Comprehensive characterization of m 6 A RNA methylation across human cancers

N6-methyladenosine (m 6 A) is the most abundant internal mRNA modification and plays essential roles in gene regulation, tumor progression, and therapeutic response. However, the biomedical and clinical significance of m 6 A RNA methylation in human cancer remains incompletely understood. Here, using m 6 A-seq profiling, we generated a comprehensive transcriptome-wide atlas of m 6 A modifications across 15,812 sites from 226 tumor samples spanning 23 cancer types in The Cancer Genome Atlas (TCGA). To elucidate the regulatory determinants and downstream consequences of m 6 A variation, we integrated these data with a broad spectrum of multi-omics features. We found that global m 6 A patterns segregate into five major clusters largely driven by cancer lineages. Somatic mutations exert widespread yet diverse effects on local m 6 A levels through alteration of DRACH motifs. Approximately 10% of protein-coding genes showed consistent positive or negative associations between m 6 A abundance and mRNA or protein expression. These genes are enriched for transcription factors, and their m 6 A levels strongly influence key tumor cell states such as epithelial-mesenchymal transition (EMT) and hypoxia. We further characterized the protein expression landscape of 15 m 6 A regulators in 7482 TCGA samples and uncovered frequent dysregulation across cancers arising from multiple distinct genetic and epigenetic mechanisms. Finally, we developed a deep-learning model that integrates local DNA sequence context, gene-level features, m 6 A regulator states, and tumor-specific context to predict m 6 A intensity. The model achieved high accuracy for a substantial fraction of m 6 A sites, enabling large-scale inference of m 6 A variation and facilitating biomarker discovery in extensive patient cohorts. Together, this study provides a key resource for understanding the genomic landscape and regulatory architecture of m 6 A methylation in cancer and establishes a foundation for leveraging m 6 A as a new class of biomarkers and therapeutic targets.