A unique transcriptomic landscape defines African-specific grade group 1 prostate cancer

Background Prostate cancer (PCa) exhibits significant ancestry-related disparity. While men of African ancestry experience higher overall mortality rates, this difference is most pronounced in Sub-Saharan Africa and for grade group 1 (GG1) disease, alluding to ancestry-specific biology. Despite this health disparity, African-relevant and prostate tumour GG1 inclusive data, specifically transcriptomic data, is lacking. In turn, this raises significant concerns with regards to adopting Eurocentric models to classify and manage assumed indolent disease for African men. The risk - suboptimal treatment decisions. Methods Using a single technical and analytical pipeline, we generated total RNA sequencing data from fresh-frozen prostate tissue for 68 Black South African (40 GG1-PCa, 28 non-PCa) and 48 Australian European men (all GG1-PCa), performing ancestry-specific differential gene expression and pathway analysis. Sourcing public data enabled limited African American inclusive The Cancer Genome Atlas cross-validation (13 of 61 GG1-PCa), while Pan Prostate Cancer Group European ancestral data provided for deeper cross-ancestral comparative analyses (106 GG1-PCa, 17 non-PCa). Results Identifying 5,652 differentially expressed genes between African and European ancestral GG1 tumours ( p  < 0.05), including top-ranked PCa tumour suppressor genes DUSP1, JUN, FOS , and JUNB downregulated in African tumours. In turn, six metabolic and six immune-related pathways showed significant African-specific negative enrichment. Concordantly, cell type analysis showed significantly lower immune, stromal, and angiogenesis scores in African over European-derived GG1 tumours. Inclusion of African American GG1 data showed pathway over gene-level ancestry-specific concordance, with significant negative enrichment verification for oxidative phosphorylation, fatty acid metabolism and glycolysis. Compared to and irrespective of PCa status, our African tissues showed a 4.9-fold increase in differential gene expression in PSA-high versus PSA-low tissues. Notably, cell type clustering revealed 29% of PSA-high non-PCa tissues exhibited cancer-like profiles, indicating potential occult disease. Conclusions Revealing substantial transcriptomic divergence from European ancestral GG1 tumours, we identify African-specific transcriptomic features that may contribute to outcome disparities in this under-appreciated clinical group. Our study highlights not only a critical shortcoming in providing equitable PCa care for African men, but it also raises major concerns with regards to managing and treating African men using European-developed criteria.