Methylation reprogramming associated with aggressive prostate cancer and ancestral disparities

African men are disproportionately impacted by aggressive prostate cancer (PCa). Key to this disparity both genetic and environmental factors, alluding to epigenetic modifications. However, African-inclusive prostate tumour DNA methylation studies are lacking. Assembling a multi-geo-ancestral prostate tissue cohort, including men with (57 African, 48 European, 23 Asian) or without (65 African) PCa, we interrogate for genome-wide differential methylation. Overall, methylation appears to be driven by ancestry over geography (152 southern Africa, 41 Australia). African tumours show substantial heterogeneity, with universal hypermethylation indicating epigenetic silencing, encompassing PCa suppressor genes and enhancer-targeted binding motifs. Conversely, African tumour-associated heterochromatic hypomethylation suggests permissive chromatin remodelling, with developmental pathway activation via enhancer targets. Taken together, we show methylation aberrations favour metastatic growth, genomic instability and disease aggressiveness in African tumours, which we hypothesise is driven by extensive plasticity of intergenic regulatory regions.