Increasing evidence have highlighted the biological significance of mRNA N6-methyladenosine (m6A) modification in regulating tumorigenicity and progression. However, the potential roles of m6A regulators in tumor microenvironment (TME) formation and immune cell infiltration in liver hepatocellular carcinoma (LIHC or HCC) requires further clarification.
RNA sequencing data were obtained from TCGA-LIHC databases and ICGC-LIRI-JP databases. Consensus clustering algorithm was used to identify m6A regulators cluster subtypes. Weighted gene co-expression network analysis (WGCNA), LASSO regression, Random Forest (RF), and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) were applied to identify candidate biomarkers, and then a m6Arisk score model was constructed. The correlations of m6Arisk score with immunological characteristics (immunomodulators, cancer immunity cycles, tumor-infiltrating immune cells (TIICs), and immune checkpoints) were systematically evaluated. The effective performance of nomogram was evaluated using concordance index (C‐index), calibration plots, decision curve analysis (DCA), and receiver operating characteristic curve (ROC).
Two distinct m6A modification patterns were identified based on 23 m6A regulators, which were correlated with different clinical outcomes and biological functions. Based on the constructed m6Arisk score model, HCC patients can be divided into two distinct risk score subgroups. Further analysis indicated that the m6Arisk score showed excellent prognostic performance. Patients with a high m6Arisk score was significantly associated with poorer clinical outcome, lower drug sensitivity, and higher immune infiltration. Moreover, we developed a nomogram model by incorporating the m6Arisk score and clinicopathological features. The application of the m6Arisk score for the prognostic stratification of HCC has good clinical applicability and clinical net benefit.
Our findings reveal the crucial role of m6A modification patterns for predicting HCC TME status and prognosis, and highlight the good clinical applicability and net benefit of m6Arisk score in terms of prognosis, immunophenotype, and drug therapy in HCC patients.