The landscape of N⁶-methyladenosine in localized primary prostate cancer

N⁶-methyladenosine (m⁶A), the most abundant internal RNA modification in humans, regulates most aspects of RNA processing. Prostate cancer is characterized by widespread transcriptomic dysregulation; therefore, we characterized the m⁶A landscape of 162 localized prostate tumors with matched DNA, RNA and protein profiling. m⁶A abundance varied dramatically across tumors, with global patterns emerging via complex germline-somatic cooperative regulation. Individual germline polymorphisms regulated m⁶A abundance, cooperating with somatic mutation of cancer driver genes and m⁶A regulators. The resulting complex patterns were associated with prognostic clinical features and established the biomarker potential of global and locus-specific m⁶A patterns. Tumor hypoxia dysregulates m⁶A profiles, bridging prior genomic and proteomic observations. Specific m⁶A sites, such as those in VCAN, drive disease aggression, associating with poor outcomes, tumor growth and metastasis. m⁶A dysregulation is thus associated with key events in the natural history of prostate cancer: germline risk, microenvironmental dysregulation, somatic mutation and metastasis.