Comprehensive analysis of m⁶A regulator-based methylation modification patterns characterized by distinct immune...

Mounting evidences have indicated that RNA N⁶-methyladenosine (m⁶A) modification played important roles in tumor formation and growth. However, it is rarely reported that m⁶A modifications are involved in the immune regulation and tumor microenvironment (TME) formation. In this study, we aimed to investigate the correlation between m⁶A modifications and TME regulation of colon adenocarcinoma (COAD) by bioinformatic analysis. NMF algorithm was applied to carry out consensus molecular subtype analysis on 36 selected m⁶A regulators regarding methylation modification, to identify m⁶A modification patterns and characteristics of m⁶A related genes in colon adenocarcinoma (COAD). Further, the relative infiltration levels of different immune cell subsets were quantified by ssGSEA and CIBERSORT algorithms, and a m⁶Sig scoring scheme was constructed to predict the prognosis and evaluate the response to immunotherapy in the patients with COAD. Among 579 COAD samples, we identified three different m⁶A modification patterns which were related to different biological pathways and clinical outcomes. Then, a scoring scheme termed "m⁶Sig score" was developed based on m⁶A-related characteristic genes, and was utilized to score patients with COAD into groups. We found that COAD patients with lower m⁶Sig scores exhibited prolonged survival and potentiated immune infiltration, which were associated with higher tumor mutation load, lower PD-L1 expression, and higher mutation rates of SMG (such as TTN and KRAS). Moreover, analysis regarding evaluation of immune response revealed that the patients with lower m⁶Sig scores had higher Immunophenoscore. Collectively, our study provided in depth insight into the interactions between m⁶A modification and regulation of TME. In addition, the quantitative evaluation of m⁶A modification patterns in our results may have implications in further immunotherapy for individual COAD patients.