Abstract
BACKGROUND: Methylation at the N(6) atom of adenosine (m(6)A) of RNA has been linked to immune responses to various types of tumors. How m(6)A methylation affects tumorigenicity, progression, and tumor microenvironment in hepatocellular carcinoma (HCC) is unclear. METHODS: Consensus clustering was used to define m(6)A methylation patterns based on expression of 26 regulatory factors in HCC. The relative abundance of various immune cell types in the tumor microenvironment was quantified using single-sample gene set enrichment analysis. Cox regression with LASSO was used to screen for genes whose expression correlated with survival of patients with HCC. RESULTS: Two patterns of m(6)A methylation in HCC were identified: pattern C1 was associated with abundant tumor infiltration by activated CD8(+) T cells and by effector memory CD8(+) T cells, as well as longer survival; pattern C2 was associated with abundant tumor infiltration by activated CD4(+) T cells and by type 2 helper T cells, as well as with shorter survival. Cox regression identified a seven-gene signature capable of predicting the characteristics of the tumor microenvironment and overall survival in HCC: patients in the high-risk group had a lower immunophenoscore, higher TIDE score, and worse survival. CONCLUSIONS: Patterns of m(6)A methylation in HCC are related to immune cell characteristics of the tumor microenvironment and to disease progression and prognosis. Analyzing these patterns in detail may clarify when and how the HCC responds to checkpoint inhibitors and guide the personalization of immunotherapy.