These results suggested that DE CDGs in the HCC play an important role in the key process in cancer development, such as epigenetic modification and various signaling pathways. (A) Survival curves stratified by the risk score in the ICGC cohort. Finally, the stepwise multivariate COX regression analysis was performed to find the optimal key prognostic-related CDGs and obtained standardized regression coefficients. cancer driver genes A total of 568 human CDGs obtained from the somatic mutations of more than 28,000 tumors of 66 cancer types were included in our study (Supplementary Table S1). (A) Heatmap of differentially expressed CDGs between HCC and normal tissues. doi:10.1158/1078-0432.CCR-17-1789, Dang, C. V. (2012). Triangles indicate active residues of the protein in which mutation occurs. Phone: +34 93 402 02 50 (D) Survival curves stratified by the nomogram score in the ICGC cohort. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. (D) Differences in the immune cells infiltrated in the tumor microenvironment between the low- and high-risk groups. By univariate Cox regression analysis, 96 genes were found to be associated with the survival of HCC patients. Nature 464, 993998 (2010). GUID:AF2692AA-862A-4585-AEC5-EA46338F53F1, GUID:550B0826-4E91-4470-87DD-E3BF7961BF72, cancer driver gene, tumor microenvironment, prognosis, nomogram, hepatocellular carcinoma. WMDS.net: a network control framework for identifying key players in transcriptome programs. Recently, the journal of Nature Reviews Cancer reported a compendium of 568 cancer driver genes (CDGs), which was identified from more than 28,000 tumors of 66 cancer types (Martinez-Jimenez et al., 2020). (C) Differences in the proportions of immune-related pathways between the low- and high-risk groups. Bookshelf A systematic approach combining several of these signals could lead to a compendium of mutational cancer genes. Independent prognostic role of the prognostic signature. Comprehensive identification of mutational cancer driver genes across 12 tumor types. Cell 173 (2), 338354. The low-score group, which showed better prognosis, had a high proportion of CD8+ T cells and elevated expression of interferon-related signaling pathways. A fundamental goal in cancer research is to understand the mechanisms of cell transformation. FIGURE 5. GO and KEGG pathway enrichment analyses were carried out to explore the functions and signaling pathways of the DE CDGs. Recently, the journal of Our method refers to the fact that cancer should not be considered as a single process but a compendium of altered biological processes causing the disease (2017). Combined effects of PLK1 and RAS in hepatocellular carcinoma reveal rigosertib as promising novel therapeutic "dual-hit" option. Comprehensive identification of mutational cancer driver Taken together, our results suggested that the risk scores based on the seven CDGs had optimal prediction ability of the prognosis of HCC patients. (A) Nomogram based on the risk score and the clinical factors. Protein domains retrieved from Pfam are depicted. The original contributions presented in the study are included in the article/Supplementary Material; further inquiries can be directed to the corresponding author. KEGG pathway enrichment analysis showed that upregulated DE CDGs were highly enriched in PI3K-Akt signaling pathway, hepatocellular carcinoma, cell cycle, and so on (Figure 1F). 568 genes identified with the potential to trigger cancer New advances in hepatocellular carcinoma. Mechanism of activation of a human oncogene. doi:10.18632/oncotarget.23188, Dietrich, P., Gaza, A., Wormser, L., Fritz, V., Hellerbrand, C., Bosserhoff, A. K., et al. Genetic interaction analysis identified that mutations of TP53 were positively correlated with mutations of FAT3 and OBSCN and negatively correlated with CTNNB1. and transmitted securely. LASSO regression and stepwise multivariate regression analyses found that a novel prognostic model comprising seven cancer driver genes was able to accurately distinguish HCC patients with different prognosis. WebThe purpose of this review is to summarize the evidence that can be used to reconstruct the etiology of human cancers from mutations found in tumors. Cancer 3 (3), 226231. A systematic approach combining several of these signals could lead to a compendium of mutational cancer genes. 2020 Oct;20(10):555-572. doi: 10.1038/s41568-020-0290-x. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). doi:10.1038/nrc1016, Malta, T. M., Sokolov, A., Gentles, A. J., Burzykowski, T., Poisson, L., Weinstein, J. N., et al. eCollection 2023. Of note, most of the DE CDGs were highly expressed in the cancer tissues than in normal tissues. The risk score of each sample was calculated by the formula presented above. doi:10.1038/nature04695, Finn, R. S., Qin, S., Ikeda, M., Galle, P. R., Ducreux, M., Kim, T. Y., et al. However, only a small fraction of HCC patients can benefit from these novel therapeutic options, and some patients inevitably suffer from drug resistance (Kimura et al., 2018). Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. Hepatology 40 (3), 677686. The expression of major immune genes, such as CCL2, CD274, CD276, CD4, CTLA4, CXCR4, IL1A, IL6, LAG3, TGFB1, TNFRSF4, TNFRSF9, and PDCD1LG2, in subgroup 2 was almost significantly lower than that in subgroup 1 and subgroup 3, which is consistent with the results of tumor purity analysis. Moreover, the infiltrating immune cell subtypes were significantly different between the high-risk group and the low-risk group, with more CD8+T cells and less M0 macrophages accumulating in low-risk score tumors (Figure 5D). To assess the prognostic capacity of the seven-gene signature, we calculated the risk score for each patient and classified the patients into low- and high-risk groups based on the medium risk score value. A compendium of mutational cancer driver genes | Request PDF Proc. Methods 12 (5), 453457. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The nomogram was also validated in the ICGC dataset, and patients with a low score had a significantly better survival rate than those with a high score (p = 1.178e-02) (Figure 6D). Gagrica S., Brookes S., Anderton E., Rowe J., Peters G. (2012). 14, 321332 (2013). In the cellular component (CC) category, nuclear chromatin, chromosomal region, and transcription factor complex were significantly enriched. Kimura T., Kato Y., Ozawa Y., Kodama K., Ito J., Ichikawa K., et al. Kudo M., Finn R. S., Qin S., Han K. H., Ikeda K., Piscaglia F., et al. A total of 230 HCC patient cases with gene expression and complete clinical information from the International Cancer Genome Consortium (ICGC) dataset were used as a validation set. Finding driver mutations in cancer: Elucidating the role of background mutational processes. Ther. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. (2000). Cumulative mutations in driver genes are the essential cause of cancer disease. doi:10.1038/s41568-020-0290-x, Morishita, A., Masaki, T., Yoshiji, H., Nakai, S., Ogi, T., Miyauchi, Y., et al. World J. Hepatol. GSEA was performed to explore the underlying biological processes related to the risk score signature. Pan-cancer analysis of somatic mutations in miRNA genes. HHS Vulnerability Disclosure, Help The molecular function (MF) term mainly included transcription coactivator activity, ubiquitin protein ligase binding, and ubiquitin-like protein ligase binding (Figure 1E). Direct small-molecule inhibitors of KRAS: From structural insights to mechanism-based design. Trimmed version of the functional interaction network integrated, (A) Diagram showing 13 selected candidate cancer genes within their functional interaction context., (A) Histogram of the proportion of samples in the pancancer dataset with PAMs, MeSH Third, most HCC patients in the TCGA database were Caucasian, and it is not clear whether the risk signature has the same predictive effect in non-Caucasian races. In this Review, we present the Integrative OncoGenomics (IntOGen) pipeline, an implementation of such an approach to obtain the compendium of mutational Cancer driver genes (CDGs) play an important role in the carcinogenesis and progression of HCC. Biomedical Genomics (C) Mutation spectrum of the top 30 most frequently mutated DE CDGs in the TCGA-LIHC cohort, with each column representing one patient and the percentage on the right side representing the corresponding gene mutation rate. (2017). Mutations in driver genes support the acquisition of cancer hallmarks (Hanahan and Weinberg, 2000; Hanahan and Weinberg, 2011). The gene mutation and clinical data of TCGA-LIHC were also downloaded from the TCGA database. 2019 Dec;59:23-35. doi: 10.1016/j.semcancer.2019.06.007. Developing novel prediction models could guide patient prognostic stratification and facilitate personalized therapy. eCollection 2023. Rev. Cancer Sci. In this study, we comprehensively investigated the expression, mutation, and prognostic significance of 568 CDGs in HCC. (2013). doi:10.1016/j.bbaexp.2004.03.008, Leroi, A. M., Koufopanou, V., and Burt, A. (2020). (2019). The https:// ensures that you are connecting to the Hallmarks of cancer: The next generation. FOIA First, the risk signature was built based on the TCGA-LIHC dataset and was only validated in the ICGC HCC dataset. (2020). International network of cancer genome projects. PLoS Comput. Patients with high-risk scores had more mortality and shorter survival time (Figures 3B,C). Science 331, 15531558 (2011). (A) Diagram showing 13 selected candidate cancer genes within their functional interaction context. Hepatocellular carcinoma: Past and future of molecular target therapy. Forkhead Box F1 promotes breast cancer cell migration by upregulating lysyl oxidase and suppressing Smad2/3 signaling. (2017). official website and that any information you provide is encrypted Moreover, it had more CD8+T cells and less M0 macrophages infiltrated. Cell 149 (1), 2235. Hepatocellular carcinoma: Clinical frontiers and perspectives. Moreover, the receiver operating characteristic (ROC) curves were generated by the SurvivalROC R package to determine the accuracy of the gene signature. (F) Correlation between risk score and cancer stemness score (RNAss) based on Spearmans correlation tests. 2023 Apr 27;14:1148848. doi: 10.3389/fneur.2023.1148848. LOX overexpression can predict early recurrence and poor prognosis of HCC (Umezaki et al., 2019). Whole-exome sequencing reveals recurrent somatic mutation networks in cancer. 2023 May 26;21:3124-3135. doi: 10.1016/j.csbj.2023.05.019. -, Consortium T. C. G. A. et al. Owing to the specific phenotypes, most HCC patients are diagnosed at an advanced stage with extremely poor prognosis (El-Serag, 2011). Biochem. (A,B) Univariate and multivariate Cox analyses for the prognostic model and other clinical features in the TCGA cohort. The .gov means its official. The most common type of liver cancer is hepatocellular carcinoma (HCC). This site needs JavaScript to work properly. Comprehensive identification of mutational cancer driver genes Our study showed the important role of CDGs in HCC and provides a novel prognostic indicator for HCC. Epub 2019 Jun 27. Mol Biosyst. MYCN, one of the members of the MYC family, plays crucial roles in regulating normal stem cellmediated tissue regeneration and stem cellmediated tumorigenesis (Dang, 2012; Qin et al., 2017). Nature 300, 143149 (1982). doi:10.1016/j.cell.2012.03.003, Dietrich, P., Freese, K., Mahli, A., Thasler, W. E., Hellerbrand, C., Bosserhoff, A. K., et al. Consistent with the TCGA dataset, high-risk score patients exhibited a significantly worse outcome (p = 3.581e-4) (Figure 3A). B., Sangro, B., Yau, T., Crocenzi, T. S., Kudo, M., Hsu, C., et al. Cancer Lett. Molecular targeted therapy for advanced hepatocellular carcinoma: Current status and future perspectives. Mutations in driver genes support the acquisition of cancer hallmarks (Hanahan and Weinberg, 2000; Hanahan and Weinberg, 2011). Further research should be conducted to elucidate the relevant mechanisms. This article describes the use of an ensemble of bioinformatics methods to identify mutational cancer driver genes across a large pan-cancer cohort as well as an approach to combine their outputs into a unified list of driver genes. These results suggested good accuracy and stability of our prognostic signature. -, Mwenifumbo, J. C. & Marra, M. A. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. Searching differentially expressed CDGs in the TCGA cohort. Cancer Res. (A,B) LASSO Cox regression analysis of the selection of CDGs. (2019). This is key to These results indicated that the heterogeneity of HCC may be due to the diverse genetic abnormalities of cancer cells. Circles represent protein affecting mutation across pan-cancer samples, and are colored according to their functional impact calculated by the Mutation Assessor method. A census of human cancer genes. Genet. Qin X. Y., Suzuki H., Honda M., Okada H., Kaneko S., Inoue I., et al. A systematic approach combining several of these signals could lead to a compendium of mutational cancer genes. In the ICGC cohort, the hazard ratio of the risk score was 1.649 and 95% confidence interval (CI) was 1.2062.265 (p = 0.002) in the univariate Cox regression and 1.653 (1.2062.656) in the multivariate regression (Figures 4D,E). LOX overexpression can predict early recurrence and poor prognosis of HCC (Umezaki et al., 2019). 57% of tumors harbor potentially actionable oncogenic events. MYC on the path to cancer. Acad. The mutation pattern of differentially expressed genes was analyzed by the Maftools R package. Oncol. Acad. No use, distribution or reproduction is permitted which does not comply with these terms. Dysregulated CDKN2C and its protease activity change are associated with the prognosis of HCC (Morishita et al., 2004). Among those genes, some have not been previously identified as cancer drivers and 16 have clear preference to sustain mutations in one specific tumor type. Research Institute For Gastroenterology & Liver Diseases, Shahid Beheshti University of Medical Sciences, Iran, Changhai Hospital, Second Military Medical University, China, School of Medicine, University of Maryland, United States. Bailey, M. H. et al. El Naofal, M., Kim, A., Yon, H. Y., Baity, M., Ming, Z., Bui-Griffith, J., et al. The prognostic signature that we constructed consisted of seven cancer driver genes (CDKN2C, HRAS, IRAK1, LOX, MYCN, NRAS, and PABPC1). doi:10.1038/nrd.2016.139, Pascual, S., Herrera, I., and Irurzun, J. doi:10.1016/j.cell.2018.03.034, Martinez-Jimenez, F., Muinos, F., Sentis, I., Deu-Pons, J., Reyes-Salazar, I., Arnedo-Pac, C., et al. Tumorigenesis is often associated with alterations in the tumor microenvironment. (F) KEGG enrichment analysis of the upregulated DE CDGs. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. GO enrichment analysis showed that the upregulated DE CDGs were mainly associated with regulation of DNA metabolic process, covalent chromatin modification, histone modification, and histone methylation of the biological process (BP) category. WebA compendium of mutational cancer driver genes. El-Khoueiry A. We found most cancer hallmarks, including the VEGF signaling pathway, cell cycle, DNA replication, ERBB signaling pathway, double strand break repair, positive regulation of intracellular transport, and regulation of mitotic cell cycle, were significantly enriched in patients in the high-risk score group (Figures 5A,B). FOIA Stratton, M. R., Campbell, P. J. Cell 144 (5), 646674. (A,B) Univariate and multivariate Cox analyses for the prognostic model and other clinical features in the TCGA cohort. Nature Reviews Cancer, 20(10), 555572. The calibration curves showed that the nomogram had good prediction performance in HCC patients (Figure 6B). symbols.gmt (Subramanian et al., 2005). Expression and prognostic roles of PABPC1 in hepatocellular carcinoma. doi:10.1111/cas.13806, Kudo, M., Finn, R. S., Qin, S., Han, K. H., Ikeda, K., Piscaglia, F., et al. doi:10.1200/JCO.19.01307, Flannery, S., and Bowie, A. G. (2010). doi:10.1158/0008-5472.CAN-11-2552, Hanahan, D., and Weinberg, R. A. 38 (3), 193202. Our study showed the important role of CDGs in HCC and provides a novel prognostic indicator for HCC. cancer drivers Mutations in driver genes support the acquisition of cancer hallmarks (Hanahan and Weinberg, 2000; Hanahan and Weinberg, 2011). LASSO regression and stepwise multivariate regression analyses found that a novel prognostic model comprising seven cancer driver genes was able to accurately distinguish HCC patients with different prognosis. Further research should be conducted to elucidate the relevant mechanisms. J. Med. Mutations in driver genes support the acquisition of cancer hallmarks (Hanahan and Weinberg, 2000; Hanahan and Weinberg, 2011). Larger cohorts containing more patients are needed to verify the prognostic value of the risk score signature and nomogram. An official website of the United States government. Transcriptome analysis uncovers a growth-promoting activity of orosomucoid-1 on hepatocytes. (C) Forest plot of the seven genes that construct the risk signature. HHS Vulnerability Disclosure, Help 2016 Aug 16;12(9):2921-31. doi: 10.1039/c6mb00274a. 107 (1), 1319. In our study, the low-risk score group showed elevated expression of Type_1_IFN_Response and Type_2_IFN_Response signaling pathways compared to its counterpart. Cheng X, Amanullah M, Liu W, Liu Y, Pan X, Zhang H, Xu H, Liu P, Lu Y. Bioinformatics. symbols.gmt and c5. 47 (5), 523528. Leroi A. M., Koufopanou V., Burt A. Targets. Unauthorized use of these marks is strictly prohibited. (2013). A nomogram consisting of the risk score and several clinical factors was constructed, which showed great accuracy to predict the prognosis of HCC patients. Natl. go.bp.v7.5. To assess the prognostic capacity of the seven-gene signature, we calculated the risk score for each patient and classified the patients into low- and high-risk groups based on the medium risk score value. The GSVA package was used to compare the immune-related pathways between the two subgroups (Hanzelmann et al., 2013). Dietrich P., Freese K., Mahli A., Thasler W. E., Hellerbrand C., Bosserhoff A. K., et al. 72 (1), 165175. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Traditional tumor markers including clinical tumor-node-metastasis (TNM) staging, vascular invasion, and other parameters help predict HCC prognosis (Bruix et al., 2016); however, these are gradually showing their limitations with the evolution of HCC management. In other words, genes with at least two signals of positive selection either in the pan-cancer analysis and/or any per-project analysis were nominated as high-confidence drivers. FOIA Anti-PD-1/L1 therapies, such as atezolizumab, pembrolizumab, and nivolumab, have shown promising benefits in a subset of HCC patients, alone or in combination with other agents (El-Khoueiry et al., 2017; Zhu et al., 2018; Finn et al., 2020a; Finn et al., 2020b). doi:10.1016/S1470-2045(18)30351-6, Keywords: cancer driver gene, tumor microenvironment, prognosis, nomogram, hepatocellular carcinoma, Citation: Zou J and Qin W (2022) Comprehensive analysis of the cancer driver genes constructs a seven-gene signature for prediction of survival and tumor immunity in hepatocellular carcinoma. Unable to load your collection due to an error, Unable to load your delegates due to an error. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lab. -. Genes annotated in the CGC are represented as round squares, HCDs not in CGC are represented as circles and non-HCDs used as linkers between HCDs as diamonds. Gene set enrichment analysis (GSEA) was performed using the gene set c2. Patients were assigned into low-risk groups and high-risk groups by the median value of the risk score, and the KaplanMeier curve was plotted by the Survival R package. Construction of the prognostic risk model based on seven CDGs. Brown A. L., Li M., Goncearenco A., Panchenko A. R. (2019). The application of this approach to the ever-growing datasets of somatic tumour mutations will support the continuous refinement of our knowledge of the genetic basis of cancer. The annotations below indicate methods that identify each gene signals of positive selection. The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signalling. These results implied that the low-risk group might have a better immune microenvironment and responded better to immune checkpoint inhibitors. A compendium of mutational cancer driver genes. - SciSpace by Machine learning identifies stemness features associated with oncogenic dedifferentiation. These results suggested good accuracy and stability of our prognostic signature. Mutations in driver genes support the acquisition of cancer hallmarks (Hanahan and Weinberg, 2000; Hanahan and Weinberg, 2011). Federal government websites often end in .gov or .mil. Contrasting behavior of the p18INK4c and p16INK4a tumor suppressors in both replicative and oncogene-induced senescence. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial, Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. 45 (8), 794807. Epub 2020 Aug 10. The seven genes identified were CDKN2C, HRAS, IRAK1, LOX, MYCN, NRAS, and PABPC1. National Library of Medicine Differentially expressed CDGs between cancer and normal tissues were identified by Wilcoxon test with |log2 fold change (FC)| 1 and FDR (false discovery rate) < 0.05. Here we show that the combination of complementary methods allows identifying a comprehensive and reliable list of cancer driver genes. MeSH Hepatocellular carcinoma. (D,E) Univariate and multivariate Cox analyses for the prognostic model and other clinical features in the ICGC cohort. Authors: Reduced expression of cell cycle regulator p18(INK4C) in human hepatocellular carcinoma. At present, cancer genome projects have identified 576 cancer driver genes on the basis of some 30,000 malignant tumors. The site is secure. However, immune-related pathways including Type_1_IFN_Response and Type_2_IFN_Response were significantly overexpressed in the low-risk score group (Figure 5C). 8600 Rockville Pike Lancet. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: A randomized, double-blind, phase III trial, The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signalling. Moreover, the receiver operating characteristic (ROC) curves were generated by the SurvivalROC R package to determine the accuracy of the gene signature. Onco. This study highlighted the significance of CDGs in the HCC and provided a novel horizon for the investigation of HCC in the future. Inheritance based on the allele combination of multiple tumor modifier genes capable of modulate the phenotype manifestation of mutant major-cancer-predisposition genes is essential to determine the risk of cancer, and the response to drug treatment in a given individual. Sci-Hub | A compendium of mutational cancer driver Cancer 20, 555572. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. In our study, the low-risk score group showed elevated expression of Type_1_IFN_Response and Type_2_IFN_Response signaling pathways compared to its counterpart. In J Pers Med. (2019). Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Third, most HCC patients in the TCGA database were Caucasian, and it is not clear whether the risk signature has the same predictive effect in non-Caucasian races. 2023 Jun 14;14:1145481. doi: 10.3389/fimmu.2023.1145481. (2016). (B) Venn diagram showing the contribution of each method in number of genes that it detects to the list of HCDs. In the present study, we systematically analyzed the expression of 568 cancer driver genes in the TCGA-LIHC cohort and found 189 differentially expressed cancer driver genes between cancer and normal tissues. We found that differentially expressed CDGs had high mutation rates in HCC, with TP53 showing the highest mutation rate (30%) followed by CTNNB1 (25%), TTN (24%), MUC16 (14%), ALB (13%), and PCLO (10%). The .gov means its official. Genetic interaction analysis identified that mutations of TP53 were positively correlated with mutations of FAT3 and OBSCN and negatively correlated with CTNNB1. Martinez-Jimenez F., Muinos F., Sentis I., Deu-Pons J., Reyes-Salazar I., Arnedo-Pac C., et al. 27 Articles, This article is part of the Research Topic, https://doi.org/10.3389/fgene.2022.937948, https://www.frontiersin.org/articles/10.3389/fgene.2022.937948/full#supplementary-material. Alterations of CDGs may influence the tumor microenvironment and affect the response to immunotherapy.

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