scholarly journals Development of a Prognostic Gene Signature For Hepatocellular Carcinoma

Author(s):  
Cuiyun Wu ◽  
Yaosheng Luo ◽  
Yinghui Chen ◽  
Hongling Qu ◽  
Lin Zheng ◽  
...  

Abstract Background: Accurate prediction of overall survival is important for prognosis and the assignment of appropriate personalized clinical treatment in hepatocellular carcinoma (HCC) patients. The aim of the present study was to establish an optimal gene model for the independent prediction of prognosis associated with common clinical patterns.Methods: Gene expression profiles and the corresponding clinical information of the LIHC cohort were obtained from The Cancer Genome Atlas. Differentially expressed genes were found using the R package “limma”. Subsequently, a prognostic gene signature was developed using the LASSO Cox regression model. Kaplan–Meier, log-rank, and receiver operating characteristic (ROC) analyses were performed to verify the predictive accuracy of the prognostic model. Finally, a nomogram and calibration plot were created using the “rms” package.Results: Differentially expressed genes were screened with threshold criteria (FDR < 0.01 and |log FC|>3) and 563 differentially expressed genes were obtained, including 448 downregulated and 115 upregulated genes. Using the LASSO Cox regression model, a prognostic gene signature was developed based on nine genes,IQGAP3, BIRC5, PTTG1, STC2, CDKN3, PBK, EXO1, NEIL3, and HOXD9, the expression levels of which were quantitated using RT-qPCR. According to the risk scores, patients were separated into high-risk and low-risk groups. Patients with lower risk scores generally had a better survival rate than those with higher risk scores. The mortality rate in the high-risk group was 42.02%, while that in the low-risk group was 12.50%. Results of the log-rank test showed significant differences in mortality between the two groups (HR: 4.86; 95% CI: 2.72–8.69; P = 1.01E-08). Subsequently, we assessed the prognostic accuracy of the gene signature using an ROC curve and the results show good sensitivity and specificity, with an average area under the curve (AUC) of 0.81 at 5 years (P < 0.01). Following multivariate adjustment for conventional clinical patterns, the prognostic gene signature remained a powerful and independent factor (HR: 4.70; 95% CI: 2.61–8.38; P = 2.06E-07), confirming its robust predictive ability of overall survival in HCC patients. Finally, a nomogram was established based on the gene signature and four clinicopathological features, which demonstrated an advantageous discriminating ability with the potential to facilitate clinical decision-making in HCC.Conclusion: Our prognostic gene signature can be used as a combined biomarker for the independent prediction of overall survival in HCC patients. Moreover, we created a nomogram that can be used to infer prognosis and aid individualized decisions regarding treatment and surveillance.

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.


2020 ◽  
Vol 27 (1) ◽  
pp. 107327482097711
Author(s):  
Jiasheng Lei ◽  
Dengyong Zhang ◽  
Chao Yao ◽  
Sheng Ding ◽  
Zheng Lu

Background: Hepatocellular carcinoma (HCC) remains the third leader cancer-associated cause of death globally, but the etiological basis for this complex disease remains poorly clarified. The present study was thus conceptualized to define a prognostic immune-related gene (IRG) signature capable of predicting immunotherapy responsiveness and overall survival (OS) in patients with HCC. Methods: Five differentially expressed IRG associated with HCC were established the immune-related risk model through univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. Patients were separated at random into training and testing cohorts, after which the association between the identified IRG signature and OS was evaluated using the “survival” R package. In addition, maftools was leveraged to assess mutational data, with tumor mutation burden (TMB) scores being calculated as follows: (total mutations/total bases) × 106. Immune-related risk term abundance was quantified via “ssGSEA” algorithm using the “gsva” R package. Results: HCC patients were successfully stratified into low-risk and high-risk groups based upon a signature composed of 5 differentially expressed IRGs, with overall survival being significantly different between these 2 groups in training cohort, testing cohort and overall patient cohort ( P = 1.745e-06, P = 1.888e-02, P = 4.281e-07). No association was observed between TMB and this IRG risk score in the overall patient cohort ( P = 0.461). Notably, 19 out of 29 immune-related risk terms differed substantially in the overall patient dataset. These risk terms mainly included checkpoints, human leukocyte antigens, natural killer cells, dendritic cells, and major histocompatibility complex class I. Conclusion: In summary, an immune-related prognostic gene signature was successfully developed and used to predict survival outcomes and immune system status in patients with HCC. This signature has the potential to help guide immunotherapeutic treatment planning for patients affected by this deadly cancer.


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 ◽  
Vol 12 ◽  
Author(s):  
Junli Wang ◽  
Qi Zhang ◽  
Fukang Shi ◽  
Dipesh Kumar Yadav ◽  
Zhengtao Hong ◽  
...  

Purpose: Hepatocellular carcinoma (HCC) is one of the most prevalent malignant diseases worldwide and has a poor prognosis. Gene-based prognostic models have been reported to predict the overall survival of patients with HCC. Unfortunately, most of the genes used in earlier prognostic models lack prospective validation and, thus, cannot be used in clinical practice.Methods: Candidate genes were selected from GEPIA (Gene Expression Profiling Interactive Analysis), and their associations with patients’ survival were confirmed by RT-PCR using cDNA tissue microarrays established from patients with HCC after radical resection. A multivariate Cox proportion model was used to calculate the coefficient of corresponding gene. The expression of seven genes of interest (MKI67, AR, PLG, DNASE1L3, PTTG1, PPP1R1A, and TTR) with two reference genes was defined to calculate a risk score which determined groups of different risks.Results: Our risk scoring efficiently classified patients (n = 129) with HCC into a low-, intermediate-, and high-risk group. The three groups showed meaningful distinction of 3-year overall survival rate, i.e., 88.9, 74.5, and 20.6% for the low-, intermediate-, and high-risk group, respectively. The prognostic prediction model of risk scores was subsequently verified using an independent prospective cohort (n = 77) and showed high accuracy.Conclusion: Our seven-gene signature model performed excellent long-term prediction power and provided crucially guiding therapy for patients who are not a candidate for surgery.


2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Jia ◽  
Yuhan Dai ◽  
Qing Zhang ◽  
Peiyu Tang ◽  
Qiang Fu ◽  
...  

BackgroundGrowing evidence has revealed the crucial roles of stromal cells in the microenvironment of various malignant tumors. However, efficient prognostic signatures based on stromal characteristics in colon cancer have not been well-established yet. The present study aimed to construct a stromal score-based multigene prognostic prediction model for colon cancer.MethodsStromal scores were calculated based on the expression profiles of a colon cancer cohort from TCGA database applying the ESTIMATE algorithm. Linear models were used to identify differentially expressed genes between low-score and high-score groups by limma R package. Univariate, LASSO, and multivariate Cox regression models were used successively to select the prognostic gene signature. Two independent datasets from GEO were used as external validation cohorts.ResultsLow stromal score was demonstrated to be a favorable factor to the overall survival of colon cancer patients in TCGA cohort (p = 0.0046). Three hundred and seven stromal score-related differentially expressed genes were identified. Through univariate, LASSO, and multivariate Cox regression analyses, a gene signature consisting of LEP, NOG, and SYT3 was recognized to build a prognostic prediction model. Based on the predictive values estimated by the established integrated model, patients were divided into two groups with significantly different overall survival outcomes (p &lt; 0.0001). Time-dependent Receiver operating characteristic curve analyses suggested the satisfactory predictive efficacy for the 5-year overall survival of the model (AUC value = 0.733). A nomogram with great predictive performance combining the multigene prediction model and clinicopathological factors was developed. The established model was validated in an external cohort (AUC value = 0.728). In another independent cohort, the model was verified to be of significant prognostic value for different subgroups, which was demonstrated to be especially accurate for young patients (AUC value = 0.763).ConclusionThe well-established model based on stromal score-related gene signature might serve as a promising tool for the prognostic prediction of colon cancer.


2021 ◽  
Vol 11 ◽  
Author(s):  
Lisa Su ◽  
Genhao Zhang ◽  
Xiangdong Kong

Hepatocellular carcinoma (HCC) has been a global health issue and attracted wide attention due to its high incidence and poor outcomes. In this study, our purpose was to explore an effective prognostic marker for HCC. Five cohort profile datasets from GEO (GSE25097, GSE36376, GSE62232, GSE76427 and GSE101685) were integrated with TCGA-LIHC and GTEx dataset to identify differentially expressed genes (DEGs) between normal and cancer tissues in HCC patients, then 5 upregulated differentially expressed genes and 32 downregulated DEGs were identified as common DEGs in total. Next, we systematically explored the relationship between the expression of 37 common DEGs in tumor tissues and overall survival (OS) rate of HCC patients in TCGA and constructed a novel prognostic model composed of five genes (AURKA, PZP, RACGAP1, ACOT12 and LCAT). Furthermore, the predicted performance of the five-gene signature was verified in ICGC and another independent clinical samples cohort, and the results demonstrated that the signature performed well in predicting the OS rate of patients with HCC. What is more, the signature was an independent hazard factor for HCC patients when considering other clinical factors in the three cohorts. Finally, we found the signature was significantly associated with HCC immune microenvironment. In conclusion, the prognostic five-gene signature identified in our present study could efficiently classify patients with HCC into subgroups with low and high risk of longer overall survival time and help clinicians make decisions for individualized treatment.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16665-e16665
Author(s):  
Taicheng Zhou ◽  
Zhihua Cai ◽  
Ning Ma ◽  
Wenzhuan Xie ◽  
Chan Gao ◽  
...  

e16665 Background: Hepatocellular carcinoma (HCC) remains a major challenge for public health worldwide and long-term outcomes remained dismal despite availability of curative treatment. We aimed to construct a multi-gene model for prognosis prediction to inform clinical management of HCC. Methods: RNA-seq data of paired tumor and normal tissue samples of HCC patients from the TCGA and GEO database were used to identify differentially expressed genes (DEGs). DEGs shared by both cohorts along with patients’ survival data of the TCGA cohort were further analyzed using univariate Cox regression and LASSO Cox regression to build a prognostic 10-gene signature, followed by validation of the signature via ICGC cohort and identification of independent prognostic predictors. A nomogram for prognosis prediction was built and Gene Set Enrichment Analysis (GSEA) was performed to further understand the underlying molecular mechanisms. Results: Of 571 patients (70.93% men and 29.07% women; median age [IQR], 65 [56-72] years), a signature of 10 genes was constructed using the training cohort. In the testing and validation cohorts, the signature significantly stratified patients into low- vs high-risk groups in terms of overall survival across and within subpopulations with stage I/II and III/IV disease and remained as an independent prognostic factor in multivariate analyses (hazard ratio range, 0.13 [95% CI, 0.07-0.24; P < 0 .001] to 0.38 [95% CI, 0.2-0.71; P < 0.001]) after adjusting for clinicopathological factors. Prognosis was significantly worse in the high-risk group than in the low-risk group across cohorts (P < 0.001 for all). The 10-gene signature achieved a higher accuracy (C-index, 0.84; AUCs for 1-, 3- and 5-year OS, 0.84, 0.81 and 0.85, respectively) than 8 previously reported multigene signatures (C-index range, 0.67 to 0.73; AUCs range, 0.68 to 0.79, 0.68 to 0.80 and 0.67 to 0.78, respectively) for estimation of survival in comparable cohorts. A nomogram incorporating tumor stage and signature-based risk group showed better predictive performance for 1- and 3- year survival than for 5 year survival. Moreover, GSEA revealed that the pathways related to cell cycle regulation were more prominently enriched in the high-risk group while the low-risk group had higher enrichment of metabolic process. Conclusions: Taken together, we established a robust 10-gene signature and a nomogram to predict overall survival of HCC patients, which may help recognize high-risk patients potentially benefiting from more aggressive treatment.


2020 ◽  
Author(s):  
Ye Liu ◽  
Zhixiang Qin ◽  
Hai Yang ◽  
Yang Gu ◽  
Kun Li

Abstract Background Hepatocellular carcinoma (HCC) represents one of the deadliest malignancies worldwide. Despite significant advances in diagnosis and treatment, the mortality rate from HCC persists at a substantial level. This research strives to establish a prognostic model based on the RNA binding proteins (RBPs) that can predict HCC patients’ OS. Methods There was an RNA-seq data set derived from the Cancer Genome Atlas (TCGA) databank which was included in our research as well as a Microarray data set (GSE14520). The differentially expressed RBPs between HCC and normal tissues were investigated in TCGA dataset. Subsequently, the TCGA data set was randomly split into a training and a testing cohort. The prognostic model of the training cohort was developed by applying univariate Cox regression and lasso Cox regression analyses and multivariate Cox regression analysis. In order to evaluate the prognostic value of the model, a comprehensive survival assessment was conducted. Results A total of 133 differentially expressed RBPs were identified. Five RBPs (RPL10L, EZH2, PPARGC1A, ZNF239, IFIT1) were used to construct the model. The model accurately predicted the prognosis of liver cancer patients in both the TCGA cohort and the GSE14520 validation cohort. HCC patients could be assigned into a high-risk group and a low-risk group by this model, and the overall survival of these two groups was significantly different. Furthermore, the risk scores obtained by our model were highly correlated with immune cell infiltration. . Conclusions Five RBPs-related prognostic models were constructed and validated to predict OS reliably in HCC individuals. It helps to identify patients at high risk of mortality with the risk prediction score, which optimizes personalized therapeutic decision-making.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sheng Zheng ◽  
Zizhen Zhang ◽  
Ning Ding ◽  
Jiawei Sun ◽  
Yifeng Lin ◽  
...  

Abstract Introduction Angiogenesis is a key factor in promoting tumor growth, invasion and metastasis. In this study we aimed to investigate the prognostic value of angiogenesis-related genes (ARGs) in gastric cancer (GC). Methods mRNA sequencing data with clinical information of GC were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. The differentially expressed ARGs between normal and tumor tissues were analyzed by limma package, and then prognosis‑associated genes were screened using Cox regression analysis. Nine angiogenesis genes were identified as crucially related to the overall survival (OS) of patients through least absolute shrinkage and selection operator (LASSO) regression. The prognostic model and corresponding nomograms were establish based on 9 ARGs and verified in in both TCGA and GEO GC cohorts respectively. Results Eighty-five differentially expressed ARGs and their enriched pathways were confirmed. Significant enrichment analysis revealed that ARGs-related signaling pathway genes were highly related to tumor angiogenesis development. Kaplan–Meier analysis revealed that patients in the high-risk group had worse OS rates compared with the low-risk group in training cohort and validation cohort. In addition, RS had a good prognostic effect on GC patients with different clinical features, especially those with advanced GC. Besides, the calibration curves verified fine concordance between the nomogram prediction model and actual observation. Conclusions We developed a nine gene signature related to the angiogenesis that can predict overall survival for GC. It’s assumed to be a valuable prognosis model with high efficiency, providing new perspectives in targeted therapy.


PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11273
Author(s):  
Lei Yang ◽  
Weilong Yin ◽  
Xuechen Liu ◽  
Fangcun Li ◽  
Li Ma ◽  
...  

Background Hepatocellular carcinoma (HCC) is considered to be a malignant tumor with a high incidence and a high mortality. Accurate prognostic models are urgently needed. The present study was aimed at screening the critical genes for prognosis of HCC. Methods The GSE25097, GSE14520, GSE36376 and GSE76427 datasets were obtained from Gene Expression Omnibus (GEO). We used GEO2R to screen differentially expressed genes (DEGs). A protein-protein interaction network of the DEGs was constructed by Cytoscape in order to find hub genes by module analysis. The Metascape was performed to discover biological functions and pathway enrichment of DEGs. MCODE components were calculated to construct a module complex of DEGs. Then, gene set enrichment analysis (GSEA) was used for gene enrichment analysis. ONCOMINE was employed to assess the mRNA expression levels of key genes in HCC, and the survival analysis was conducted using the array from The Cancer Genome Atlas (TCGA) of HCC. Then, the LASSO Cox regression model was performed to establish and identify the prognostic gene signature. We validated the prognostic value of the gene signature in the TCGA cohort. Results We screened out 10 hub genes which were all up-regulated in HCC tissue. They mainly enrich in mitotic cell cycle process. The GSEA results showed that these data sets had good enrichment score and significance in the cell cycle pathway. Each candidate gene may be an indicator of prognostic factors in the development of HCC. However, hub genes expression was weekly associated with overall survival in HCC patients. LASSO Cox regression analysis validated a five-gene signature (including CDC20, CCNB2, NCAPG, ASPM and NUSAP1). These results suggest that five-gene signature model may provide clues for clinical prognostic biomarker of HCC.


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