The Landscape of Prostate Tumor Methylation

Abstract Prostate cancer is characterized by profound clinical and molecular heterogeneity. Although its genomic heterogeneity is well characterized, its epigenomic heterogeneity remains less understood. We therefore created a compendium of 3,001 multiancestry prostate methylomes spanning normal tissue through localized disease of all grades to polymetastatic disease. A subset of 884 samples had multiomic DNA and/or RNA characterization. We identify four epigenomic subtypes that risk-stratify patients and reflect distinct evolutionary trajectories. We demonstrate extensive regulatory interplay between DNA copy number and methylation, with transcriptional consequences that vary across genes and disease stages. We define epigenetic dysregulation signatures for 15 important clinicomolecular features, creating predictive models for each. For example, we identify specific epigenetic features that predict patient outcome and are synergistic with clinical prognostic features. These results define a complex interplay between tumor genetics and epigenetics that converges to modify gene expression programs and clinical presentation, in part through modulation of epigenetic aging. Significance: We define the largest prostate cancer methylome resource to date, revealing four epigenomic subtypes that stratify cancers by their genetics, evolution, and clinical phenotypes. These data demonstrate that genome–epigenome interactions are stage-dependent, positioning DNA methylation as a central, clinically informative driver of prostate cancer heterogeneity.