Systematic pan-cancer analysis identifies cGAS as an immunological and prognostic biomarker

Chen, Peng; Xian, Yuezhong; Wang, Peiyuan; He, Hao; Chen, Yujie; Yu, Lingfeng; Fang, Huipeng; Wang, Rui; Huang, Zhijian

doi:10.21037/atm-22-6318

Cited by 4 publications

(2 citation statements)

References 69 publications

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“…Major risk factors include smoking, obesity, advanced age, alcohol consumption, and gastroesophageal reflux disease ( Kamangar et al, 2009 ; Then et al, 2020 ). cGAS has been implicated in the development and progression of esophageal cancer through a variety of mechanisms ( Chen et al, 2023 ).…”

Section: Cgas Signaling Pathways In Gi Malignanciesmentioning

confidence: 99%

The role of cGAS in epithelial dysregulation in inflammatory bowel disease and gastrointestinal malignancies

Ramos,

Bizri,

Novak

et al. 2024

Front. Pharmacol.

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The gastrointestinal tract is lined by an epithelial monolayer responsible for selective permeability and absorption, as well as protection against harmful luminal contents. Recognition of foreign or aberrant DNA within these epithelial cells is, in part, regulated by pattern recognition receptors such as cyclic GMP-AMP synthase (cGAS). cGAS binds double-stranded DNA from exogenous and endogenous sources, resulting in the activation of stimulator of interferon genes (STING) and a type 1 interferon response. cGAS is also implicated in non-canonical pathways involving the suppression of DNA repair and the upregulation of autophagy via interactions with PARP1 and Beclin-1, respectively. The importance of cGAS activation in the development and progression of inflammatory bowel disease and gastrointestinal cancers has been and continues to be explored. This review delves into the intricacies of the complex role of cGAS in intestinal epithelial inflammation and gastrointestinal malignancies, as well as recent therapeutic advances targeting cGAS pathways.

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Section: Cgas Signaling Pathways In Gi Malignanciesmentioning

confidence: 99%

The role of cGAS in epithelial dysregulation in inflammatory bowel disease and gastrointestinal malignancies

Ramos,

Bizri,

Novak

et al. 2024

Front. Pharmacol.

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“…This elevation often correlates with the presence of cytosolic DNA, genomic instability, and an activated immune response within the tumor microenvironment [ 60 ]. In some studies, increased cGAS expression has been associated with advanced cancer stages and poorer prognosis, indicating a possible role in tumor progression under certain conditions [ 61 ]. For therapeutic purposes, particularly in conditions with dysregulated cGAS-STING pathways, several specific cGAS inhibitors have been identified.…”

Section: Cgas Inhibitors Possessing Chemopreventive Activitymentioning

confidence: 99%

Cyclic GMP-AMP Synthase in Cancer Prevention

Chen,

Lee,

Jeung

et al. 2023

J Cancer Prev

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Cyclic GMP-AMP (cGAMP), synthesized by cGAMP synthase (cGAS), serves as a secondary messenger that modulates various cellular processes, including cell proliferation, cell death, immune response, and inflammation. cGAS is activated upon detecting cytoplasmic DNA, which may originate from damaged genomic and mitochondrial DNA or from viral and bacterial infections. The presence of DNA in the cytoplasm can trigger a substantial inflammatory reaction and cytokine production via the cGAS-STING signaling pathway. Consequently, specific inhibitors targeting this pathway hold significant potential as chemopreventive agents. In this review, we explore the potential effectiveness of modulating cGAS activity. We discuss the role of cGAMP, the mechanism of action for distinguishing between self and foreign DNA, and the possible functions of cGAS within the nucleus.

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Prognostic clinical phenotypes associated with tumor stemness in the immune microenvironment of T-cell exhaustion for hepatocellular carcinoma

Zhang

2023

Discov Onc

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T-cell exhaustion (TEX) and high heterogeneity of cancer stem cells (CSCs) are associated with progression, metastasis, and treatment resistance in hepatocellular carcinoma (HCC). Here, we aim to characterize TEX-stemness-related genes (TEXSRGs) and screen for HCC patients who are more sensitive to immunotherapy. The immune cell abundance identifier (ImmuCellAI) was utilized to precisely evaluate the abundance of TEX and screen TEX-related genes. The stemness index (mRNAsi) of samples was analyzed through the one-class logistic regression (OCLR) algorithm. Application of the non-negative matrix decomposition algorithm (NMF) for subtype identification of HCC samples. The different subtypes were assessed for differences in prognosis, tumor microenvironment (TME) landscape, and immunotherapy treatment response. Then, the TEXSRGS-score, which can accurately forecast the survival outcome of HCC patients, was built by LASSO-Cox and multivariate Cox regression, and experimentally validated for the most important TEXSRGs. We also analyzed the expression of TEXSRGs and the infiltration of CD8+ T cells in clinical samples using qRT-PCR and immunohistochemistry (IHC). Based on 146 TEXSRGs, we found two distinct clinical phenotypes with different TEX infiltration abundance, tumor stemness index, enrichment pathways, mutational landscape, and immune cell infiltration through the non-negative matrix decomposition algorithm (NMF), which were confirmed in the ICGC dataset. Utilizing eight TEXSRGs linked to clinical outcome, we created a TEXSRGs-score model to further improve the clinical applicability. Patients can be divided into two groups with substantial differences in the characteristics of immune cell infiltration, TEX infiltration abundance, and survival outcomes. The results of qRT-PCR and IHC analysis showed that PAFAH1B3, ZIC2, and ESR1 were differentially expressed in HCC and normal tissues and that patients with high TEXSRGs-scores had higher TEX infiltration abundance and tumor stemness gene expression. Regarding immunotherapy reaction and immune cell infiltration, patients with various TEXSRGs-score levels had various clinical traits. The outcome and immunotherapy efficacy of patients with low TEXSRGs-score was favorable. In conclusion, we identified two clinical subtypes with different prognoses, TEX infiltration abundance, tumor cell stemness index, and immunotherapy response based on TEXSRGs, and developed and validated a TEXSRGs-score capable of accurately predicting survival outcomes in HCC patients by comprehensive bioinformatics analysis. We believe that the TEXSRGs-score has prospective clinical relevance for prognostic assessment and may help physicians select prospective responders in preference to current immune checkpoint inhibitors (ICIs).

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Systematic pan-cancer analysis identifies cGAS as an immunological and prognostic biomarker

Cited by 4 publications

References 69 publications

The role of cGAS in epithelial dysregulation in inflammatory bowel disease and gastrointestinal malignancies

The role of cGAS in epithelial dysregulation in inflammatory bowel disease and gastrointestinal malignancies

Cyclic GMP-AMP Synthase in Cancer Prevention

Prognostic clinical phenotypes associated with tumor stemness in the immune microenvironment of T-cell exhaustion for hepatocellular carcinoma

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