Project description:The heterogeneity of hepatocellular carcinoma (HCC) poses a challenge for accurate prognosis prediction. DNA damage repair genes (DDRGs) have an impact on a wide range of malignancies. However, the relevance of these genes in HCC prognosis has received little attention. In this study, we aimed to develop a prognostic signature to identify novel therapy options for HCC. We acquired mRNA expression profiles and clinical data for HCC patients from The Cancer Genome Atlas (TCGA) database. A polygenic prognostic model for HCC was constructed using selection operator Cox analysis and least absolute shrinkage. The model was validated using International Cancer Genome Consortium (ICGC) data. Overall survival (OS) between the high-risk and low-risk groups was compared using Kaplan‒Meier analysis. Independent predictors of OS were identified through both univariate and multivariate Cox analyses. To determine immune cell infiltration scores and activity in immune-related pathways, a single-sample gene set enrichment analysis was performed. The protein and mRNA expression levels of the prognostic genes between HCC and normal liver tissues were also examined by immunohistochemistry (IHC), immunofluorescence (IF) and quantitative real-time PCR (qRT-PCR). A novel ten-gene signature (CHD1L, HDAC1, KPNA2, MUTYH, PPP2R5B, NEIL3, POLR2L, RAD54B, RUVBL1 and SPP1) was established for HCC prognosis prediction. Patients in the high-risk group had worse OS than those in the low-risk group. Receiver operating characteristic curve analysis confirmed the predictive ability of this prognostic gene signature. Multivariate Cox analysis showed that the risk score was an independent predictor of OS. Functional analysis revealed a strong association with cell cycle and antigen binding pathways, and the risk score was highly correlated with tumor grade, tumor stage, and types of immune infiltrate. High expression levels of the prognostic genes were significantly correlated with increased sensitivity of cancer cells to antitumor drugs. IHC, IF and qRT-PCR all indicated that the prognostic genes were highly expressed in HCC relative to normal liver tissue, consistent with the results of bioinformatics analysis. Ten DDRGs were utilized to create a new signature for identifying the immunological state of HCC and predicting prognosis. In addition, blocking these genes could represent a promising treatment.

Project description:Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype in renal cell carcinoma with relatively poor clinical outcomes DNA damage repair genes (DDRGs) as potential biomarkers are rarely reported in predicting immunotherapy response and clinical prognosis for ccRCC. Methods: RNA-seq and clinical data of ccRCC cohort were collected form TCGA database. Univariate Cox regression and LASSO analysis were performed to construct a DDRG risk signature. Functional enrichment analysis was performed to explore latently enriched pathways associated with DDRG signature. Immune cell infiltration level was estimated using gene set enrichment analysis, and immune response of ccRCC was predicted by tumor immune dysfunction and exclusion (TIDE) algorithm. To predict 1-, 3-, and 5-years overall survival (OS), a nomogram was constructed based on independent prognostic factors, whose performance would be evaluated by calibration curve. Results: A total of 47 DNA damage repair related genes (DDRGs) with significant prognostic value were identified in the ccRCC cohort (n = 519). A DDRG risk signature comprising six DRRGs (MSH3, RAD54L, RAD50, EME1, UNG, and NEIL3) were constructed by the LASSO analysis. ccRCC patients were then divided into low- and high-risk groups based on the risk score. Survival analysis revealed that patients in high-risk groups exhibited significantly poorer OS and progression-free survival (PFS), as was confirmed by the testing dataset. Functional enrichment analysis indicated that differentially expressed genes (DEGs) between high- and low-risk groups were mainly associated with immune-related biological processes in ccRCC, among which the immunodeficiency pathway was significantly enriched in the high-risk group. Though the risk signature was significantly correlated with the immune cell infiltration, PD-1 and PD-L1 were less expressed in the DDRG signature, which might indicate the poor response to immunotherapy in the high-risk group. Furthermore, the Cox regression analysis indicated that the DDRG signature can be served as an independent prognostic predictor when compared to clinical characteristics. Based on the independent prognostic predictors, we constructed a nomogram with excellent predictive ability in OS prediction for ccRCC patients. Conclusion: We developed a reliable DDRG risk signature that can independently predict the OS and PFS of ccRCC, which is also promising for predicting immunotherapeutic responses in ccRCC patients.

Project description:Background - Hepatocellular carcinomas (HCCs) are heterogeneous tumors with respect to etiology, cell of origin and biology. The course of the disease is unpredictable and is in part dependent on the tumor microenvironment. One of the microenvironmental factors is hypoxia, which is known to promote aggressiveness in other malignant tumors. We hypothesized that certain regions in HCC exist with chronic hypoxia and a characteristic gene expression pattern. Moreover, during the development of HCC there is an important contribution of this chronic hypoxia on prognosis via this gene expression. Until now, most research has been performed in acute hypoxic models (< 24 hours). Methods – Human hepatoblastoma cells HepG2 were cultured in either normoxic (20% O2) or hypoxic (2% O2) conditions for 72 hrs, the time it takes to adapt to chronic hypoxia. After 3 days the cells were harvested and analyzed by microarray technology. The highly significant differentially expressed genes were selected and used to assess the clinical value of our in vitro chronic hypoxia gene signature in four published patient studies. Three of these independent microarray studies on HCC patients were used as training sets to determine a minimal prognostic gene set and one study was used for validation. Gene expression analysis and correlation with clinical outcome was assessed with the bioinfomatic method of Goeman et al (). Results – In the HepG2 cells, 3592 genes were differentially expressed in cells cultured at 2% oxygen for 72 hrs. Out of these, 265 showed a high significant change (2-fold change and p=0.0001). The level of gene expression after 72 hrs was different from the acute hypoxic response (during the first 24 hours) and represented chronicity. Using computational methods we identified 7 out of the 265 highly significant genes that showed correlation with prognosis in all three different training sets and this was independently validated in a 4th dataset. With our approach we could include the largest number of HCC patients in one single study. Conclusion – We identified a 7-gene signature, which is associated with chronic hypoxia and predicts prognosis in patients with HCC. In the future this signature could be used as a diagnostic tool. In addition, chronic hypoxia gene expression information can be used in the search for new therapeutic targets. Two conditions were compared and each sample has a biological replicate. Samples are hybridized in dye-swap, resulting in 4 hybridizations.

Project description:Background: Nowadays, although the cause of hepatocellular carcinoma (HCC) mortality and recurrence remains at a high level, the 5-year survival rate is still very low. The DNA damage response and repair (DDR) pathway may affect HCC patients' survival by influencing tumor development and therapeutic response. It is necessary to identify a prognostic DDR-related gene signature to predict the outcome of patients. Methods: Level 3 mRNA expression and clinical information were extracted from the TCGA website. The GSE14520 datasets, ICGC-LIRI datasets, and a Chinese HCC cohort were served as validation sets. Univariate Cox regression analysis and LASSO-penalized Cox regression analysis were performed to construct the DDR-related gene pair (DRGP) signature. Kaplan-Meier survival curves and time-dependent receiver operating characteristic (ROC) analysis curves were calculated to determine the predictive ability of this prognostic model. Then, a prognostic nomogram was established to help clinical management. We investigated the difference in biological processes between HRisk and LRisk by conducting several enrichment analyses. The TIDE algorithm and R package "pRRophetic" were applied to estimate the immunotherapeutic and chemotherapeutic response. Results: We constructed the prognostic signature based on 23 DDR-related gene pairs. The patients in the training datasets were divided into HRisk and LRisk groups at median cut-off. The HRisk group had significantly poorer OS than the LRisk group, and the signature was an independent prognostic indicator in HCC. Furthermore, a nomogram of the riskscore combined with TNM stage was constructed and detected by the calibration curve and decision curve. The LRisk group was associated with higher expression of HBV oncoproteins and metabolism pathways, while DDR-relevant pathways and cell cycle process were enriched in the HRisk group. Moreover, patients in the LRisk group may be more beneficial from immunotherapy. We also found that TP53 gene was more frequently mutated in the HRisk group. As for chemotherapeutic drugs commonly used in HCC, the HRisk group was highly sensitive to 5-fluorouracil, while the LRisk group presented with a significantly higher response to gefitinib and gemcitabine. Conclusion: Overall, we developed a novel DDR-related gene pair signature and nomogram to assist in predicting survival outcomes and clinical treatment of HCC patients. It also helps understand the underlying mechanisms of different DDR patterns in HCC.

Project description:Background - Hepatocellular carcinomas (HCCs) are heterogeneous tumors with respect to etiology, cell of origin and biology. The course of the disease is unpredictable and is in part dependent on the tumor microenvironment. One of the microenvironmental factors is hypoxia, which is known to promote aggressiveness in other malignant tumors. We hypothesized that certain regions in HCC exist with chronic hypoxia and a characteristic gene expression pattern. Moreover, during the development of HCC there is an important contribution of this chronic hypoxia on prognosis via this gene expression. Until now, most research has been performed in acute hypoxic models (< 24 hours). Methods – Human hepatoblastoma cells HepG2 were cultured in either normoxic (20% O2) or hypoxic (2% O2) conditions for 72 hrs, the time it takes to adapt to chronic hypoxia. After 3 days the cells were harvested and analyzed by microarray technology. The highly significant differentially expressed genes were selected and used to assess the clinical value of our in vitro chronic hypoxia gene signature in four published patient studies. Three of these independent microarray studies on HCC patients were used as training sets to determine a minimal prognostic gene set and one study was used for validation. Gene expression analysis and correlation with clinical outcome was assessed with the bioinfomatic method of Goeman et al (). Results – In the HepG2 cells, 3592 genes were differentially expressed in cells cultured at 2% oxygen for 72 hrs. Out of these, 265 showed a high significant change (2-fold change and p=0.0001). The level of gene expression after 72 hrs was different from the acute hypoxic response (during the first 24 hours) and represented chronicity. Using computational methods we identified 7 out of the 265 highly significant genes that showed correlation with prognosis in all three different training sets and this was independently validated in a 4th dataset. With our approach we could include the largest number of HCC patients in one single study. Conclusion – We identified a 7-gene signature, which is associated with chronic hypoxia and predicts prognosis in patients with HCC. In the future this signature could be used as a diagnostic tool. In addition, chronic hypoxia gene expression information can be used in the search for new therapeutic targets.

Project description:BackgroundDue to the viral infection, chronic inflammation significantly increases the likelihood of hepatocellular carcinoma (HCC) development. Nevertheless, an inflammation-based signature aimed to predict the prognosis and therapeutic effect in virus-related HCC has rarely been established.MethodBased on the integrated analysis, inflammation-associated genes (IRGs) were systematically assessed. We comprehensively investigated the correlation between inflammation and transcriptional profiles, prognosis, and immune cell infiltration. Then, an inflammation-related risk model (IRM) to predict the overall survival (OS) and response to treatment for virus-related HCC patients was constructed and verified. Also, the potential association between IRGs and tumor microenvironment (TME) was investigated. Ultimately, hub genes were validated in plasma samples and cell lines via qRT-PCR. After transfection with shCCL20 combined with overSLC7A2, morphological change of SMMC7721 and huh7 cells was observed. Tumorigenicity model in nude mouse was established.ResultsAn inflammatory response-related gene signature model, containing MEP1A, CCL20, ADORA2B, TNFSF9, ICAM4, and SLC7A2, was constructed by conjoint analysis of least absolute shrinkage and selection operator (LASSO) Cox regression and gaussian finite mixture model (GMM). Besides, survival analysis attested that higher IRG scores were positively relevant to worse survival outcomes in virus-related HCC patients, which was testified by external validation cohorts (the ICGC cohort and GSE84337 dataset). Univariate and multivariate Cox regression analyses commonly proved that the IRG was an independent prognostic factor for virus-related HCC patients. Thus, a nomogram with clinical factors and IRG was also constructed to superiorly predict the prognosis of patients. Featured with microsatellite instability-high, mutation burden, and immune activation, lower IRG score verified a superior OS for sufferers. Additionally, IRG score was remarkedly correlated with the cancer stem cell index and drug susceptibility. The measurement of plasma samples further validated that CCL20 upexpression and SLC7A2 downexpression were positively related with virus-related HCC patients, which was in accord with the results in cell lines. Furthermore, CCL20 knockdown combined with SLC7A2 overexpression availably weakened the tumor growth in vivo.ConclusionsCollectively, IRG score, serving as a potential candidate, accurately and stably predicted the prognosis and response to immunotherapy in virus-related HCC patients, which could guide individualized treatment decision-making for the sufferers.

Dataset Information

DNA Damage Repair Status Predicts Opposite Clinical Prognosis Immunotherapy and Non-Immunotherapy in Hepatocellular Carcinoma.

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