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Background:  N6-methyladenosine (m 6 A) RNA methylation, associated with cancer initiation and progression, is dynamically regulated by the m 6 A 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 (m 6 Ascore) The prognostic value of m 6 Ascore was finally validated in another two GEO datasets.   Results:  We demonstrated that 11 m 6 A 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 m 6 A 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 m 6 Ascore, using four m 6 A regulators, predicting HCC prognosis well at three (AUC = 0.7) or 5 years (AUC=0.7) in validation. The prognostic value of m 6 Ascore also was validated successfully in two GEO datasets ( P  < 0.05). Finally, we discovered that mutations and copy number variations of m 6 A 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 m 6 A level and worse survival, especially in TP53-mutated HCC patients. Genetic alterations of m 6 A genes might cooperate with TP53 and its regulator targets in the HCC pathogenesis. Our m 6 Ascore may be applied in the clinical trials for patient stratification in HCC.

frontiers in oncology

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