RNA m6A Methylation Regulators Multi-Omics Analysis in Prostate Cancer.
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ABSTRACT:
SUBMITTER: Su H
PROVIDER: S-EPMC8661905 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective: M6A RNA modification is closely associated with tumor genesis and progression of several malignancies; however, its role in prostate cancer (PCa) remains poorly understood. Materials and methods: Expression data and corresponding clinicopathologic information were available freely from the Cancer Genome Atlas (TCGA) dataset. We compared the expression level of m6A RNA methylation regulators in PCa with different clinicopathologic characteristics and identified subgroups based on their expressions with consensus clustering. To build the signature and assess its prognostic value, several methods were used for the analysis, including univariate Cox regression analysis, Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, time-dependent receiver operating curve (ROC), and Kaplan-Meier (KM) survival analysis. Results: Most of the m6A RNA methylation regulators were differentially expressed not only between normal and tumor tissue but also among PCa stratified by different clinicopathologic characteristics. There were obvious differences between two clusters, cluster 1 and 2, regarding clinicopathologic features, and the recurrence-free survival (RFS) in cluster 2 was significantly worse than cluster 1. We developed an eleven-gene signature which exhibited a high prognostic value and was able to independently predict RFS. Moreover, a nomogram which integrated clinical information and the gene signature was capable of distinguishing high-risk recurrent patients. Conclusion: These methylation regulators are correlated to clinicopathologic characteristics in PCa and a prognostic model using m6A methylation-related genes is constructed and of high predictive value for recurrence after RP.
| S-EPMC8120168 | biostudies-literature
Project description:BackgroundThe modification 6-methyladenine (m6 A) is the most common type in RNA methylation. Our study aims to explore the bioinformatic analysis of m6 A in endometrial cancer.MethodsThe expression of 23 m6 A RNA methylation regulators was compared through The Cancer Genome Atlas (TCGA) database among 406 endometrial tissue and 19 normal tissue samples. The Wilcoxon test was applied to compare the relationship between the clinicopathological characteristics and expression. Cox regressions were performed to identify the prognostic factors associated with overall survival. Gene ontology (GO) and Gene Set Enrichment Analysis (GSEA) were performed to evaluate the potential pathways.ResultsYTHDF2, HNRNPA2B1, HDRNPA2B1, YTHDF1, FMR1, IGF2BP3, METTL13, RBM15B, IGF2BP1, YTHDF3, YTHDC1, ZC3H13 IGF2BP2, KIAA1429, METTL14, RBMX, FTO, ALKBH5, and METTL16 were significantly abnormally expressed in endometrial cancer tissue samples. Both univariate and multivariate Cox regression analyses indicated that age, grade, and risk score were independent risk factors. High expression of FTO was associated with worse overall survival.ConclusionM6 A RNA methylation regulators play vital role in endometrial cancer.
| S-EPMC8418492 | biostudies-literature
Project description:BackgroundEpigenetic reprogramming reportedly has a crucial role in prostate cancer (PCa) progression. RNA modification is a hot topic in epigenetics, and N6-methyladenosine (m6A) accounts for approximately 60% of RNA chemical modifications. The aim of this study was to evaluate the m6A modification patterns in PCa patients and construct a risk prediction model using m6A RNA regulators.Materials and methodsAnalyses were based on the levels of 25 m6A regulators in The Cancer Genome Atlas (TCGA). Differentially expressed gene (DEG) and survival analyses were performed according to TCGA-PRAD clinicopathologic and follow-up information. To detect the influences of m6A regulators and their DEGs, consensus clustering analysis was performed, and tumor mutational burden (TMB) estimation and tumor microenvironment (TME) cell infiltration were assessed. mRNA levels of representative genes were verified using clinical PCa data.ResultsDiverse expression patterns of m6A regulators between tumor and normal (TN) tissues were detected regarding Gleason score (GS), pathological T stage (pT), TP53 mutation, and survival comparisons, with HNRNPA2B1 and IGFBP3 being intersecting genes. HNRNPA2B1 was upregulated in advanced stages (GS > 7, pT3, HR > 1, and TP53 mutation), as verified using clinical PCa tissue. Three distinct m6A modification patterns were identified through consensus clustering analysis, but no significant difference was found among these groups in recurrence-free survival (RFS) analysis. Six DEGs of m6A clusters (m6Aclusters) were screened through univariate Cox regression analysis. MMAB and PAIAP2 were intersecting genes for the five clinical factors. MMAB, which was upregulated in PCa compared with TN, was verified using clinical PCa samples. Three distinct subgroups were established according to the 6 DEGs. Cluster A involved the most advanced stages and had the poorest RFS. The m6A score (m6Ascore) was calculated based on the 6 genes, and the low m6Ascore group showed poor RFS with a negative association with infiltration for 16 of 23 immune-related cells.ConclusionWe screened DEGs of m6Aclusters and identified 6 genes (BAIAP2, TEX264, MMAB, JAGN1, TIMM8AP1, and IMP3), with which we constructed a highly predictive model with prognostic value by dividing TCGA-PRAD into three distinct subgroups and performing m6Ascore analysis. This study helps to elucidate the integral effects of m6A modification patterns on PCa progression.
| S-EPMC8772220 | biostudies-literature
Project description:Colon cancer is a common and leading cause of death and malignancy worldwide. N6-methylation of adenosine (m6A) is the most common reversible mRNA modification in eukaryotes, and it plays a crucial role in various biological functions in vivo. Dysregulated expression and genetic changes of m6A regulators have been correlated with tumorigenesis, cancer cell proliferation, tumor microenvironment, and prognosis in cancers. This study used RNA-seq and colon cancer clinical data to explore the relationship between N6-methylation and colon cancer. Based on the seven m6A regulators related to prognosis, three molecular subgroups of colon cancer were identified. Surprisingly, we found that each subgroup had unique survival characteristics. We then identified three subtypes of tumors based on 299 m6A phenotype-related genes, and one subtype was characterized as an immunosuppressive tumor and patients in this subtype may be more suitable for immunotherapy than other subtypes. Finally, using m6A-related genes and clinical information from The Cancer Genome Atlas cohort, we constructed a prognosis model, and this model could be used to predict the prognosis of patients in clinics.
| S-EPMC7926939 | biostudies-literature
Project description:BACKGROUND:N6-methyladenosine (m6A) is the most prevalent RNA modification. While the role of m6A in prostate cancer remains unknown. We aim to measure the effects of m6A methylation regulatory genes during the development and progression of prostate cancer. METHODS:We collected transcriptome information and gene-level alteration data from The Cancer Genome Atlas datasets. The log-rank test and Cox regression model were used to examine the prognosis value of m6A methylation regulatory genes of prostate cancer. RESULTS:We discovered that most of m6A methylation regulators were highly expressed in aggressive prostate cancer. Univariable and multivariable Cox regression results showed that the expression of Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), Heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1) and N6-adenosine-methyltransferase non-catalytic subunit (METTL14) and copy number variant of AlkB Homolog 5 (ALKBH5) were considerably associated with a recurrence-free survival of prostate cancer. Furthermore, a high level of m6A methylation in mRNA promotes the progression of prostate cancer via regulating subcellular protein localization. CONCLUSION:Patients with a high level of mRNA methylation resulted from overexpression of reader proteins and methyltransferase complexes had poor survival benefits through influencing protein subcellular location in prostate cancer.
| S-EPMC7425456 | biostudies-literature
Project description:BackgroundN6-methyladenosine (m6A) is the most common form of mRNA modification under the field of "RNA epigenetics." However, its role in ovarian cancer (OC) development is poorly understood. In the current study, we aimed to identify gene signatures and prognostic values of m6A RNA methylation regulators.MethodSpecifically, we downloaded Mutations and Copy number variant (CNV) data from the TCGA database for 579 OC patients, then analyzed gene expression and prognosis value using integrative bioinformatics. Thereafter, we verified the related biological processes of Wilms' tumor 1-associating protein (WTAP) gene using Gene set enrichment analysis (GSEA).ResultsResults showed that almost all ovarian cancer patients (99.31%) have CNVs with at least 1 m6A regulatory gene, whereas 83.76% of cases exhibited concurrence of CNVs in more than 4 m6A regulatory genes. Additionally, alteration of m6A regulators was associated with historical grade, whereas integrative bioinformatics and Cox multivariate model analysis revealed a significant correlation between high WTAP expression and worse ovarian cancer outcomes. Moreover, GSEA revealed that high WTAP expression was associated with cell cycle regulation and MYC targets.ConclusionOverall, our findings demonstrate the significance of high-frequency genetic alterations of m6A RNA methylation regulators and WTAP's poor prognosis value in OC. These findings provide valuable insights into the role of m6A methylation in OC, and will be vital in guiding development of novel treatment therapies.
| S-EPMC7791456 | biostudies-literature
Project description:Pancreatic cancer (PAAD) is one of the most malignant cancers and immune microenvironment has been proved to be involved in pathogenesis of PAAD. m6A modification, related to the expression of m6A regulators, participates in the development of multiple cancers. However, the correlation between m6A regulators and immune microenvironment was largely unknown in PAAD. And because of the small sample size of pancreatic cancer in the TCGA database, it is not enough to draw a convincing conclusion. In the present study, we downloaded seven pancreatic cancer datasets with survival data and removed batch effects among these datasets to be used as the PAAD cohort to analyze the immune landscape of PAAD and the expression pattern of m6A regulators and divided the integrated dataset into cluster 1 and cluster 2 by consensus clustering for m6A regulators. Lower m6A regulators were found to be related to higher immune cell infiltration and a better survival. Moreover, we identified six m6A regulators and constructed the prognostic signature of m6A regulators. Patients with low-risk score had a higher response to immune checkpoint inhibitor and a longer overall survival. To figure out the underlying mechanism, we analyzed the cancer immunity cycle, most altered genes, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) in risk subtypes. In summary, the present study proved m6A regulators modulated the PAAD immune microenvironment. And risk scores served as predictive indicator for immunotherapy and played a prognostic role for PAAD patients. Our study provided novel therapeutic targets to improve immunotherapy efficacy.
| S-EPMC8602908 | biostudies-literature
Project description:Background:N6-methyladenosine (m6A) modification holds an important position in tumorigenesis and metastasis because it can change gene expression and even function in multiple levels including RNA splicing, stability, translocation and translation. In present study, we aim to conducted comprehensive investigation on m6A RNA methylation regulators and m6A-related genes in pancreatic cancer and their association with survival time. Methods:Based on Univariate Cox regression analysis, protein-protein interaction analysis, LASSO Cox regression, a risk prognostic model, STRING, Spearman and consensus clustering analysis, data from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) database was used to analyze 15 m6A RNA methylation regulators that were widely reported and 1,393 m6A-related genes in m6Avar. Results:We found that 283 candidate m6A RNA methylation-related genes and 4 m6A RNA methylation regulatory factors, including RNA binding motif protein 15 (RBM15), methyltransferase like 14 (METTL14), fat mass and obesity-associated protein (FTO), and ?-ketoglutarate-dependent dioxygenase AlkB homolog 5 (ALKBH5), differed significantly among different stages of the American Joint Committee on Cancer (AJCC) staging system. Protein-protein interaction analysis indicated epidermal growth factor receptor (EGFR), plectin-1 (PLEC), BLM RecQ like helicase (BLM), and polo like kinase 1 (PLK1) were closely related to other genes and could be considered as hub genes in the network. The results of LASSO Cox regression and the risk prognostic model indicated that AJCC stage, stage T and N, KRAS mutation status and x8q23.3 CNV fragment mutation differed significantly between the high-risk and the low-risk subgroups. The AUCs of 1 to 5 years after surgery were all more than 0.7 and increased year by year. Finally, we found KRAS mutation status and AJCC stage differed significantly among these groups after TCGA samples divided into subgroups with k=7. Moreover, we identified four m6A RNA methylation related genes expressed significantly differently among these seven subgroups, including collagen type VII alpha 1 chain (COL7A1), branched chain amino acid transaminase 1 (BCAT1), zinc finger protein 596 (ZNF596), and PLK1. Conclusions:Our study systematically analyzed the m6A RNA methylation related genes, including expression, protein-protein interaction, potential function, and prognostic value and provides important clues to further research on the function of RNA m6A methylation and its related genes in pancreatic cancer.
| S-EPMC7186697 | biostudies-literature
Project description:N6-methyladenosine (m6A) is the most prevalent modification of RNA in mammals. m6A RNA methylation levels are dynamically regulated by m6A RNA methylation regulators. While increasing evidence has suggested that m6A RNA methylation is vital in the initiation and progression of human carcinoma, little is known about the expression and effect of m6A RNA methylation regulators in differentiated thyroid carcinoma (DTC). Herein, we demonstrate that most of the thirteen main m6A RNA methylation regulators are differentially expressed in DTC tissues and normal thyroid tissues. Based on consensus clustering of m6A RNA methylation regulators, DTC cases were divided into two subgroups (TC1 and TC2). Compared with the TC1 subgroup, the TC2 subgroup was associated with a poorer prognosis, older age, higher T grade, higher N grade and higher TNM stage. The results indicated that alteration of m6A RNA methylation regulators was closely related to DTC. We further established a risk signature of four m6A RNA methylation regulators that could evaluate prognosis and clinicopathological features in DTC. Finally, the results of the TCGA analysis were verified by other cohorts from Gene Expression Omnibus (GEO) database. In conclusion, m6A RNA methylation regulators play a crucial part in the progression of DTC and are potentially useful for evaluating the prognosis and providing potential novel insights into treatment strategies.
| S-EPMC7378910 | biostudies-literature
Project description:Purpose:N6-methyladenosine (m6A) is reported to play a critical role in cancer through various mechanisms. We aimed to construct and validate an m6A RNA methylation regulators-based prognostic signature for Esophageal cancer (ESCA). Materials and Methods:The RNA sequencing transcriptome data of 13 m6A RNA methylation regulators as well as clinical data were obtained from The Cancer Genome Atlas (TCGA) ESCA database. The differential expression of the regulators between ESCA tissues and normal tissues was assessed. Consensus clustering was conducted to explore the different ESCA clusters based on the expression of these regulators. LASSO Cox regression analysis was used to generate a prognostic signature based on m6A RNA methylation regulators expression. Results:Eight regulators (KIAA1429, HNRNPC, RBM15, METTL3, WTAP, YTHDF1, YTHDC1, and YTHDF2) were found to be significantly upregulated in ESCA tissues. Significant differences of survival rate and clinicopathological features were found between the two clusters. A prognostic signature, which consists of HNRNPC and ALKBH5, was constructed based on the TCGA ESCA cohort, which can serve as an independent prognostic predictor. The results of bioinformatics analysis were further successfully validated in the clinical ESCA cohort by qRT-PCR and immunohistochemistry staining. Conclusion:Our study constructed and validated an m6A RNA methylation regulators-based prognostic signature. This might provide important information for developing diagnostic and therapeutic strategies.
| S-EPMC7352013 | biostudies-literature