Abstract A015: Epigenetic Drivers of Localised Prostate Cancers Reveal Neuronal and Microenvironmental Reprogramming and inform Liquid Biopsy Biomarkers

Abstract Background: Prostate cancer is genomically heterogeneous with few shared drivers. We characterized tumor-specific DNA methylation programs that define evolutionary subtypes, remodel the tumor–microenvironment ecosystem, and yield liquid-biopsy biomarkers. Methods: Illumina EPIC-seq methylation was profiled in matched benign/tumor tissues from the UK Prostate ICGC cohort. A covariance-based DMR caller identified robust tumor-specific regions that were intersected with bulk RNA-seq, network analyses, and single-cell/spatial transcriptomics to localize programs in situ. A FACS-sorted, cell-type methylome atlas (luminal, basal, endothelial, fibroblast, immune, smooth muscle) anchored cell-of-origin assignments. Cell-free DNA was deconvolved against this atlas to quantify luminal tumor DNA and circulating microenvironmental DNA (cmDNA). Prognostic associations used penalized Cox models. Results: Tumor-specific DMRs separated cancers into two “mevotypes” mirroring genomic evotypes (ERG-fusion vs SPOP-mutant), indicating genomic–epigenomic interplay in evolutionary commitment. Cell-resolved methylomes attributed most tumor DMRs to luminal epithelium and uncovered neuronal/plasticity pathways in luminal cells, while immune/endothelial-assigned DMRs converged on ECM remodeling, angiogenesis, TGF-β, and Rho-GTPase signaling. Single-cell pseudotime and spatial mapping localized neuronal-enriched luminal programs to late-trajectory regions and a CHGA/CHGB-positive duct-adjacent epithelial circuit interfacing with fibroblasts at tumor–stroma borders. Network analysis highlighted MYC-centric modules and EZH2-linked transcription factor contexts, consistent with epigenetic priming toward quasi-neuroendocrine states in treatment-naïve localized adenocarcinoma. In plasma, deconvolution detected both luminal ctDNA and cmDNA; luminal fractions tracked tumor burden in metastatic disease (ichorCNA-concordant), whereas cmDNA—predominantly attributable to immune compartments—suggested an early, tumor-specific microenvironmental response that can precede and is independent of luminal ctDNA shedding. Methylation signatures derived from neuronal and microenvironmental gene sets associated with inferior relapse-free survival. Conclusions: Epigenetic drivers in early prostate cancer encode luminal neuronal plasticity and reorganize the tumor niche. A cell-resolved atlas enables cfDNA deconvolution to reveal luminal ctDNA plus cmDNA, supporting liquid-biopsy biomarker strategies for earlier detection and improved risk stratification in prostate cancer. Citation Format: Harveer Dev, Toby Milne-Clark, Henson Lee Yu, CRUK-ICGC Prostate Cancer Group. Epigenetic Drivers of Localised Prostate Cancers Reveal Neuronal and Microenvironmental Reprogramming and inform Liquid Biopsy Biomarkers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A015.