Identification of N6-Methyladenosine-Related LncRNAs for Predicting Overall Survival and Clustering of a Potentially Novel Molecular Subtype of Breast Cancer
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SUBMITTER: Zhong X
PROVIDER: S-EPMC8554333 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveGastric cancer (GC) is one of the most prevalent malignant tumors in Asian countries. Studies have proposed that lncRNAs can be used as diagnostic and prognostic indicators of GC due to the high specificity of lncRNAs expression involvement in GC. Recently, N6-methyladenosine (m6A) has also emerged as an important modulator of the expression of lncRNAs in GC. This study aimed at establishing a novel m6A-related lncRNAs prognostic signature that can be used to construct accurate models for predicting the prognosis of GC in the Asian population.MethodsFirst, the levels of m6A modification and m6A methyltransferases expression in GC samples were determined using dot blot and western blot analyses. Next, we evaluated the lncRNAs expression profiles and the corresponding clinical data of 88 Asian GC patients retrieved from The Cancer Genome Atlas (TCGA) database. Differential expression of m6A-related lncRNAs between GC and normal tissues was investigated. The relationship between these target lncRNAs and potential immunotherapeutic signatures was also analyzed. Gene set enrichment analysis (GSEA) was performed to identify the malignancy-associated pathways. Univariate Cox regression, LASSO regression, and multivariate Cox regression analyses were performed to establish a novel prognostic m6A-related lncRNAs prognostic signature. Moreover, we constructed a predictive nomogram and determined the expression levels of nine m6A-related lncRNAs in 12 pairs of clinical samples.ResultsWe found that m6A methylation levels were significantly increased in GC tumor samples compared to adjacent normal tissues, and the increase was positively correlated with tumor stage. Patients were then divided into two clusters (cluster 1 and cluster 2) based on the differential expression of the m6A-related lncRNAs. Results showed that there was a significant difference in survival probability between the two clusters (p = 0.018). Notably, the low survival rate in cluster 2 may be associated with high expression of immune cells (resting memory CD4+ T cells, p = 0.027; regulatory T cells, p = 0.0018; monocytes, p = 0.00095; and resting dendritic cells, p = 0.015), and low expression of immune cells (resting NK cells, p = 0.033; and macrophages M1, p = 0.045). Enrichment analysis indicated that malignancy-associated biological processes were more common in the cluster 2 subgroup. Finally, the risk model comprising of six m6A-related lncRNAs was identified as an independent predictor of prognoses, which could divide patients into high- or low-risk groups. Time-dependent ROC analysis suggested that the risk score could accurately predict the prognosis of GC patients. Patients in the high-risk group had worse outcomes compared to patients in the low-risk group, and the risk score showed a positive correlation with immune cells (resting memory CD4+ T cells, R = 0.31, P = 0.038; regulatory T cells, R = 0.42, P = 0.0042; monocytes, R = 0.42, P = 0.0043). However, M1 macrophages (R = -0.37, P = 0.012) and resting NK cells (R = -0.31, P = 0.043) had a negative correlation with risk scores. Furthermore, analysis of clinical samples validated the weak positive correlation between the risk score and tumor stage.ConclusionsThe risk model described here, based on the six m6A-related lncRNAs signature, and may predict the clinical prognoses and immunotherapeutic response in Asian GC patients.
| S-EPMC9248105 | biostudies-literature
Project description:The prognostic value of N6-methylandenosine-related long non-coding RNAs (m6A-related lncRNAs) was investigated in 646 lower-grade glioma (LGG) samples from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) datasets. We implemented Pearson correlation analysis to explore the m6A-related lncRNAs, and then univariate Cox regression analysis was performed to screen their prognostic roles in LGG patients. Twenty-four prognostic m6A-related lncRNAs were identified as prognostic lncRNAs and they were inputted in a least absolute shrinkage and selection operator (LASSO) Cox regression to establish a m6A-related lncRNA prognostic signature (m6A-LPS, including 9 m6A-related prognostic lncRNAs) in the TCGA dataset. Corresponding risk scores of patients were calculated and divided LGG patients into low- and high-risk subgroups by the median value of risk scores in each dataset. The m6A-LPS was validated in the CGGA dataset and it showed a robust prognostic ability in the stratification analysis. Principal component analysis showed that the low- and high-risk subgroups had distinct m6A status. Enrichment analysis indicated that malignancy-associated biological processes, pathways and hallmarks were more common in the high-risk subgroup. Moreover, we constructed a nomogram (based on m6A-LPS, age and World Health Organization grade) that had a strong ability to forecast the overall survival (OS) of the LGG patients in both datasets. We also establish a competing endogenous RNA (ceRNA) network based on seven of the twenty-four m6A-related lncRNAs. Besides, we also detected five m6A-related lncRNA expression levels in 22 clinical samples using quantitative real-time polymerase chain reaction assay.
| S-EPMC7390977 | biostudies-literature
Project description:The N6-methyladenosine (m6A) RNA modification can modify long non-coding RNAs (lncRNAs), thereby affecting the tumorigenesis and progression of tumors. However, the underlying role of m6A-modified lncRNAs in colorectal cancer (CRC) remains largely unknown. Therefore, our aim was to assess the prognostic value of m6A-modified lncRNAs in CRC patients. The gene expression and clinicopathological data of CRC were extracted from The Cancer Genome Atlas (TCGA) database. Pearson correlation analysis was used to investigate the m6A-modified lncRNAs. Consensus clustering was conducted to identify molecular subtypes of CRC, and the clinical significance of molecular subtypes was identified. The least absolute shrinkage and selection operator analysis (LASSO) was applied to establish a risk signature. Finally, a prognostic nomogram with risk score and clinicopathological variables was established. In total, 29 m6A-modified lncRNAs were identified as prognostic lncRNAs. Two molecular clusters were identified and significant differences were found with respect to clinicopathological features and prognosis. Cluster1 is associated with poor overall survival (OS), down-regulation of Programmed cell death ligand-1 (PD-L1) expression, lower immune score, and less immune cell infiltration. Then, an m6A-modified lncRNA signature for predicting OS was constructed in the TCGA training cohort. The signature demonstrated favorable prediction performance in both training and validation sets. Compared with low-risk patients, patients with high risk showed worse clinical outcomes, lower immune scores, and downregulated PD-L1 expression. Further analysis indicated that the signature was an independent prognostic indicator, and then a prognostic nomogram based on risk score, tumor location, and tumor stage was established. Our study identified a seven m6A-modified lncRNA signature and established a prognostic nomogram that reliably predicts OS in CRC. These findings may improve the understanding of m6A modifications in CRC and provide insights into the prognosis and treatment strategy of CRC.
| S-EPMC8472391 | biostudies-literature
Project description:BackgroundSeveral recent studies have confirmed epigenetic regulation of the immune response. However, the potential role of RNA N6-methyladenosine (m6A) modifications in cervical cancer and tumour microenvironment (TME) cell infiltration remain unclear.ResultsWe evaluated and analysed m6A modification patterns in 307 cervical cancer samples from The Cancer Genome Atlas (TCGA) dataset based on 13 m6A regulators. Pearson correlation analysis was used to identify lncRNAs associated with m6A, followed by univariate Cox regression analysis to screen their prognostic role in cervical cancer patients. We also correlated TME cell infiltration characteristics with modification patterns. We screened six m6A-associated lncRNAs as prognostic lncRNAs and established the prognostic profile of m6A-associated lncRNAs by least absolute shrinkage and choice of operator (LASSO) Cox regression. The corresponding risk scores of the patients were derived based on their prognostic features, and the correlation between this feature model and disease prognosis was analysed. The prognostic model constructed based on the TCGA-CESC (The Cancer Genome Cervical squamous cell carcinoma and endocervical adenocarcinoma) dataset showed strong prognostic power in the stratified analysis and was confirmed as an independent prognostic indicator for predicting the overall survival of patients with CESC. Enrichment analysis showed that biological processes, pathways, and markers associated with malignancy were more common in the high-risk subgroup. Risk scores were strongly correlated with the tumour grade. ECM receptor interactions and pathways in cancer were enriched in Cluster 2, while oxidative phosphorylation and other biological processes were enriched in Cluster 1. The expression of immune checkpoint molecules, including programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), was significantly increased in the high-risk subgroup, suggesting that this prognostic model could be a predictor of immunotherapy.ConclusionsThis study reveals that m6A modifications play an integral role in the diversity and complexity of TME formation. Assessing the m6A modification patterns of individual tumours will help improve our understanding of TME infiltration characteristics and thus guide immunotherapy more effectively. We also developed an independent prognostic model based on m6A-associated lncRNAs as a predictor of overall survival, which can also be used as a predictor of immunotherapy.
| S-EPMC8767716 | biostudies-literature
Project description:Accumulating evidence indicates the role of N 6-methyladenosine (m6A) regulator-mediated RNA methylation in cancer progression and metastasis; yet its potential clinical significance, if any, remains unclear. In this first-of-its-kind study, we systematically evaluated the role of m6A regulators as potential disease biomarkers based on comprehensive analysis of gene expression profiles of 9770 cancer cell lines and clinical specimens from 25 publicly available datasets, encompassing 13 human cancers. We developed and established RNAMethyPro-a gene expression signature of seven m6A regulators, which robustly predicted patient survival in multiple human cancers. Pan-cancer analysis identified activated epithelial-mesenchymal transition (EMT), as a highly conserved pathway in high-risk patients predicted by RNAMethyPro in 10 of the 13 cancer types. A network-based analysis revealed an intimate functional interplay between m6A regulators and EMT-associated factors via druggable targets such as XPO1 and NTRK1. Finally, the clinical significance of RNAMethyPro was further exemplified in colorectal cancer, where high-risk patients demonstrated strong associations with a mesenchymal subtype, activated stromal infiltration, and poor therapeutic response to targeted anti-EGFR therapy. In summary, RNAMethyPro is a novel, EMT-associated prognostic gene-expression signature in multiple human cancers and may offer an important clinical decision-making tool in the future.
| S-EPMC6494854 | biostudies-literature
Project description:BackgroundBreast cancer (BC) displays striking genetic, epigenetic and phenotypic diversity. N6-methyladenosine (m6A) in mRNA has emerged as a crucial epitranscriptomic modification that controls cancer self-renewal and cell fate. However, the key enzymes of m6A expression and function in human breast carcinogenesis remain unclear.MethodsThe expression of m6A methylases (METTL3, METTL14 and WTAP) and demethylases (FTO and ALKBH5) were analyzed by using ONCOMINE and The Cancer Genome Atlas databases and in 36 pairs of BC and adjacent non-cancerous tissue. The level of m6A in BC patients was detected by ELISA, and the function of m6A was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay and transwell assay. The database of bc-GenExMiner v4.0, Kaplan-Meier Plotter and cBioPortal were queried for correlation, mutation and prognosis analysis of BC.ResultsThe m6A methylases and demethylases were dysregulated in several major malignant tumors. Specifically, the expression of all m6A methylases was reduced in BC as compared with normal controls, but the demethylase ALKBH5 was induced in ONCOMINE databases and confirmed in clinical patients. METTL14 expression was positively correlated with METTL3 expression, and both showed high expression in normal breast-like and luminal-A and -B BC. Functionally, reducing m6A expression by overexpressing METTL14 and/or knockdown of ALKBH5 could inhibit breast cell viability, colony formation and cell migration. Furthermore, Kaplan-Meier, meta-analysis and univariate Cox assay showed that the expression of m6A members including METTL3, METTL14, WTAP and FTO but not their gene mutation and amplification, was tightly associated with cancer progression and poor survival.ConclusionsChanges of m6A modulators reduced m6A may promote tumorigenesis and predict poor prognosis in BC.
| S-EPMC6451293 | biostudies-literature
Project description:Purpose: The ectopic expression of N6-methyladenosine (m6A) associated genes is a common feature of multiple tumors. However, little is known about the expression status and the prognostic value of these genes in human breast cancer (BRC). Herein, we conducted a comprehensive analysis to identify the expression profiling and clinical significance of m6A-related genomic targets in BRC. Materials and Methods: The expression data including 1109 BRC tissues and 113 normal breast tissues were obtained from The Cancer Genome Atlas (TCGA) database to evaluate the mRNA expression levels of m6A-related genomic targets. In addition, 6 independent BRCA cohorts retrieved from the Gene Expression Omnibus (GEO) database were enrolled to further ascertain the expression profiling of m6A-related genomic targets. Meanwhile, the immunohistochemical (IHC) staining data from BRC tissue microarray (TMA) cohort and the Human Protein Atlas (HPA) database were used to evaluate the proteomic expression of m6A-related genomic targets. Immunofluorescence (IF) analysis was performed to validate the subcellular location of m6A-related genomic targets. Moreover, the prognostic value of m6A-related genomic targets in BRC was analyzed by Kaplan-Meier analysis and Cox regression models. Results: m6A-related genomic targets were differentially expressed in BRC tissues. TMA IHC staining showed that most of the m6A-related genomic targets were significantly altered at the protein level (either upregulated or downregulated), consistent with their changes in the genomic profile. IF analysis showed the subcellular location of m6A-related genomic targets in BRC cell lines. Furthermore, we demonstrated that overexpression of YTHDF1 (P=0.049), YTHDF3 (P<0.001) and KIAA1429 (P=0.032) predicted poor prognosis in terms of overall survival (OS). Upregulation of YTHDF3 was an independent prognostic factor for OS in patients with BRC (P=0.036). Conclusion: m6A-related genomic targets are significantly altered in BRC and predict poor prognosis. These m6A-related genomic targets could serve as novel prognostic biomarkers for BRC.
| S-EPMC6775703 | biostudies-literature
Project description:N6-methyladenosine (m6A) modification is the most prevalent internal mRNA modification and is involved in many biological processes in eukaryotes. Accumulating evidence has demonstrated that m6A may play either a promoting or suppressing role in breast cancer, including in tumorigenesis, metastasis and angiogenesis. In this review, we summarize the latest research progress on the biological function and prognostic value of m6A modification in breast cancer, as well as potential related therapeutic strategies.
| S-EPMC8161983 | 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:N6-Adenosine methylation, yielding N6-methyladenosine (m6A), is a reversible epigenetic modification found in messenger RNAs and long non-coding RNAs (lncRNAs), which affects the fate of modified RNA molecules and is essential for the development and differentiation of immune cells in the tumor microenvironment (TME). Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents, and is characterized by high mortality. Currently, the possible role of m6A modifications in the prognosis of OS is unclear. In the present study, we investigated the correlation between m6A-related lncRNA expression and the clinical outcomes of OS patients via a comprehensive analysis. Clinical and workflow-type data were obtained from the Genotype-Tissue Expression Program and The Cancer Genome Atlas. We examined the relationship between m6A modifications and lncRNA expression, conducted Kyoto Encyclopedia of Genes analysis and also gene set enrichment analysis (GSEA), implemented survival analysis to investigate the association of clinical survival data with the expression of m6A-related lncRNAs, and utilized Lasso regression to model the prognosis of OS. Furthermore, we performed immune correlation analysis and TME differential analysis to investigate the infiltration levels of immune cells and their relationship with clinical prognosis. LncRNA expression and m6A levels were closely associated in co-expression analysis. The expression of m6A-related lncRNAs was quite low in tumor tissues; this appeared to be a predicting factor of OS in a prognostic model, independent of other clinical features. The NOD-like receptor signaling pathway was the most significantly enriched pathway in GSEA. In tumor tissues, SPAG4 was overexpressed while ZBTB32 and DEPTOR were downregulated. Tissues in cluster 2 were highly infiltrated by plasma cells. Cluster 2 presented higher ESTIMATE scores and stromal scores, showing a lower tumor cell purity in the TME. In conclusion, m6A-related lncRNA expression is strongly associated with the occurrence and development of OS, and can be used to as a prognostic factor of OS. Moreover, m6A-related lncRNAs and infiltrating immune cells in the TME could serve as new therapeutic targets and prognostic biomarkers for OS.
| S-EPMC8790065 | biostudies-literature