m6A RNA Methylation Regulators Elicit Malignant Progression and Predict Clinical Outcome in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and N6-methyladenosine (m(6)A) is a predominant internal modification of RNA in various cancers. We obtained the expression profiles of m(6)A-related genes for HCC patients from the International Cancer Genome Consortium and The Cancer Genome Atlas datasets. Most of the m(6)A RNA methylation regulators were confirmed to be differentially expressed among groups stratified by clinical characteristics and tissues. The clinical factors (including stage, grade, and gender) were correlated with the two subgroups (cluster 1/2). We identified an m(6)A RNA methylation regulator-based signature (including METTL3, YTHDC2, and YTHDF2) that could effectively stratify a high-risk subset of these patients by univariate and LASSO Cox regression, and receiver operating characteristic (ROC) analysis indicated that the signature had a powerful predictive ability. Immune cell analysis revealed that the genes in the signature were correlated with B cell, CD4 T cell, CD8 T cell, dendritic cell, macrophage, and neutrophil. Functional enrichment analysis suggested that these three genes may be involved in genetic and epigenetic events with known links to HCC. Moreover, the nomogram was established based on the signature integrated with clinicopathological features. The calibration curve and the area under ROC also demonstrated the good performance of the nomogram in predicting 3- and 5-year OS in the ICGC and TCGA cohorts. In summary, we demonstrated the vital role of m(6)A RNA methylation regulators in the initial presentation and progression of HCC and constructed a nomogram which would predict the clinical outcome and provide a basis for individualized therapy.

Automated summary

The expression levels of m(6)A RNA methylation regulators are correlated with clinical characteristics in HCC patients, and a signature based on these regulators can effectively stratify high-risk patients and predict prognosis. Immune cell analysis and functional enrichment suggest the involvement of these regulators in genetic and epigenetic events linked to HCC. The constructed nomogram incorporating the signature and clinicopathological factors demonstrates good performance in predicting overall survival in HCC patients.