Comprehensive analysis of m6A regulators and relationship with tumor microenvironment, immunotherapy strategies in colorectal adenocarcinoma.

Background: The N6-methyladenosine (m6A) RNA modification is the most prevalent and abundant type found in eukaryotic cells. It plays a crucial role in the initiation and progression of cancers. In this study, we aimed to comprehensively investigate the landscape of m6A regulators and their association with tumor microenvironment (TME), immunotherapeutic strategies in colon adenocarcinoma (COAD).

Results: The differential expression, mutation, CNV frequency and prognostic value of 27 m6A regulators were systematically analyzed in COAD. Patients were classified into two clusters based on m6A regulators through consistent clustering analysis, with cluster A showing significant survival benefits. Most of the m6A regulators were negatively correlated with immune cells, except for WTAP, IGF2BP3, FTO, ALKBH5, which showed a positive correlation. We developed an m6A scoring system to calculate the m6Ascore for each patient. Patients with a high-m6Ascore had a better outcome, with the AUC of 0.775. An independent cohort of 416 COAD patients acquired from GSE38832 database was used to validate the prognosis prediction ability of m6Ascore. Moreover, the m6Ascore was negatively correlated with infiltration of anti-tumor immune cells. Additionally, patients with a high-m6Ascore responded better to anti-PD1 and anti-CTLA4 therapies, and those with MSI-H had a higher m6Ascore. Finally, we investigated the value of m6Ascore in predicting the response of patients to 15 commonly used drugs.

Conclusions: We comprehensively analyzed m6A regulators in COAD, including RNA expression, CNV changes, mutations and their correlation with TME. Our results showed that the m6A scoring system had significant predictive power for the prognosis of COAD patients, potentially leading to new personalized immunotherapy strategies.