Comprehensive analysis of m6A regulator-based methylation modification patterns characterized by distinct immune profiles in colon adenocarcinomas

Abstract

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.