Abnormal genetic and epigenetic patterns of m6A regulators associated with tumor microenvironment in colorectal cancer

BACKGROUND: N6-methyladenosine (m6A) has a critical role in the development and progression of cancer. However, the genetic and epigenetic patterns, as well as tumor microenvironment (TME) infiltration characteristics of m6A regulators in colorectal cancer (CRC) remain largely unknown. METHODS: Molecular patterns of m6A modifications of 24 m6A regulators in CRC samples were evaluated using data from The Cancer Genome Atlas (TCGA). Mutations, copy number variations (CNVs), DNA methylation, and chromatin accessibility were examined to investigate the underlying mechanisms of the aberrant expression of m6A regulators. Correlations between m6A-related genes and TME cell-infiltrating characteristics were evaluated using Tumor Immune Estimation Resource (TIMER). RESULTS: The m6A regulators were frequently dysregulated in CRC, with two downregulated and 16 upregulated. All the m6A regulators had mutations (frequency ranging from 0.9% to 7%), with active mutations tending to occur in RBM15 and inactive mutations in ZC3H13. Only five m6A regulators had CNV frequency greater than 1%: YTHDC2 (2.4%), YTHDF1 (7.0%), YTHDF3 (1.9%), VIRMA (1.7%), and ZC3H13 (3.0%). The copy numbers of these five genes were positively correlated with their expression levels. The m6A regulators frequently showed imbalanced methylation in CRC, with hypomethylation of YTHDF2, IGF2BP3, FTO, and hypermethylation of HNRNPC, METTL3, and WTAP. Most m6A regulators had high chromatin accessibility, which was positively correlated with their gene expression. IGF2BP1 was identified as an independent prognostic factor for overall survival. Moreover, the expression of most m6A regulators was positively correlated with the infiltration of B cells, CD8(+) T cells, CD4(+) T cells, macrophages, neutrophils, and dendritic cells. CONCLUSIONS: Aberrant expression of m6A regulators is associated with mutation, CNV, and chromatin accessibility, owing to both genetic and epigenetic modifications. The TME infiltration characterization of m6A regulators could guide the development of more effective immunotherapy strategies in CRC.