The landscape of N(6)-methyladenosine in localized primary prostate cancer.

N(6)-methyladenosine (m(6)A), 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 m(6)A landscape of 162 localized prostate tumors with matched DNA, RNA and protein profiling. m(6)A abundance varied dramatically across tumors, with global patterns emerging via complex germline-somatic cooperative regulation. Individual germline polymorphisms regulated m(6)A abundance, cooperating with somatic mutation of cancer driver genes and m(6)A regulators. The resulting complex patterns were associated with prognostic clinical features and established the biomarker potential of global and locus-specific m(6)A patterns. Tumor hypoxia dysregulates m(6)A profiles, bridging prior genomic and proteomic observations. Specific m(6)A sites, such as those in VCAN, drive disease aggression, associating with poor outcomes, tumor growth and metastasis. m(6)A dysregulation is thus associated with key events in the natural history of prostate cancer: germline risk, microenvironmental dysregulation, somatic mutation and metastasis.