The Landscape of Prostate Tumour Methylation

Prostate cancer is characterized by profound clinical and molecular heterogeneity. While its genomic heterogeneity is well-characterized, its epigenomic heterogeneity remains less understood. We therefore created a compendium of 3,001 multi-ancestry prostate methylomes spanning normal tissue through localized disease of all grades to poly-metastatic disease. A subset of 884 samples had multi-omic 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 ploidy and DNA methylation, with transcriptional consequences that vary across genes and disease stages. We define the epigenetic dysregulation signatures of the 15 most important clinico-molecular features, creating predictive models for each. For example, we identify specific epigenetic features that predict patient outcome and that are synergistic with clinico-genomic prognostic features. These results define a complex interplay between tumour genetics and epigenetics that converges to modify gene-expression programs and clinical presentation.