Gene Signature to Identify Vascular Invasion in Human Hepatocellular Carcinoma
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ABSTRACT: This SuperSeries is composed of the following subset Series: GSE9843: Gene expression profiling of 91 hepatocellular carcinomas with hepatitis C virus etiology, Samples with "vascular invasion: Yes/No" were included in the study. GSE20017: Gene Signature to Identify Vascular Invasion in Hepatocellular Carcinoma Refer to individual Series
Project description:This SuperSeries is composed of the following subset Series: GSE9843: Gene expression profiling of 91 hepatocellular carcinomas with hepatitis C virus etiology, Samples with "vascular invasion: Yes/No" were included in the study. GSE20017: Gene Signature to Identify Vascular Invasion in Hepatocellular Carcinoma Refer to individual Series
Project description:Background: The presence of vascular invasion (VI) in pathology specimens has been widely described as closely linked to poor outcome in hepatocellular carcinoma (HCC) patients after tumor resection. Previous attempts have been conducted to achieve molecular markers or signatures to predict HCC recurrence in HCC. Here, we aim to develop a diagnostic model combining clinical and genomic variables able to detect the presence of VI prior to surgery and link it to survival estimation. Methods: Seventy-nine HCV related HCC samples from patients that underwent surgical resection as a treatment for HCC were subjected to Genome-wide gene expression profiling and a predictive model of vascular invasion was constructed. The model was tested in an independent-validation set of 153 fixed tissue samples of resected HCC. Quantitative RTPCR and inmunohistochemistry were performed in HCC samples to test a potential biomarker. Results: A 39-gene signature was able to accurately (72%) identify vascular invasion in HCC patients treated with resection. A model including tumor size and the signature is able to predict presence of VI with 85% accuracy in HCV-related HCC patients, and is able to exclude VI in up to 87% cases in HCC from all etiologies. Conclusions: Using the VI gene signature together with tumor size, VI can be successfully detected in HCC patients. The diagnostic model, integrated in a previously reported survival chart is able to provide an estimated survival for selected cases. Clinical implications of this fact are relevant to provide objective data to further apply expanded indication of curative treatments in HCC.
Project description:Background: The presence of vascular invasion (VI) in pathology specimens has been widely described as closely linked to poor outcome in hepatocellular carcinoma (HCC) patients after tumor resection. Previous attempts have been conducted to achieve molecular markers or signatures to predict HCC recurrence in HCC. Here, we aim to develop a diagnostic model combining clinical and genomic variables able to detect the presence of VI prior to surgery and link it to survival estimation. Methods: Seventy-nine HCV related HCC samples from patients that underwent surgical resection as a treatment for HCC were subjected to Genome-wide gene expression profiling and a predictive model of vascular invasion was constructed. The model was tested in an independent-validation set of 153 fixed tissue samples of resected HCC. Quantitative RTPCR and inmunohistochemistry were performed in HCC samples to test a potential biomarker. Results: A 39-gene signature was able to accurately (72%) identify vascular invasion in HCC patients treated with resection. A model including tumor size and the signature is able to predict presence of VI with 85% accuracy in HCV-related HCC patients, and is able to exclude VI in up to 87% cases in HCC from all etiologies. Conclusions: Using the VI gene signature together with tumor size, VI can be successfully detected in HCC patients. The diagnostic model, integrated in a previously reported survival chart is able to provide an estimated survival for selected cases. Clinical implications of this fact are relevant to provide objective data to further apply expanded indication of curative treatments in HCC. Gene-expression profiling was performed using formalin-fixed, paraffin-embedded hepatocellular carcinoma tissues obtained at the time of surgical resection.
Project description:Vascular invasion is a major predictor of tumor recurrence after surgical treatments for hepatocellular carcinoma (HCC). While macroscopic vascular invasion can be detected by radiological techniques, pre-operative detection of microscopic vascular invasion, which complicates 30-40% of patients with early tumors, remains elusive.A total of 214 patients with hepatocellular carcinoma who underwent resection were included in the study. By using genome-wide gene-expression profiling of 79 hepatitis C-related hepatocellular carcinoma samples (training set), a gene-expression signature associated with vascular invasion was defined. The signature was validated in formalin-fixed paraffin-embedded tissues obtained from an independent set of 135 patients with various etiologies.A 35-gene signature of vascular invasion was defined in the training set, predicting vascular invasion with an accuracy of 69%. The signature was independently associated with the presence of vascular invasion (OR 3.38, 95% CI 1.48-7.71, p=0.003) along with tumor size (diameter greater than 3 cm, OR 2.66, 95% CI 1.17-6.05, p=0.02). In the validation set, the signature discarded the presence of vascular invasion with a negative predictive value of 0.77, and significantly improved the diagnostic power of tumor size alone (p=0.045).The assessment of a gene-expression signature obtained from resected biopsied tumor specimens improved the diagnosis of vascular invasion beyond clinical variable-based prediction. The signature may aid in candidate selection for liver transplantation, and guide the design of clinical trials with experimental adjuvant therapies.
Project description:The aim of the present study was to identify a vascular invasion-associated gene signature for predicting prognosis in patients with hepatocellular carcinoma (HCC). Using RNA-sequencing data of 292 HCC samples from The Cancer Genome Atlas (TCGA), the present study screened differentially expressed genes (DEGs) between patients with and without vascular invasion. Feature genes were selected from the DEGs by support vector machine (SVM)-based recursive feature elimination (RFE-SVM) algorithm to build a classifier. A multi-gene signature was selected by L1 penalized (LASSO) Cox proportional hazards (PH) regression model from the feature genes selected by the RFE-SVM to develop a prognostic scoring model. TCGA set was defined as the training set and was divided by the gene signature into a high-risk group and a low-risk group. Involvement of the DEGs between the two risk groups in pathways was also investigated. The presence and absence of vascular invasion between patients of training set was 175 DEGs. A classification model of 42 genes performed well in differentiating patients with and without vascular invasion on the training set and the validation set. A 14-gene prognostic model was built that could divide the training set or the validation set into two risk groups with significantly different survival outcomes. A total of 762 DEGs in the two risk groups of the training set were revealed to be significantly associated with a number of signaling pathways. The present study provided a 42-gene classifier for predicting vascular invasion, and identified a vascular invasion-associated 14-gene signature for predicting prognosis in patients with HCC. Several genes and pathways in HCC development are characterized and may be potential therapeutic targets for this type of cancer.
Project description:ObjectivesMost signatures are constructed on the basis of RNA or protein expression levels. The value of vascular invasion-related signatures based on lncRNA pairs, regardless of their specific expression level in hepatocellular carcinoma (HCC), is not yet clear.MethodsVascular invasion-related differentially expressed lncRNA (DElncRNA) pairs were identified with a two-lncRNA combination strategy by using a novel modeling algorithm. Based on the optimal cutoff value of the ROC curve, patients with HCC were classified into high- and low-risk subgroups. We used KM survival analysis to evaluate the overall survival rate of patients in the high- and low-risk subgroups. The independent indicators of survival were identified using univariate and multivariate Cox analyses.ResultsFive pairs of vascular invasion-related DElncRNAs were selected to develop a predictive model for HCC. High-risk subgroups were closely associated with aggressive clinicopathological characteristics and genes, chemotherapeutic sensitivity, and highly expressed immune checkpoint inhibitors.ConclusionsWe identified a signature composed of 5 pairs of vascular invasion-related lncRNAs that does not require absolute expression levels of lncRNAs and shows promising clinical predictive value for HCC prognosis. This predictive model provides deep insight into the value of vascular invasion-related lncRNAs in prognosis.
Project description:Background: Understanding risk factors for vascular invasion (VI) is crucial for assessing the risk of recurrence and overall prognosis of hepatocellular carcinoma (HCC). This study aimed to construct a prognostic long non-coding RNA (lncRNA) signature and a ceRNA Network associated with vascular invasion in HCC. Methods: Differentially expressed genes (DEGs) of HCC patients associated with VI were identified by analyzing data from TCGA. Weighted gene co-expression network analysis (WGCNA) was used to identify associations between gene expression modules and clinical features. A VI-related prognostic lncRNA signature was then established using univariate, LASSO and multivariate Cox proportional hazards regression analyses. Based on the hub modules identified by the WGCNA, we constructed a VI-related lncRNA-miRNA-mRNA ceRNA network and screened hub lncRNAs for further research. Finally, we conducted in vitro and in vivo experiments to determine the biological roles of the identified hub gene BBOX1-AS1. Results: The key module related to VI and OS was identified using WGCNA, after which a prognostic model consisting of eight lncRNAs was established, and verified using time-dependent receiver operating characteristic (ROC) curve analysis. BBOX1-AS1 was confirmed to be highly expressed in HCC tissues, and its expression was significantly correlated with a poor prognosis. Silencing BBOX1-AS1 in vitro significantly suppressed the proliferation, migration and invasion of HCC cells. In vivo experiments demonstrated that knocking down of BBOX1-AS1 could result in significant decrease of tumor volume and tumor weight. Conclusions: The VI-related lncRNA signature established in this study can be used to predict the clinical outcomes of HCC patients. In addition, we constructed a VI-related lncRNA-miRNA-mRNA ceRNA network and demonstrated that BBOX1-AS1 might be a novel biomarker associated with VI in HCC.