M5C Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Papillary Thyroid Carcinoma.
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ABSTRACT:
SUBMITTER: Li F
PROVIDER: S-EPMC8597900 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThere is increasing evidence of the epigenetic regulation of the immune response in cancer. However, the specific functions and mechanisms of RNA N6-methyladenosine (m6A) modification in the cell infiltration in the hepatocellular carcinoma (HCC) tumor microenvironment (TME) is unknown.MethodsWe systematically analyzed the m6A-modification patterns of 371 HCC samples based on 23 m6A regulators, and determined their correlation with TME cell-infiltrating characteristics. Principal-component analysis algorithms was used to calculate the m6Ascore and clarify the m6A-modification patterns of individual tumors.ResultsThree different m6A-modification patterns were identified in HCC, wherein the m6Acluster B and m6Acluster A had the best and worst prognosis, respectively. These three patterns had different TME cell infiltration characteristics and biological behavior. An m6A-scoring signature was constructed to evaluate the m6A-modification patterns within individual tumors. A low m6Ascore was associated with a low overall survival and high clinical stage. Moreover, the m6A-scoring signature was characterized by distinct immunotherapeutic landscapes; a high m6A score indicated a higher immune checkpoint inhibitor score in the anti-PD-1 treatment alone, anti-CTLA-4 treatment alone, or combined anti-CTLA-4/PD-1 treatment cohorts, which reflected significant treatment and clinical benefits.ConclusionsOur study highlights the significant role of the m6A modification in the HCC TME. A scoring signature to clarify the individual m6A-modification pattern would help us understand the HCC TME infiltration characterization and, thus, would guide the selection of more effective immunotherapeutic strategies.
| S-EPMC8436903 | biostudies-literature
Project description:Background: 5-Methylcytosine (m5C) plays essential roles in hepatocellular carcinoma (HCC), but the association between m5C regulation and immune cell infiltration in HCC has not yet been clarified. Methods: In this study, we analysed 371 patients with HCC from The Cancer Genome Atlas (TCGA) database, and the expression of 13 m5C regulators was investigated. Additionally, gene set variation analysis (GSVA), unsupervised clustering analysis, single-sample gene set enrichment analysis (ssGSEA), correlation analysis, and immunohistochemical (IHC) staining were performed. Results: Among the 371 patients, 41 had mutations in m5C regulators, the frequency of which was 11.26%. Compared with normal hepatic tissues, the expression of m5C regulators with copy number variations (CNVs) expansion was significantly higher than that in HCC tissues. Then, we identified three m5C modification patterns that had obvious tumour microenvironment (TME) cell infiltration characteristics. The prognostic analysis of the three major m5C modification subtypes showed that Cluster-2 had a clear survival advantage over the others. In addition, we found that DNMT1 was highly expressed in tumour tissues compared with normal tissues in a tissue microarray (TMA) and that it was positively correlated with many TME-infiltrating immune cells. High expression of the m5C regulator DNMT1 was related to a poor prognosis in patients with HCC. Furthermore, we developed three distinct Immu-clusters. Importantly, mRNAs related to the transcription of growth factor β (TGF-β)/EMT pathway were significantly up-regulated in Immu-cluster 2, indicating that this cluster is considered to be the immune rejection phenotype. Immu-cluster 3 showed elevated expression of mRNAs related to immune checkpoint genes. Conclusion: Our work revealed the association between m5C modification and immune regulators in the TME. These findings also suggest that DNMT1 has great potential as a prognostic biomarker and therapeutic target for HCC.
| S-EPMC8475949 | biostudies-literature
Project description:BackgroundThe epigenetic regulation of immune response has been demonstrated in recent studies. Nonetheless, potential roles of RNA N6-methyladenosine (m6A) modification in tumor microenvironment (TME) cell infiltration remain unknown.MethodsWe comprehensively evaluated the m6A modification patterns of 1938 gastric cancer samples based on 21 m6A regulators, and systematically correlated these modification patterns with TME cell-infiltrating characteristics. The m6Ascore was constructed to quantify m6A modification patterns of individual tumors using principal component analysis algorithms.ResultsThree distinct m6A modification patterns were determined. The TME cell-infiltrating characteristics under these three patterns were highly consistent with the three immune phenotypes of tumors including immune-excluded, immune-inflamed and immune-desert phenotypes. We demonstrated the evaluation of m6A modification patterns within individual tumors could predict stages of tumor inflammation, subtypes, TME stromal activity, genetic variation, and patient prognosis. Low m6Ascore, characterized by increased mutation burden and activation of immunity, indicated an inflamed TME phenotype, with 69.4% 5-year survival. Activation of stroma and lack of effective immune infiltration were observed in the high m6Ascore subtype, indicating a non-inflamed and immune-exclusion TME phenotype, with poorer survival. Low m6Ascore was also linked to increased neoantigen load and enhanced response to anti-PD-1/L1 immunotherapy. Two immunotherapy cohorts confirmed patients with lower m6Ascore demonstrated significant therapeutic advantages and clinical benefits.ConclusionsThis work revealed the m6A modification played a nonnegligible role in formation of TME diversity and complexity. Evaluating the m6A modification pattern of individual tumor will contribute to enhancing our cognition of TME infiltration characterization and guiding more effective immunotherapy strategies.
| S-EPMC7066851 | biostudies-literature
Project description:BackgroundFew studies have been reported the potential role of N6-methyladenosine (m6A) modification in osteoarthritis (OA). We investigated the patterns of m6A modification in the immune microenvironment of OA.MethodsWe evaluated the m6A modification patterns based on 22 m6A regulators in 139 OA samples and systematically associated these modification patterns with immune cell infiltration characteristics. The function of m6A phenotype-related differentially expressed genes (DEGs) was investigated using gene enrichment analysis. An m6A score model was constructed using principal component analysis (PCA), and an OA prediction model was established based on the key m6A regulators. We used real-time PCR analysis to detect the changes of gene expression in the cell model of OA.ResultsHealthy and OA samples showed significant differences in the expression of m6A regulators. Nine key m6A regulators, two m6A modification patterns, m6A-related genes and two gene clusters were identified. Some m6A regulators had a strong correlation with each other. Gene clusters and m6A clusters have high similarity, and cluster A corresponds to a high m6A score. Immunocytes infiltration differed significantly between the two clusters, with the m6A cluster B and gene cluster B having more types of infiltrating immunocytes than cluster A. The predictive model can also predict the progression of OA through m6A regulators expression. The results of real-time PCR analysis showed that the gene expression in the cell model of OA is similar to that of the m6A cluster B.ConclusionsOur study reveals for the first time the potential regulatory mechanism of m6A modification in the immune microenvironment of OA. This study also sheds new light on the pathogenesis of OA.
| S-EPMC9728527 | biostudies-literature
Project description:Osteoarthritis (OA) is a common disease in orthopedics. RNA N6-methyladenosine (m6A) exerts an essential effect in a variety of biological processes in the eukaryotes. In this study, we determined the effect of m6A regulators in the OA along with performing the subtype classification. Differential analysis of OA and normal samples in the database of Gene Expression Omnibus identified 9 significantly differentially expressed m6A regulators. These regulators were monitored by a random forest algorithm so as to evaluate the risk of developing OA disease. On the basis of these 9 moderators, a nomogram was established. The results of decision curve analysis suggested that the patients could benefit from a nomogram model. The OA sample was classified as 2 m6A models through a consensus clustering algorithm in accordance with these 9 regulators. These 2 m6A patterns were then assessed with principal component analysis. We also determined the m6A scores for the 2 m6A patterns and their correlation with immune infiltration. The results indicated that type A had a higher m6A score than type B. Thus, we suggest that the m6A pattern may provide a new approach for diagnose and provide novel ideas for molecular targeted therapy of OA.
| S-EPMC9805027 | biostudies-literature
Project description:BackgroundGlioblastoma is one of the most common brain cancers in adults, and is characterized by recurrence and little curative effect. An effective treatment for glioblastoma patients remains elusive worldwide. 7-methylguanosine (m7G) is a common RNA modification, and its role in tumors has become a research hotspot.MethodsBy searching for differentially expressed genes related to m7G, we generated a prognostic signature via cluster analysis and established classification criteria of high and low risk scores. The effectiveness of classification was validated using the Non-negative matrix factorization (NMF) algorithm, and repeatedly verified using training and test groups. The dimension reduction method was used to clearly show the difference and clinical significance of the data. All analyses were performed via R (version 4.1.2).ResultsAccording to the signature that included four genes (TMOD2, CACNG2, PLOD3, and TMSB10), glioblastoma patients were divided into high and low risk score groups. The survival rates between the two groups were significantly different, and the predictive abilities for 1-, 3-, and 5-year survivals were effective. We further established a Nomogram model to further examine the signature,as well as other clinical factors, with remaining significant results. Our signature can act as an independent prognostic factor related to immune-related processes in glioblastoma.ConclusionsOur research addresses the gap in knowledge in the m7G and glioblastoma research fields. The establishment of a prognostic signature and the extended analysis of the tumor microenvironment, immune correlation, and tumor mutation burden further suggest the important role of m7G in the development and development of this disease. This work will provide support for future research.
| S-EPMC9251941 | biostudies-literature
Project description:The invasion of immune cells in the tumor microenvironment (TME) is closely related to cancer development. Studies have demonstrated that N6-methyladenosine (m6A) can affect the invasion of immune cells in TME as well as cancer development. We comprehensively analyzed the RNA-seq data of 16 different cancer types based on 20 m6A regulators and identified two distinct m6A modification patterns, which were closely associated with TME cell infiltration and overall patient survival. Then, we used principal component analysis (PCA) to construct m6Ascore based on the expression of m6A-related prognostic genes, which can successfully predict patient survival. The low-m6Ascore subtype is characterized by more immune cell infiltration, good prognosis and lower TNM stages, while the high-m6Ascore subtype is characterized by low immune infiltration, stromal activation, and poor prognosis. m6Ascore was also closely associated with immunotherapy response and was significantly higher in complete response/partial response (CR/PR) patients than in stable disease/progressive disease (SD/PD) patients in both immunotherapy cohorts. Therefore, our study indicates that m6A modification plays an important role in the prognosis of pan-cancer and the formation of complex TME in pan-cancer. Our research helps to improve the cognition of m6A modifications at pan-cancer levels and identify more effective strategies for immunotherapy.
| S-EPMC9570346 | biostudies-literature
Project description:Accumulating studies have highlighted the biologic significances of ferroptosis modification in tumor progression, but little is known whether ferroptosis modification patterns have potential roles in tumor microenvironment (TME) immune cell infiltration of hepatocellular carcinoma (HCC). In this study, we evaluated 51 ferroptosis regulators and performed consensus clustering algorithm to determine ferroptosis modification patterns and the ferroptosis related gene signature in HCC. Gene set variation analysis (GSVA) was employed to explore biological molecular variations in distinct ferroptosis modification patterns. Single sample gene set enrichment analysis (ssGSEA) algorithm was performed to quantify the relative infiltration levels of various immune cell subsets. Principal component analysis (PCA) algorithm was used to construct the ferroptosisSig score to quantify ferroptosis modification patterns of individual tumors with immune responses. Three distinct ferroptosis modification patterns were identified. GSVA enrichment analysis indicated that three ferroptosis modification subgroups were enriched in different metabolic pathways. ssGSEA analysis determined that 19 of 24 immune infiltrating cells had significant differences in three distinct ferroptosis patterns. A 91-ferroptosis gene signature was constructed to stratify patients into two ferroptosisSig score groups. Patients in the higher ferroptosisSig score were characterized by significantly prolonged survival time compared with patients in the lower ferroptosisSig score group (p < .0001). An immunotherapy cohort confirmed patients with higher ferroptosisSig score determined significant therapeutic advantages and clinical benefits. Receiver operating characteristic (ROC) curve analysis confirmed the predictive capacity of anti-PD/L1 immunotherapy by ferroptosisSig score. Our study indicated the ferroptosis modification played a significant role in TME heterogeneity and complexity. Evaluating the ferroptosis modification pattern of individual tumor could strengthen our cognition of TME infiltration characteristics and guide more effective clinic immunotherapy strategies.
| S-EPMC8832196 | biostudies-literature
Project description:PurposeThe role of RNA N6-methyladenosine (m6A) modification in the progression of multiple tumours and the tumour microenvironment (TME) has been progressively demonstrated and promises a new direction for tumour therapy. However, there have been no reports on systematic analyses of RNA m6A modification in TME in non-small cell lung cancer (NSCLC).Patients and methodsIn this study, we used unsupervised cluster analysis to identify three m6A modification patterns of 28 m6A regulators and three m6A gene signature subgroups of commonly differentially expressed genes (co-DEGs) in the three m6A modification patterns. Quantifying these subtypes using the ssGSEA and ESTIMATE algorithms to characterise the tumour immune microenvironment (TIME) in NSCLC. Based on the principal component analysis (PCA), we used co-DEGs to construct m6A scores to analyse the characteristics of m6A modifications in individual patients and assessed the practical clinical utility of m6A scores using a nomogram for survival prediction.ResultsA total of 28 m6A regulators in 1210 NSCLC samples were mainly enriched in RNA modification and metabolic biological processes. The three following m6A modification patterns were identified based on the role of the 28 m6A regulators in TME: immune inflammation, immune evasion and immune desert. The m6A scores calculated based on co-DEGs in these modification patterns were significantly positively correlated with immune infiltration and significantly negatively correlated with tumour mutational burden (TMB). Survival was significantly better in the high-m6A-score group than in the low-m6A-score group, and the m6A score could be used as an independent favourable prognostic factor. In addition, assessment of both immune checkpoint inhibitors (ICIs) and immunophenoscore (IPS) revealed a better immunotherapeutic effect in the high-m6A-score group.ConclusionThe modification characteristics of 28 m6A regulators in the TIME of NSCLC were analysed from a comprehensive to an individual basis, which may facilitate the development of more effective clinical immunotherapeutic strategies.
| S-EPMC8958726 | biostudies-literature
Project description:Recent studies have shown that RNA N6-methyladenosine (m6A) modification plays an important part in tumorigenesis and immune-related biological processes. However, the comprehensive landscape of immune cell infiltration characteristics in the tumor microenvironment (TME) mediated by m6A methylation modification in pancreatic cancer has not yet been elucidated. Based on consensus clustering algorithm, we identified two m6A modification subtypes and then determined two m6A-related gene subtypes among 434 pancreatic cancer samples. The TME characteristics of the identified gene subtypes were highly consistent with the immune-hot phenotype and the immune-cold phenotype respectively. According to the m6A score extracted from the m6A-related signature genes, patients can be divided into high and low m6A score groups. The low score group displayed a better prognosis and relatively strong immune infiltration. Further analysis showed that low m6A score correlated with lower tumor mutation burden and PD-L1 expression, and indicated a better response to immunotherapy. In general, m6A methylation modification is closely related to the diversity and complexity of immune infiltration in TME. Evaluating the m6A modification pattern and immune infiltration characteristics of individual tumors can help deepen our understanding of the tumor microenvironment landscape and promote a more effective clinical practice of immunotherapy.
| S-EPMC8488339 | biostudies-literature