A novel m6A/m5C/m1A score signature to evaluate prognosis and its immunotherapy value in colon cancer patients

Abstract

Background Colon cancer features strong heterogeneity and invasiveness, with high incidence and mortality rates. Recently, RNA modifications involving m6A, m5C, and m1A play a vital part in tumorigenesis and immune cell infiltration. However, integrated analysis among various RNA modifications in colon cancer has not been performed. Methods RNA-seq profiling, clinical data and mutation data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus. We first explored the mutation status and expression levels of m6A/m5C/m1A regulators in colon cancer. Then, different m6A/m5C/m1A clusters and gene clusters were identified by consensus clustering analysis. We further constructed and validated a scoring system, which could be utilized to accurately assess the risk of individuals and guide personalized immunotherapy. Finally, m6A/m5C/m1A regulators were validated by immunohistochemical staining and RT-qPCR. Results In our study, three m6A/m5C/m1A clusters and gene clusters were identified. Most importantly, we constructed a m6A/m5C/m1A scoring system to assess the clinical risk of the individuals. Besides, the prognostic value of the score was validated with three independent cohorts. Moreover, the level of the immunophenoscore of the low m6A/m5C/m1A score group increased significantly with CTLA-4/PD-1 immunotherapy. Finally, we validated that the mRNA and protein expression of VIRMA and DNMT3B increased in colon cancer tissues. Conclusions We constructed and validated a stable and powerful m6A/m5C/m1A score signature to assess the survival outcomes and immune infiltration characteristics of colon cancer patients, which further guides optimization of personalized treatment, making it valuable for clinical translation and implementation.