Abstract 3599: Proteomic risk factors for prostate cancer: A case-cohort study in EPIC

Abstract Background: Prostate cancer (PCa) is the most prevalent cancer among men in Europe, yet its aetiology is poorly understood. Proteins contribute to the development of carcinogenesis and are also the target of most pharmacological interventions. The examination of associations between plasma proteins and PCa may enhance understanding of the aetiology of the PCa. Aim: Identify proteins associated with PCa risk within a large European prospective cohort, with emphasis on associations with aggressive subtypes of the disease. Methods: We conducted a case-cohort study in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with data for a sub-cohort of 1, 573 individuals and for 982 incident PCa cases. The SomaLogic® 7K panel was used to measure 7, 363 aptamers (representing 6, 412 unique proteins) in plasma samples drawn at recruitment. PCa diagnosis was ascertained by linkage to cancer and death registry data, and was further stratified into aggressive subtypes based on histological grade, tumour stage and mortality information. The Prentice-weight Cox regression model was applied to estimate associations between individual proteins and PCa risk, with adjustment for body mass index, smoking, alcohol intake and education level. Subgroup analyses examined associations with high-grade, advanced-stage, aggressive and extended lag-time (diagnosis more than 15 years after blood draw) PCa risk. We sought external replication for our significant findings in an independent multi-ancestry cohort, the Atherosclerosis Risk in Communities (ARIC) study (SomaLogic® 5K). Results: Following a median follow-up period of 16.2 years, the sub-cohort developed 79 cases of PCa. ACP3, FLT4, and KLK3 [HRs (95% CI): 1.20 (1.10, 1.31), 1.26 (1.13, 1.40) and 2.28 (1.96, 2.65), respectively] were associated with overall PCa risk in EPIC at FDR (false discovery rate) <0.05. In the subgroup analyses, 12 proteins were associated with high-grade, 9 with advanced stage, and 7 with aggressive PCa risk. Among these, ANKRD1 was associated with approximately a 25% higher risk of all three of these clinically relevant subtypes per SD increase. Twelve proteins were associated with PCa risk diagnosed more than 15 years after blood draw, including ANXA2, OSCAR, and SAT2. Two well-established biomarkers of PCa (ACP3 and KLK3) were replicated in ARIC, together with two novel proteins (ANXA2 and APOC2). Conclusion: Multiple novel circulating proteins were associated with PCa risk, particularly with risk for aggressive subtypes. While some proteins may serve as early biomarkers of PCa, those with evidence from long-lag time highlight underlying aetiological mechanisms in the development of PCa. Citation Format: Zhe Huang, Mahboubeh Parsaeian, Vivian Viallon, Ziqiao Wang, Keren Papier, Trishna Desai, Stephanie Chan, Antonio Agudo, Carlotta Sacerdote, David C. Muller, Domenico Pali, Giovanna Masala, Nicholas Wareham, Raul Zamora-Ros, Roel C. Vermeulen, Rosario Tumino, Ian G. Mills, Nilanjan Chatterjee, Elizabeth A. Platz, Pietro Ferrari, Marc Gunter, Elio Riboli, Tim J. Key, Joshua R. Atkins, Karl Smith-Byrne, Ruth C. Travis, The EPIC SomaLogic Working Group. Proteomic risk factors for prostate cancer: A case-cohort study in EPIC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3599.