Abstract A048: The Northern Ireland Fatal Intermediate Risk (FIR) prostate cancer study; a population-based case-cohort resource

Abstract Introduction: Prostate cancer incidence and mortality continue to rise globally, with Ireland among the regions with the highest incidence rates. In Northern Ireland, intermediate risk disease now comprises over 50% of all incident cases, increasing from 28% in 2010. This group is clinically heterogeneous, and distinguishing men whose disease will follow an indolent course from those who will progress to fatal outcomes remains a major challenge. Methods: The Northern Ireland Fatal Intermediate Risk (FIR) study is a population-based case-cohort study of men diagnosed with Gleason score 7 prostate cancer between 2010 and 2018, who received radiotherapy as primary treatment. Of 2071 eligible men identified by the Northern Ireland Cancer Registry, a random subcohort (n=153) was selected, and cases defined as those meeting eligibility criteria who went on to die from prostate cancer were oversampled (n=17). Archival formalin fixed paraffin embedded (FFPE) diagnostic biopsy blocks for these men were retrieved and sectioned by the Northern Ireland Biobank. Pathologist-annotated tumor regions were macrodissected for RNA extraction, and RNA exome sequencing was performed on tumor tissue for 159 men, with sufficient tumor-adjacent normal tissue for sequencing in roughly one third of men (n=51). Multiplex immunofluorescence was performed using CD3, CD4, CD8, CD68, FoxP3, and PD-1 to characterise the immune microenvironment. Results: The subcohort was representative of the source population in age (median 69 years), stage (68% stage I-II), and Gleason distribution (56% Gleason 3+4, 44% Gleason 4+3). In line with treatment patterns in Northern Ireland, 93% received radiotherapy with androgen deprivation therapy; the remaining 7% were treated with radiation only. Differential gene expression analysis in tumor vs adjacent normal samples showed marked upregulation of known prostate cancer markers AMACR, MYC, and HPN (TMPRSS1) in tumor (all FDR p<0.05), while RHBDL2 and KRTAP1-1 were among the most downregulated. Gene set enrichment analysis using Hallmark pathways indicated tumor enrichment of MYC targets and androgen response, together with unfolded protein response/protein secretion, cell cycle programs (G2M checkpoint, E2F targets, miotic spindle), growth signaling (PI3K-AKT-mTOR, mTORC1), DNA repair, and oxidative/lipid metabolism, while epithelial mesenchymal transition, KRAS signaling and myogenesis were depleted in tumor relative to adjacent normal tissue. Conclusions: The FIR study provides a population-representative multimodal resource for investigating biological drivers of fatal intermediate-risk prostate cancer. Work is currently underway to expand the study. Our preliminary findings highlight transcriptional reprogramming in tumor tissue, reflecting proliferative, metabolic and androgen-driven oncogenic signaling. Ongoing analyses will compare gene expression between fatal and non-fatal cases and integrate immune cell density, nuclear morphology and spatial immune profiling to refine molecular risk stratification and identify prognostic biomarkers. Citation Format: Jack T. Murphy, Lanshan Huang, Sarah J . Winter, Emma Craig, Stephanie Craig, Christine Greene, Claire Lewis, Deirdre Fitzpatrick, Konrad Stopsack, Courtney Ward, Silvia Ferreira Carvalho, Suneil Jain, Sarah Maguire, Ross G. Murphy, Emma H. Allott. The Northern Ireland Fatal Intermediate Risk (FIR) prostate cancer study; a population-based case-cohort resource [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 A048.