RNA N6-Methyladenosine Patterns in Hepatocellular Carcinoma Reveal a Distinct Immune Infiltration Landscape and Clinical Significance.

Abstract

BackgroundRNA N6-methyladenosine (m6A) methylation, the most abundant and prominent form of epigenetic modification, is involved in hepatocellular carcinoma (HCC) initiation and progression. However, the role of m6A methylation in HCC tumor microenvironment (TME) formation is unexplored. This study aimed to reveal the TME features of HCC patients with distinct m6A expression patterns and establish a prognostic model based on m6A signatures for HCC cohorts.Material/MethodsWe classified the m6A methylation patterns in 365 HCC samples based on 21 m6A modulators using a consensus clustering algorithm. Single-sample gene set enrichment analysis algorithm was used to quantify the abundance of immune cell infiltration. Gene set variation analysis revealed the biological characteristics between the m6A modification patterns. The m6A-based prognostic model was constructed using a training set with least absolute shrinkage and selection operator regression and validated in internal and external datasets.ResultsTwo distinct m6A modification patterns exhibiting different TME immune-infiltrating characteristics, heterogeneity, and prognostic variations were identified in the HCC cohort. After depicting the immune landscape of TME in HCC, we found patients with high LRPPRC m6A modulator expression had depletion of T cells, cytotoxic cells, dendritic cells, and cytolytic activity response. A high m6A score, characterized by suppression of immunity, indicated an immune-excluded TME phenotype, with poor survival. A nomogram was developed to facilitate HCC clinical decision making.ConclusionsOur results highlight the nonnegligible role of m6A methylation in TME formation and reveal a potential clinical application of the m6A-associated prognostic model for patients with HCC.