An N6-Methyladenosine-Related Gene Set Variation Score as a Prognostic Tool for Lung Adenocarcinoma.
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SUBMITTER: Zhang H
PROVIDER: S-EPMC8295598 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeThe prognostic value of an N6-methyladenosine (m6A) methylation-related immune gene signature for lung adenocarcinoma (LUAD) was investigated.Patients and methodsGene expression and clinical phenotype data of LUAD patients were downloaded from The Cancer Genome Atlas database. A list of immune-related genes was retrieved from the InnateDB database. Correlation analysis, survival analysis, and univariate and multivariate Cox regression analyses were performed. After allocating patients into a high-risk or a low-risk group, the corresponding survival rates, immune microenvironment, expression of immune checkpoint genes, and modulation of Kyoto Encyclopedia of Genes and Genomes pathways were examined. Finally, the expression levels of prognostic biomarkers were assessed in the GSE126044 dataset.ResultsSeven m6A-related immune prognostic genes were identified. High expression of PSMD10P1, DIDO1, ABCA5, and CIITA was associated with high survival rates, while that of PRC1, ZWILCH, and ANLN was associated with low survival rates. The high- and low-risk groups showed significant differences in terms of the abundance of six tumor-infiltrating immune cell types and expression of 12 immune checkpoint genes. The risk group acted as an independent prognostic factor (hazard ratio = 0.398, 95% confidence interval = 0.217-0.729, P = 0.003). Finally, the developed nomogram could predict most efficiently the 1-, 2-, and 3-year survival probability of LUAD patients with a C-index of 0.833.ConclusionA seven-gene risk signature, associated with the immune microenvironment in LUAD, showed independent prognostic value.
| S-EPMC8643173 | biostudies-literature
Project description:Aberrant regulation of m6A mRNA modification can lead to changes in gene expression, thus contributing to tumorigenesis in several types of solid tumors. In this study, by integrating analyses of m6A methylation and mRNA expression, we identified 84 m6A-regulated mRNAs in lung adenocarcinoma (LUAD). Although the m6A methylation levels of total RNA in LUAD patient tumor tissue were reduced, the majority (75.2%) of m6A-regulated mRNAs were hypermethylated. The m6A-hypermethylated mRNAs were mainly enriched in terms related to transcription factor activity. We established a 10-m6A-regulated-mRNA signature score system through least absolute shrinkage and selection operator Cox regression analysis, with its predictive value validated by Kaplan-Meier curve and time-dependent receiver operating characteristic curves. RFXAP and KHDRBS2 from the signature also exhibited an independent prognostic value. The co-expression and interaction network analyses demonstrated the strong correlation between m6A regulators and the genes in the signature, further supporting the results of the m6A methylation modification patterns. These findings highlight the potential utility of integrating multi-omics data (m6A methylation level and mRNA expression) to accurately obtain potential prognostic biomarkers, which may provide important insights into developing novel and effective therapies for LUAD.
| S-EPMC8377381 | biostudies-literature
Project description:Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death. Among these, lung adenocarcinoma (LUAD) accounts for most cases. Due to the improvement of precision medicine based on molecular characterization, the treatment of LUAD underwent significant changes. With these changes, the prognosis of LUAD becomes diverse. N6-methyladenosine (m6A) is the most predominant modification in mRNAs, which has been a research hotspot in the field of oncology. Nevertheless, little has been studied to reveal the correlations between the m6A-related genes and prognosis in LUAD. Thus, we conducted a comprehensive analysis of m6A-related gene expressions in LUAD patients based on The Cancer Genome Atlas (TCGA) database by revealing their relationship with prognosis. Different expressions of the m6A-related genes in tumor tissues and non-tumor tissues were confirmed. Furthermore, their relationship with prognosis was studied via Consensus Clustering Analysis, Principal Components Analysis (PCA), and Least Absolute Shrinkage and Selection Operator (LASSO) Regression. Based on the above analyses, a m6A-based signature to predict the overall survival (OS) in LUAD was successfully established. Among the 479 cases, we found that most of the m6A-related genes were differentially expressed between tumor and non-tumor tissues. Six genes, HNRNPC, METTL3, YTHDC2, KIAA1429, ALKBH5, and YTHDF1 were screened to build a risk scoring signature, which is strongly related to the clinical features pathological stages (p < 0.05), M stages (p < 0.05), T stages (p?<?0.05), gender (p = 0.04), and survival outcome (p = 0.02). Multivariate Cox analysis indicated that risk value could be used as an independent prognostic factor, revealing that the m6A-related genes signature has great predictive value. Its efficacy was also validated by data from the Gene Expression Omnibus (GEO) database.
| S-EPMC7066421 | biostudies-literature
Project description:Aberrant expression of adipogenic regulatory factors (ADIRF) in tumor cells is critical for tumor growth and metastasis. N6-methyladenosine (m6A) modifications have an important role in a variety of biological activities. Our study aimed to investigate the role of ADIRF in adenocarcinoma and to elucidate the regulatory role of m6A signaling on ADIRF. Differential expression of genes in tumor and normal tissues was analyzed using the LUAD dataset (GSE1987). The Kaplan-Meier method and receiver operating characteristic (ROC) curve analysis were performed to evaluate the prognostic and diagnostic value of ADIRF in LUAD. Loss-of-function or gain-of-function experiments were performed to study the effect of ADIRF on LUAD growth in vitro. The molecular mechanism of action of ADIRF in LUAD was confirmed using a dual-luciferase reporter system and MeRIP-qPCR. We identified a loss of ADIRF expression in LUAD tissues and cells. Furthermore, the restoration of ADIRF levels attenuated LUAD cell growth and metastasis in vitro. Mechanistically, an m6A "eraser," α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5), eliminated the ADIRF m6A modification motif and further blocked the binding of the YTH domain-containing 2 (YTHDC2)-binding protein to ADIRF. At the molecular level, ALKBH5 enrichment increased ADIRF mRNA levels and prevented the attenuation of ADIRF mRNA by YTHDC2. The effects of ALKBH5 overexpression could also extend to the inhibition of LUAD cell proliferation and metastasis. This study linked ADIRF with the m6A modifying regulators ALKBH5 and YTHDC2, providing a promising molecular intervention for LUAD and deepening the understanding of LUAD mechanisms.
| S-EPMC10501161 | biostudies-literature
Project description:BackgroundLung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, which is one of the most commonly diagnosed tumors and the leading causes of death from cancer around the world. Since RNA methylation is a posttranscriptional modification and affects so much biological progress, it is urged to explore the role of N6-methyladenosine (m6A) methylation in LUAD.MethodsWe explored the expression of 24 m6A methylation genes, as well as their correlations with LAG3 in 561 LUAD samples from TCGA. Consensus clustering was applied to m6A methylation genes, and two LUAD subgroups were identified. The expression of m6A genes was analyzed by the Wilcoxon test. KEGG and GO enrichment analyses were performed to indicate the pathway affected by differentially expressed genes in the two groups. A prognostic model based on LASSO regression using an eleven-m6A gene signature was constructed according to the expression of these genes. Receiver operating characteristic (ROC) curve was used to confirm the accuracy of the model in the TCGA cohort, as well as in the test cohort from the Gene Expression Omnibus (GEO) database.ResultsCompared to cluster 1, cluster 2 showed poorer overall survival (OS) and higher LAG3 expression. In addition, KEGG and GO enrichment analyses indicated that differentially expressed genes are enriched in the immune response. We also observed that the expression of LAG3 is positively correlated with IGF2BP2, CBLL1, and HNRNPA2B1 and negatively correlated with YTHDF2, YTHDF3, and FTO. For patients in the TCGA cohort, the AUC score is 0.7, and the AUC score for the GSE50081 cohort is 0.675. Patients with lower risk scores exhibited better overall survival and lower expression of LAG3 than patients with higher risk scores.ConclusionsIn brief, our results indicated the important role of m6 methylation in affecting the tumor immune microenvironment and the survival of patients with LUAD. The m6A methylation gene signatures might serve as promising therapeutic targets and help the immunotherapy of LUAD in the future.
| S-EPMC9427291 | biostudies-literature
Project description:Background: Lung adenocarcinoma (LUAD) is the major subtype of lung cancer and is associated with very high mortality. Emerging studies have shown that N6-methyladenosine (m6A)-related long non-coding (lnc) RNAs play crucial roles in tumor prognosis and the tumor immune microenvironment (TME). We aimed to explore the expression patterns of different m6A-related lncRNAs concerning patient prognosis and construct an m6A-related lncRNA prognostic model for LUAD. Methods: The prognostic value of m6A-related lncRNAs was investigated in LUAD samples from The Cancer Genome Atlas (TCGA). Potential prognostic m6A-related lncRNAs were selected by Pearson's correlation and univariate Cox regression analysis. Patients were divided into clusters using principal component analysis and the m6A-related lncRNA prognostic signature was calculated using least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Results: Based on 91 prognostic m6A-related lncRNAs, we identified two m6A-related-lncRNA pattern clusters with different overall survival (OS) and different TMEs. We subsequently verified our findings multidimensionally by constructing a 13 m6A-related lncRNA prognostic signature (m6A-LPS) to calculate the risk score, which was robust in different subgroups. The receiver operating characteristic (ROC) curves and concordance index demonstrated that m6A-LPS harbored a promising ability to predict OS in TCGA data set and independent GSE11969 cohort. The risk score was also related to OS, TME, and clinical stage, and the risk score calculated by our model was also identified as independent prognostic predictive factors for LUAD patients after adjustment for age, smoking, gender, and stage. Enrichment analysis indicated that malignancy and drug resistance-associated pathways were more common in cluster2 (LUAD-unfavorable m6A-LPS). Furthermore, the results indicated that the signaling pathway enriched by the target gene of 13 m6A-related lncRNAs may be associated with metastasis and progression of cancer according to current studies. Conclusion: The current results indicated that different m6A-related-lncRNA patterns could affect OS and TME in patients with LUAD, and the prognostic signature based on 13 m6A-related lncRNAs may help to predict the prognosis in LUAD patients.
| S-EPMC8585518 | biostudies-literature
Project description:Background: Immune and stromal cells in the tumor microenvironment (TME) significantly contribute to the prognosis of lung adenocarcinoma; however, the TME-related immune prognostic signature is unknown. The aim of this study was to develop a novel immune prognostic model of the TME in lung adenocarcinoma. Methods: First, the immune and stromal scores among lung adenocarcinoma patients were determined using the ESTIMATE algorithm in accordance with The Cancer Genome Atlas (TCGA) database. Differentially expressed immune-related genes (IRGs) between high and low immune/stromal score groups were analyzed, and a univariate Cox regression analysis was performed to identify IRGs significantly correlated with overall survival (OS) among patients with lung adenocarcinoma. Furthermore, a least absolute shrinkage and selection operator (LASSO) regression analysis was performed to generate TME-related immune prognostic signatures. Gene set enrichment analysis was performed to analyze the mechanisms underlying these immune prognostic signatures. Finally, the functions of hub IRGs were further analyzed to delineate the potential prognostic mechanisms in comprehensive TCGA datasets. Results: In total, 702 intersecting differentially expressed IRGs (589 upregulated and 113 downregulated) were screened. Univariate Cox regression analysis revealed that 58 significant differentially expressed IRGs were correlated with patient prognosis in the training cohort, of which three IRGs (CLEC17A, INHA, and XIRP1) were identified through LASSO regression analysis. A robust prognostic model was generated on the basis of this three-IRG signature. Furthermore, functional enrichment analysis of the high-risk-score group was performed primarily on the basis of metabolic pathways, whereas analysis of the low-risk-score group was performed primarily on the basis of immunoregulation and immune cell activation. Finally, hub IRGs CLEC17A, INHA, and XIRP1 were considered novel prognostic biomarkers for lung adenocarcinoma. These hub genes had different mutation frequencies and forms in lung adenocarcinoma and participated in different signaling pathways. More importantly, these hub genes were significantly correlated with the infiltration of CD4+ T cells, CD8+ T cells, macrophages, B cells, and neutrophils. Conclusions: The robust novel TME-related immune prognostic signature effectively predicted the prognosis of patients with lung adenocarcinoma. Further studies are required to further elucidate the regulatory mechanisms of these hub IRGs in the TME and to develop new treatment strategies.
| S-EPMC7538811 | biostudies-literature
Project description:N6-Methyladenosine (m6A) is one of the most prominent modification regulating RNA processing and metabolism. Increasing studies have illuminated the vital role of m6A methylation in carcinogenesis. However, little is known about the interaction between m6A-related genes and survival of ovarian cancer (OC) patients. The purpose of this study was to obtain more reliable m6A-related genes that could be used as prognostic markers of OC using bioinformatics analysis performed on the RNA-seq data of OC. Gene expression datasets of all m6A-related genes as well as corresponding clinical data were obtained from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) databases. We detected differential expressed m6A-related candidate genes as well as their relationship and interaction. m6A RNA methylation regulator ALKBH5 and 35 m6A-related genes are dysregulated in OC. A gene set that could be used as a potential independent prognostic risk feature was further screened including NEBL, PDGFRA, WDR91, and ZBTB4. The results of mRNA expression analysis by PCR were consistent with those of bioinformatics analysis. We applied consensus clustering analysis on the expression of the four prognostic genes and obtained four OC subgroups TM1-TM4. There were significant differences in age, stage and grade among the subgroups, and the overall survival (OS) as well as Disease-free survival (DFS) of TM2 group were shorter than those of the other three groups. Further GO and KEGG enrichment analysis indicated that these differential genes were closely related to biological processes and key signaling pathways involved in OC. In summary, our study has indicated that m6A-related genes are key factors in the progression of OC and have potential effects on the prognostic stratification of OC and the development of treatment strategies.
| S-EPMC8416414 | biostudies-literature
Project description:Background: Adrenocortical adenocarcinoma (ACC) is known to be a relatively uncommon malignant tumor of the adrenal gland with patients having a poor prognosis. At present, few reports are available concerning the m6A modifications of lncRNAs as well as their clinical and immunological significance in the occurrence and progression of ACC. Materials and Methods: In the present research, 21 m6A-related genes were analyzed. Both multivariate and univariate Cox regression analyses were conducted to examine the prognostic m6A-related lncRNAs. A sum of 165 m6A-related lncRNAs was obtained from The Cancer Genome Atlas (TCGA) dataset. Based on the expressions of m6A-related lncRNAs, all ACC patients were classified into distinct subgroups using the consistent clustering method. Finally, m6A-related lncRNAs that were shown to have prognostic value were utilized to develop an m6A-related lncRNA risk model, which may be employed in the prediction of prognosis and survival. Results: Using TCGA data set, 26 m6A-associated lncRNAs having putative prognostic values were identified according to their expression levels, TCGA-AAC patients were classified into two clusters with the aid of consistent clustering analysis. The correlation between the two clusters was low, in which cluster1 consisted of 42% of all ACC patients. The survival analysis showed that cluster1 was associated with an unfavorable prognosis relative to cluster2. A risk model was constructed incorporating 26 m6A-associated lncRNAs that were correlated with patient prognosis. The model was subsequently validated by univariate and multivariate Cox, receiver operating characteristic (ROC) curve, and survival analyses. We also observed that the m6A-related risk model performed well in anticipating prognoses and survival status of patients with AAC. The overall survival (OS) of the high-risk cohort, as predicted by the model, was lower as opposed to that of the low-risk cohort. Conclusion: In the present research, we developed a risk model consisting of 4 m6A-related long-noncoding RNAs (lncRNAs), which can exert independent predictive values in patients with ACC. Our findings demonstrated that these 4 m6A-related lncRNAs perform integral functions in the tumor immune microenvironment, and also revealed the possibility of using these lncRNAs to guide the development of prognostic classifications and therapy approaches for ACC patients.
| S-EPMC9163712 | biostudies-literature
Project description:Accumulating evidence indicates that N6-methyladenosine (m6A) and long noncoding RNAs (lncRNAs) play crucial roles in cancer development. However, the biological roles of m6A and lncRNAs in lung cancer tumorigenesis are largely unknown. In this study, SVIL antisense RNA 1 (SVIL-AS1) was downregulated in lung adenocarcinoma (LUAD) tissues and was associated with a favorable prognosis in patients with LUAD. SVIL-AS1 overexpression suppressed LUAD cell proliferation and blocked cell cycle arrest. Mechanistically, METTL3 increased the m6A modification and transcript stability of SVIL-AS1. The enhanced SVIL-AS1 expression mediated by METTL3 suppressed E2F1 and E2F1-target genes. Moreover, SVIL-AS1 accelerated E2F1 degradation. The reduction in cell proliferation induced by SVIL-AS1 overexpression could be rescued by E2F1 overexpression or METTL3 knockdown. In conclusion, our work demonstrated the role and mechanism of METTL3-induced SVIL-AS1 in LUAD, which connects m6A and lncRNA in lung cancer carcinogenesis.
| S-EPMC8973833 | biostudies-literature