Ancestry-Informed Transcriptomic Analysis Identifies YY1 Axis Disruption and Stromal Program Loss in African American Prostate Cancer 2258332

Abstract Introduction Prostate cancer (PCa) shows racial disparities, with African American (AA) men experiencing higher incidence and worse outcomes than European American men. We investigated ancestry-associated molecular programs to better understand these differences. Methods RNA-seq data from high-grade PCa were analyzed using DESeq2 and GSEA to identify differentially expressed genes and pathways. Candidate genes and pathways were then examined through ongoing wet-lab assays in MDA-PCa-2b and LN-CaP cell-line to evaluate their effect in PCa. Results Multiple genes and pathways exhibited ancestry-associated dysregulation linked to tumor progression and aggressiveness. Notably, several noncoding and pseudogene transcripts, traditionally considered transcriptionally inert, showed reproducible overexpression patterns, suggesting potential epigenetic activation and regulatory cross-talk in AA tumors. Pathway-level findings revealed broad depletion of muscle/contractile programs, robust enrichment of olfactory receptor signaling, and downregulation of YY1 target gene sets, consistent with stroma loss and transcriptional reprogramming observed in experimental models. Conclusion Ancestry-informed transcriptomic analysis identifies chemosensory GPCR activation through olfactory receptor signaling enrichment and loss of stromal support programs, providing a framework for biomarker discovery and therapeutic exploration in AA PCa. These findings highlight transcriptional and microenvironmental alterations that may contribute to tumor aggressiveness and provide a foundation for biomarker discovery and ancestry-tailored therapeutic strategies. Funding Source n/a Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)