The m6A methylation landscape stratifies hepatocellular carcinoma into 3 subtypes with distinct metabolic characteristics

Shen, Xiaotian; Hu, Beiyuan; Xu, Jing; Qin, Wei; Fu, Yan; Wang, Shun; Dong, Qiongzhu; Qin, Lun–Xiu

doi:10.20892/j.issn.2095-3941.2020.0402

Cited by 20 publications

(16 citation statements)

References 61 publications

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“…In this study, we used a widely accepted gene set enrichment analysis (GSEA)-based approach ( 34 , 35 ) to evaluate features of NETs in 8,059 samples from 22 cancer types. Using a range of methods, we showed that NET score is correlated with key cancer hallmarks, in particular inflammatory responses and EMT ( 36 – 38 ).…”

Section: Discussionmentioning

confidence: 99%

Pan-Cancer Analysis Reveals a Distinct Neutrophil Extracellular Trap-Associated Regulatory Pattern

Shen

Xie

et al. 2022

Front. Immunol.

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BackgroundNeutrophils form extracellular net-like structures called neutrophil extracellular traps (NETs). Emerging evidence has shown that cancer can induce NET formation; however, it is not fully understood how NETs influence cancer biology, and no consensus has been reached on their pro- or antitumor effects. A comprehensive analysis of the global NET-associated gene regulatory network is currently unavailable and is urgently needed.MethodsWe systematically explored and discussed NET enrichment, NET-associated gene regulatory patterns, and the prognostic implications of NETs in approximately 8,000 patients across 22 major human cancer types. We identified NET-associated regulatory gene sets that we then screened for NET-associated regulatory patterns that might affect patient survival. We functionally annotated the NET-associated regulatory patterns to compare the biological differences between NET-related survival subgroups.ResultsA gene set variation analysis (GSVA) based on 23 major component genes was used to calculate a metric called the NET score. We found that the NET score was closely associated with many important cancer hallmarks, particularly inflammatory responses and epithelial-to-mesenchymal transition (EMT)-induced metastasis. Higher NET scores were related to poor immunotherapy response. Survival analysis revealed that NETs had diverse prognostic impacts among various cancer types. The NET-associated regulatory patterns linked to shorter or longer cancer patient survival were distinct from each other. Functional analysis revealed that more of the NET-associated regulatory genes linked to poor cancer survival were associated with extracellular matrix (ECM) remodeling and pan-cancerous risk factors. SPP1 was found to be highly expressed and correlated with NET formation in cancers with poor survival. We also found that the co-upregulation of NET formation and SPP1 expression was closely linked to increased EMT and poor survival, that SPP1 influenced NET-induced malignant capacity, and that SPP1 overproduction induced a robust formation of metastatic-promoting NETs.ConclusionNETs were common across cancers but displayed a diverse regulatory pattern and outcome readouts in different cancer types. SPP1 is potentially the key to NET-related poor outcomes.

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Section: Discussionmentioning

confidence: 99%

Pan-Cancer Analysis Reveals a Distinct Neutrophil Extracellular Trap-Associated Regulatory Pattern

Shen

Xie

et al. 2022

Front. Immunol.

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“…An increasing number of studies have found that m6A modification is involved in a variety of biological processes, including embryonic development disorders, tumor development, and immune cell infiltration (12)(13)(14). Notably, the imbalance of m6A modification is significantly associated with the occurrence and progression of various cancers, such as bladder cancer, pancreatic cancer, hepatocellular carcinoma, and colorectal cancer (15)(16)(17)(18). In brief, m6A modification plays a role in carcinogenesis and tumor inhibition in diverse scenarios.…”

Section: Introductionmentioning

confidence: 99%

Radiogenomics Map Reveals the Landscape of m6A Methylation Modification Pattern in Bladder Cancer

Gao

et al. 2021

Front. Immunol.

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We aimed to develop a noninvasive radiomics approach to reveal the m6A methylation status and predict survival outcomes and therapeutic responses in patients. A total of 25 m6A regulators were selected for further analysis, we confirmed that expression level and genomic mutations rate of m6A regulators were significantly different between cancer and normal tissues. Besides, we constructed methylation modification models and explored the immune infiltration and biological pathway alteration among different models. The m6A subtypes identified in this study can effectively predict the clinical outcome of bladder cancer (including m6AClusters, geneClusters, and m6Ascore models). In addition, we observed that immune response markers such as PD1 and CTLA4 were significantly corelated with the m6Ascore. Subsequently, a total of 98 obtained digital images were processed to capture the image signature and construct image prediction models based on the m6Ascore classification using a radiomics algorithm. We constructed seven signature radiogenomics models to reveal the m6A methylation status, and the model achieved an area under curve (AUC) degree of 0.887 and 0.762 for the training and test datasets, respectively. The presented radiogenomics models, a noninvasive prediction approach that combined the radiomics signatures and genomics characteristics, displayed satisfactory effective performance for predicting survival outcomes and therapeutic responses of patients. In the future, more interdisciplinary fields concerning the combination of medicine and electronics remains to be explored.

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“…Other m6A-related prognostic signatures also achieved good performance in predicting the prognosis of multiple malignant tumors, including hepatocellular carcinoma, rectum adenocarcinoma, gastric cancer ( Guan et al, 2020 ; Huang et al, 2020 ; Shen et al, 2020 ). Compared with other clinical factors (gender, age, TNM stage), the risk signature showed a beneficial supplement to prognostic factors for melanoma.…”

Section: Discussionmentioning

confidence: 97%

Identification of an m6A Regulators-Mediated Prognosis Signature For Survival Prediction and Its Relevance to Immune Infiltration in Melanoma

Dai

et al. 2021

Front. Cell Dev. Biol.

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Despite robust evidence for the role of m6A in cancer development and progression, its association with immune infiltration and survival outcomes in melanoma remains obscure. Here, we aimed to develop an m6A-related risk signature to improve prognostic and immunotherapy responder prediction performance in the context of melanoma. We comprehensively analyzed the m6A cluster and immune infiltration phenotypes of public datasets. The TCGA (n = 457) and eleven independent melanoma cohorts (n = 758) were used as the training and validation datasets, respectively. We identified two m6A clusters (m6A-clusterA and m6A-clusterB) based on the expression pattern of m6A regulators via unsupervised consensus clustering. IGF2BP1 (7.49%), KIAA1429 (7.06%), and YTHDC1 (4.28%) were the three most frequently mutated genes. There was a correlation between driver genes mutation statuses and the expression of m6A regulators. A significant difference in tumor-associated immune infiltration between two m6A clusters was detected. Compared with m6A-clusterA, the m6A-clusterB was characterized by a lower immune score and immune cell infiltration but higher mRNA expression-based stemness index (mRNAsi). An m6A-related risk signature consisting of 12 genes was determined via Cox regression analysis and divided the patients into low- and high-risk groups (IL6ST, MBNL1, NXT2, EIF2A, CSGALNACT1, C11orf58, CD14, SPI1, NCCRP1, BOK, CD74, PAEP). A nomogram was developed for the prediction of the survival rate. Compared with the high-risk group, the low-risk group was characterized by high expression of immune checkpoints and immunophenoscore (IPS), activation of immune-related pathways, and more enriched in immune cell infiltrations. The low-risk group had a favorable prognosis and contained the potential beneficiaries of the immune checkpoint blockade therapy and verified by the IMvigor210 cohort (n = 298). The m6A-related signature we have determined in melanoma highlights the relationships between m6A regulators and immune cell infiltration. The established risk signature was identified as a promising clinical biomarker of melanoma.

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The m6A methylation landscape stratifies hepatocellular carcinoma into 3 subtypes with distinct metabolic characteristics

Cited by 20 publications

References 61 publications

Pan-Cancer Analysis Reveals a Distinct Neutrophil Extracellular Trap-Associated Regulatory Pattern

Pan-Cancer Analysis Reveals a Distinct Neutrophil Extracellular Trap-Associated Regulatory Pattern

Radiogenomics Map Reveals the Landscape of m6A Methylation Modification Pattern in Bladder Cancer

Identification of an m6A Regulators-Mediated Prognosis Signature For Survival Prediction and Its Relevance to Immune Infiltration in Melanoma

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