Epigenetic modulation of prostate cancer disparities in men with African ancestry.

Prostate cancer disproportionately affects men of African ancestry, yet the molecular mechanisms underlying these disparities remain poorly defined. Genomic studies have begun to reveal ancestry-linked risk alleles and somatic alterations, but the role of epigenetic dysregulation is only emerging. Drawing on multi-ancestral comparative analyses, with emphasis on cohorts from sub-Saharan Africa, we speculate that germline and somatic variation converge in epigenetic machinery genes to drive tumour evolution. African tumours harbour a heightened burden and diversity of both inherited and acquired variants, supporting a model of 'oncogenic cooperation' whereby germline diversity interacts with somatic mutations to broaden the range of pathogenic interactions. Limited yet complementary methylation analyses reveal tumour-specific and ancestry-specific reprogramming of promoters, enhancers and heterochromatin, suggesting that African tumours might be epigenetically primed for aggressive phenotypes. Chromatin remodelling defects emerge as potentially under-recognized disparity drivers, promoting genomic instability, altered gene regulation and therapeutic resistance. Collectively, these findings support a genome-epigenome-environment model in which inherited susceptibility, somatic variation and environmentally reinforced epigenetic reprogramming converge to shape aggressive African-associated prostate cancer. However, current insights are limited by European-centred baselines, under-representation of African cohorts and platform mismatches. Reducing prostate cancer health disparities requires equitable prostate cancer genomics and epigenomic research efforts that embrace the rich African ancestral population identifier.