohort (n=243), ERS-related genes were extracted to identify three common pathways IRE1, PEKR, and ATF6 using the GSEA database. Through univariate and multivariate Cox regression analysis, 5 gene signals in the training cohort were found to be related to ERS and closely correlated with the prognosis in patients of HCC. A novel 5-gene signature (including HDGF, EIF2S1, SRPRB, PPP2R5B and DDX11) was created and had power as a prognostic biomarker. The prognosis of patients with high-risk HCC was worse than that of patients with low-risk HCC. Multivariate Cox regression analysis confirmed that the signature was an independent prognostic biomarker for HCC. The results were further validated in an independent external testing cohort (ICGC). Also, GSEA indicated a series of significantly enriched oncological signatures and different metabolic processes that may enable a better understanding of the potential molecular mechanism mediating the progression of HCC. The 5-gene biomarker has a high potential for clinical applications in the risk stratification and overall survival prediction of HCC patients. In addition, the abnormal expression of these genes may be affected by copy number variation, methylation variation, and post-transcriptional regulation. Together, this study indicated that the genes may have potential as prognostic biomarkers in HCC and may provide new evidence supporting targeted therapies in HCC.


Sign in / Sign up

Export Citation Format

Share Document