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Genetic Alterations and Transcriptional Expression of m⁶A RNA Methylation Regulators Drive a Malignant Phenotype and Have Clinical Prognostic Impact in Hepatocellular Carcinoma.

ABSTRACT: Background: N6-methyladenosine (m⁶A) RNA methylation, associated with cancer initiation and progression, is dynamically regulated by the m⁶A RNA regulators. However, its role in liver carcinogenesis is poorly understood. Methods: Three hundred seventy-one hepatocellular carcinoma (HCC) patients from The Cancer Genome Atlas database with sequencing and copy number variations/mutations data were included. Survival analysis was performed using Cox regression model. We performed gene set enrichment analysis to explore the functions associated with different HCC groups. Finally, we used a machine-learning model on selected regulators for developing a risk signature (m⁶Ascore) The prognostic value of m⁶Ascore was finally validated in another two GEO datasets. Results: We demonstrated that 11 m⁶A RNA regulators are significantly differentially expressed among 371 HCC patients stratified by clinicopathological features (P<0.001). We then identified two distinct HCC clusters by applying consensus clustering to m⁶A RNA regulators. Compared with the cluster2 subgroup, the cluster1 subgroup correlates with poorer prognosis (P < 0.001). Moreover, the cell cycle, splicesome and notch signaling pathway are significantly enriched in the cluster1 subgroup. We further derived m⁶Ascore, using four m⁶A regulators, predicting HCC prognosis well at three (AUC = 0.7) or 5 years (AUC=0.7) in validation. The prognostic value of m⁶Ascore also was validated successfully in two GEO datasets (P < 0.05). Finally, we discovered that mutations and copy number variations of m⁶A regulators, conferring worse survival, are strongly associated with TP53 mutations in HCC. Conclusions: We find a significant relationship between the alterations and different expressions causing increased m⁶A level and worse survival, especially in TP53-mutated HCC patients. Genetic alterations of m⁶A genes might cooperate with TP53 and its regulator targets in the HCC pathogenesis. Our m⁶Ascore may be applied in the clinical trials for patient stratification in HCC.

SUBMITTER: Zhu GQ

PROVIDER: S-EPMC7396691 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeN6-methyladenosine (m6A) is the most prevalent modification in mRNA methylation which has a wide effect on biological functions. This study aims to figure out the efficacy of m6A RNA methylation regulator-based biomarkers with prognostic significance in breast cancer.Patients and methodsThe 23 RNA methylation regulators were firstly analyzed through ONCOMINE, then relative RNA-seq transcriptome and clinical data of 1,096 breast cancer samples and 112 normal tissue samples were acquired from The Cancer Gene Atlas (TCGA) database. The expressive distinction was also showed by the Gene Expression Omnibus (GEO) database. The gene expression data of m6A RNA regulators in human tissues were acquired from the Genotype-Tissue Expression (GTEx) database. The R v3.5.1 and other online tools such as STRING, bc-GeneExminer v4.5, Kaplan-Meier Plotter were applied for bioinformatics analysis.ResultsResults from ONCOMINE, TCGA, and GEO databases showed distinctive expression and clinical correlations of m6A RNA methylation regulators in breast cancer patients. The high expression of YTHDF3, ZC3H13, LRPPRC, and METTL16 indicated poor survival rate in patients with breast cancer, while high expression of RBM15B pointed to a better survival rate. Both univariate and multivariate Cox regression analyses revealed that age and risk scores were related to overall survival (OS). Univariate analysis also delineated that stage, tumor (T) status, lymph node (N) status, and metastasis (M) status were associated with OS. From another perspective, Kaplan-Meier Plotter platform showed that the relatively high expression of YTHDF3 and LRPPRC and the relatively low expression of RBM15B, ZC3H13, and METTL16 in breast cancer patients had worse Relapse-Free Survival (RFS). Breast Cancer Gene-Expression Miner v4.5 showed that LRPPRC level was negatively associated with ER and PR expression, while METTL16, RBM15B, ZC3H13 level was positively linked with ER and PR expression. In HER-2 (+) breast cancer patients, the expression of LRPPRC, METTL16, RBM15B, and ZC3H13 were all lower than the HER-2 (-) group.ConclusionThe significant difference in expression levels and prognostic value of m6A RNA methylation regulators were analyzed and validated in this study. This signature revealed the potential therapeutic value of m6A RNA methylation regulators in breast cancer.

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Genetic Alterations and Transcriptional Expression of m⁶A RNA Methylation Regulators Drive a Malignant Phenotype and Have Clinical Prognostic Impact in Hepatocellular Carcinoma.

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Genetic Alterations and Transcriptional Expression of m6A RNA Methylation Regulators Drive a Malignant Phenotype and Have Clinical Prognostic Impact in Hepatocellular Carcinoma.

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OmicsDI is part of the ELIXIR infrastructure

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Genetic Alterations and Transcriptional Expression of m⁶A RNA Methylation Regulators Drive a Malignant Phenotype and Have Clinical Prognostic Impact in Hepatocellular Carcinoma.