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 more pervasive epigenetic silencing, encompassingPCa suppressor genes and enhancer-targeted binding motifs. Conversely, African tumour-associated heterochromatic hypomethylation suggests chromatin relaxation anddevelopmental pathway activation via enhancer targets. Notably, non-prostate lineage elements appeared preferentially exploited in African tumorigenesis, with ancestry potentiallyinfluencing the extent of lineage-inappropriate activation, and tumour progression marked by repression of developmental regulators. Together, these findings point to extensive epigenetic plasticity in African tumours, with intergenic regulatory remodelling promoting genomic instability, metastatic potential and aggressive disease phenotypes. This study included a total of 286 prostate tissue samples from men with or without prostate cancer, of which 193 samples were selected for downstream analysis. Samples were derived from snap-frozen prostate cores collected across two geographic regions: southern Africa and Australia. Each sample was assigned to one of three genetically confirmed ancestry groups: African (n = 122), European (n = 48) or Asian (n = 23). Samples included both tumour (n = 128) and non-tumour (n = 65) tissues. Genome-wide DNA methylation profiling was conducted using the Illumina Infinium MethylationEPIC BeadChip platform (v1.0 and v2.0). Epigenome-wide association studies were performed to identify ancestry-associated (African vs. non-African) and tumour-associated (African tumour vs. non-tumour) differential methylation.