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Open accessJournal ArticleDOI: 10.3389/FONC.2021.619242

The Identification and Validation of Two Heterogenous Subtypes and a Risk Signature Based on Ferroptosis in Hepatocellular Carcinoma.

02 Mar 2021-Frontiers in Oncology (Frontiers Media SA)-Vol. 11, pp 619242-619242
Abstract: Background Ferroptosis is essential for tumorigenesis and progression of hepatocellular carcinoma (HCC). The heterogeneity of ferroptosis and its relationship with tumor microenvironment (TME) have still remain elusive. Methods Based on 74 ferroptosis related genes (FRGs) and 3,933 HCC samples from 32 datasets, we comprehensively explored the heterogenous ferroptosis subtypes. The clinical significance, functional status, immune infiltration, immune escape mechanisms, and genomic alterations of different subtypes were further investigated. Results We identified and validated two heterogeneous ferroptosis subtypes: C1 was metabolismlowimmunityhigh subtype and C2 was metabolismhighimmunitylow subtype. Compared to C2, C1 owned worse prognosis, and C1 tended to occur in the patients with clinical characteristics such as younger, female, advanced stage, higher grade, vascular invasion. C1 and C2 were more sensitive to immunotherapy and sorafenib, respectively. The immune escape mechanisms of C1 might be accumulating more immunosuppressive cells, inhibitory cytokines, and immune checkpoints, while C2 was mainly associated with inferior immunogenicity, defecting in antigen presentation, and lacking leukocytes. In addition, C1 was characterized by BAP1 mutation, MYC amplification, and SCD1 methylation, while C2 was characterized by the significant alterations in cell cycle and chromatin remodeling processes. We also constructed and validated a robust and promising signature termed ferroptosis related risk score (FRRS) for assessing prognosis and immunotherapy. Conclusion We identified and validated two heterogeneous ferroptosis subtypes and a reliable risk signature which used to assess prognosis and immunotherapy. Our results facilitated the understood of ferroptosis as well as clinical management and precise therapy of HCC.

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9 results found

Open accessJournal ArticleDOI: 10.1111/JCMM.16791
Libo Wang1, Zaoqu Liu1, Long Liu1, Chunguang Guo1  +5 moreInstitutions (1)
Abstract: CUGBP Elav-like family member 2(CELF2) plays crucial roles in the development and activation of T cell. However, the impacts of CELF2 on tumour-infiltrating immune cells (TIICs) and clinical outcomes of tumours remain unclear. In this study, we found that elevated CELF2 expression was markedly correlated with prolonged survival in multiple tumours, particularly in breast and lung cancers. Notably, CELF2 only impacted the prognosis of triple-negative breast cancer (TNBC) with lymph node metastasis. Further investigation showed CELF2 expression was positively correlated with the infiltration abundance of dendritic cells (DCs), CD8+ T cells and neutrophils in breast invasive carcinoma (BRCA) and DCs in lung squamous cell carcinoma (LUSC). CELF2 also had strong correlations with markers of diverse TIICs such as T cells, tumour-associated macrophages and DCs in BRCA and LUSC. Importantly, CELF2 was significantly associated with plenty of immune checkpoint molecules (ICMs) and outperformed five prevalent biomarkers including PD-1, PD-L1, CTLA-4, CD8 and tumour mutation burden in predicting immunotherapeutic responses. Immunohistochemistry also revealed lower protein levels of CELF2 in TNBC and LUSC compared to normal tissues, and patients with high expression showed significantly prolonged prognosis. In conclusion, we demonstrated that increased CELF2 expression was closely related to better prognosis and superior TIIC infiltration and ICM expression, particularly in BRCA and LUSC. CELF2 also performed well in evaluating the immunotherapeutic efficacy, suggesting CELF2 might be a promising biomarker.

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Topics: Triple-negative breast cancer (54%), Breast cancer (54%), Immunotherapy (52%) ... read more

1 Citations

Open accessPosted ContentDOI: 10.3389/FIMMU.2021.762120
Tao Feng1, Jiahui Zhao1, Dechao Wei1, Pengju Guo1  +7 moreInstitutions (1)
Abstract: Background Renal cell carcinoma (RCC) is associated with poor prognostic outcomes. The current stratifying system does not predict prognostic outcomes and therapeutic benefits precisely for RCC patients. Here, we aim to construct an immune prognostic predictive model to assist clinician to predict RCC prognosis. Methods Herein, an immune prognostic signature was developed, and its predictive ability was confirmed in the kidney renal clear cell carcinoma (KIRC) cohorts based on The Cancer Genome Atlas (TCGA) dataset. Several immunogenomic analyses were conducted to investigate the correlations between immune risk scores and immune cell infiltrations, immune checkpoints, cancer genotypes, tumor mutational burden, and responses to chemotherapy and immunotherapy. Results The immune prognostic signature contained 14 immune-associated genes and was found to be an independent prognostic factor for KIRC. Furthermore, the immune risk score was established as a novel marker for predicting the overall survival outcomes for RCC. The risk score was correlated with some significant immunophenotypic factors, including T cell infiltration, antitumor immunity, antitumor response, oncogenic pathways, and immunotherapeutic and chemotherapeutic response. Conclusions The immune prognostic, predictive model can be effectively and efficiently used in the prediction of survival outcomes and immunotherapeutic responses of RCC patients.

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Topics: Immunotherapy (52%), Cancer (51%)

Open accessJournal ArticleDOI: 10.3389/FGENE.2021.785185
Abstract: Background: Both hypoxia and long non-coding RNAs (lncRNAs) contribute to the tumor progression in hepatocellular carcinoma (HCC). We sought to establish a hypoxia-related lncRNA signature and explore its correlation with immunotherapy response in HCC. Materials and Methods: Hypoxia-related differentially expressed lncRNAs (HRDELs) were identified by conducting the differential gene expression analyses in GSE155505 and The Cancer Genome Atlas (TCGA)- liver hepatocellular carcinoma (LIHC) datasets. The HRDELs landscape in patients with HCC in TCGA-LIHC was dissected by an unsupervised clustering method. Patients in the TCGA-LIHC cohort were stochastically split into the training and testing dataset. The prognostic signature was developed using LASSO (least absolute shrinkage and selection operator) penalty Cox and multivariable Cox analyses. The tumor immune microenvironment was delineated by the single-sample gene set enrichment analysis (ssGSEA) algorithm. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was applied to evaluate the predictive value of the constructed signature in immunotherapeutic responsiveness. Results: A total of 55 HRDELs were identified through integrated bioinformatical analyses in GSE155505 and TCGA-LIHC. Patients in the TCGA-LIHC cohort were categorized into three HRDELs-specific clusters associated with different clinical outcomes. The prognostic signature involving five hypoxia-related lncRNAs (LINC00869, CAHM, RHPN1-AS1, MKLN1-AS, and DUXAP8) was constructed in the training dataset and then validated in the testing dataset and entire TCGA-LIHC cohort. The 5-year AUC of the constructed signature for prognostic prediction reaches 0.705 and is superior to that of age, AJCC stage, and histopathological grade. Patients with high-risk scores consistently had poorer overall survival outcomes than those with low-risk scores irrespective of other clinical parameters status. The low-risk group had more abundance in activated CD8+ T cell and activated B cell and were predicted to be more responsive to immunotherapy and targeted therapy than the high-risk group. Conclusion: We established a reliable hypoxia-related lncRNAs signature that could accurately predict the clinical outcomes of HCC patients and correlate with immunotherapy response and targeted drug sensitivity, providing new insights for immunotherapy and targeted therapy in HCC.

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Topics: Targeted therapy (51%)

Open accessJournal ArticleDOI: 10.3389/FGENE.2021.777931
Abstract: Background: Globally, hepatocellular carcinoma (HCC) is the sixth most frequent malignancy with a high incidence and a poor prognosis. Immune cell infiltration (ICI) underlies both the carcinogenesis and immunogenicity of tumors. However, a comprehensive classification system based on the immune features for HCC remains unknown. Methods: The HCC dataset from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) cohorts was used in this study. The ICI patterns of 571 patients were characterized using two algorithms: the patterns were determined based on the ICI using the ConsensusClusterPlus package, and principal component analysis (PCA) established the ICI scores. Differences in the immune landscape, biological function, and somatic mutations across ICI scores were evaluated and compared, followed by a predictive efficacy evaluation of ICI scores for immunotherapy by the two algorithms and validation using an external immunotherapy cohort. Results: Based on the ICI profile of the HCC patients, three ICI patterns were identified, including three subtypes having different immunological features. Individual ICI scores were determined; the high ICI score subtype was characterized by enhanced activation of immune-related signaling pathways and a significantly high tumor mutation burden (TMB); concomitantly, diminished immunocompetence and enrichment of pathways associated with cell cycle and RNA degradation were found in the low ICI score subtype. Taken together, our results contribute to a better understanding of an active tumor and plausible reasons for its poor prognosis. Conclusion: The present study reveals that ICI scores may serve as valid prognostic biomarkers for immunotherapy in HCC.

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Open accessJournal ArticleDOI: 10.1016/J.INTIMP.2021.108340
Zaoqu Liu1, Long Liu1, Chunguang Guo1, Sun Yu1  +3 moreInstitutions (1)
Abstract: Introduction The tumor microenvironment (TME) has profound impacts on prognosis and immunotherapy. The TME can be altered by the genomic mutations on specific tumor-suppressor genes (TSG), thus, comprehending the association between TME and TSG in hepatocellular carcinoma (HCC) is imperative. Methods With a total of 1699 HCC patients from 6 international multicenter cohorts, we delineated the mutational landscape of TSG and summarized the proportion of TSG mutated HCC in different countries. Using the genomic and transcriptomic data, we comprehensively explored the impacts of TSG mutations on TME and immunity in HCC. A dataset of 31 HCC patients from the cBioPortal database was utilized to evaluate the predictive value of TSG subtypes for immunotherapy response. Results Interestingly, TSG non-mutated HCC will have more “immune-hot” tumors, and display the infiltration abundance of immune cells such as B cell, CD4+/CD8+T cell, and neutrophil. Moreover, TSG non-mutated HCC was characterized by the higher expression level of three immune checkpoints, including CD40, CD40LG, and TNFRSF4. In line with the TME characterization and immune checkpoint profiles, TSG non-mutated HCC displayed prolonged overall survival and relapse-free survival, notably, are more likely to respond to immune checkpoint inhibitors. Conclusions Our findings suggested the TSG subtypes could serve as a promising biomarker for guiding surveillance protocol and immunotherapeutic decisions for patients with HCC.

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Topics: Immune checkpoint (53%)


56 results found

Open accessJournal ArticleDOI: 10.3322/CAAC.21492
Abstract: This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions There will be an estimated 181 million new cancer cases (170 million excluding nonmelanoma skin cancer) and 96 million cancer deaths (95 million excluding nonmelanoma skin cancer) in 2018 In both sexes combined, lung cancer is the most commonly diagnosed cancer (116% of the total cases) and the leading cause of cancer death (184% of the total cancer deaths), closely followed by female breast cancer (116%), prostate cancer (71%), and colorectal cancer (61%) for incidence and colorectal cancer (92%), stomach cancer (82%), and liver cancer (82%) for mortality Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality) Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts CA: A Cancer Journal for Clinicians 2018;0:1-31 © 2018 American Cancer Society

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Topics: Cancer registry (78%), Cancer (72%), Breast cancer (63%) ... read more

39,828 Citations

Open accessJournal ArticleDOI: 10.3322/CAAC.21551
Abstract: Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.

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Topics: Cancer Death Rate (71%), Cancer prevention (66%), Mortality rate (60%) ... read more

11,980 Citations

Journal ArticleDOI: 10.1126/SCIENCE.1203486
25 Mar 2011-Science
Abstract: Understanding how the immune system affects cancer development and progression has been one of the most challenging questions in immunology. Research over the past two decades has helped explain why the answer to this question has evaded us for so long. We now appreciate that the immune system plays a dual role in cancer: It can not only suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promote tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. Here, we discuss a unifying conceptual framework called "cancer immunoediting," which integrates the immune system's dual host-protective and tumor-promoting roles.

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Topics: Immunoediting (59%), Tumor progression (56%), Tumor microenvironment (53%) ... read more

4,153 Citations

Open accessJournal ArticleDOI: 10.1016/J.CELL.2012.03.042
25 May 2012-Cell
Abstract: Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration.

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Topics: Programmed cell death (53%), SLC7A11 (52%), Cancer cell (50%) ... read more

3,349 Citations

Open accessJournal ArticleDOI: 10.1126/SCIENCE.AAA4971
03 Apr 2015-Science
Abstract: The clinical relevance of T cells in the control of a diverse set of human cancers is now beyond doubt. However, the nature of the antigens that allow the immune system to distinguish cancer cells from noncancer cells has long remained obscure. Recent technological innovations have made it possible to dissect the immune response to patient-specific neoantigens that arise as a consequence of tumor-specific mutations, and emerging data suggest that recognition of such neoantigens is a major factor in the activity of clinical immunotherapies. These observations indicate that neoantigen load may form a biomarker in cancer immunotherapy and provide an incentive for the development of novel therapeutic approaches that selectively enhance T cell reactivity against this class of antigens.

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2,839 Citations