The role of recurrent somatic mutations that alter conserved m6A motifs in human cancer.

Abstract

N⁶-methyladenosine (m⁶A) is the most abundant internal RNA modification in eukaryotes and plays a key role in cellular growth and development. Global changes in cellular methylated RNA and m⁶A-mediated transcript regulation significantly impact oncogenesis. Here, we investigate how recurrent synonymous and non-synonymous somatic mutations abolishing individual canonical methylated m⁶A motifs affect transcript levels and survival of patients with cancer. Moreover, we explore the effect of these mutations on creating de novo m⁶A motifs. To this end, we compared publicly available data on m⁶A sites with mutations reported in The Cancer Genome Atlas (TCGA). We find that mutations disrupting or creating m⁶A motifs display a low recurrence and have a negligible impact on RNA abundance. Patients with the highest number of disrupted m⁶A sites or newly generated m⁶A motifs did not generally exhibit alterations in mortality risk or outcomes. Hence, our data suggest that mutational alterations in the m⁶A motif landscape are unlikely to be a primary mechanism for regulating gene function across most cancer types. This may be attributed to the fact that mutations typically affect individual m⁶A sites, which is likely insufficient to significantly impact gene expression.