Abstract 2337: Prediagnostic circulating proteins and risk of bladder cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Abstract Background: Bladder cancer is the tenth most common cancer globally. Circulating proteins are key regulators of cellular functions, and proteomic analyses allow for a comprehensive investigation of proteins that may have causal roles in cancer development. Methods: We investigated the association between plasma proteins and bladder cancer risk in a case-cohort study within EPIC using a SomaLogic assay, comprising 4,047 sub-cohort members (15.3 years mean follow-up) and 254 bladder cancer cases (9.8 years mean follow-up), including 160 urothelial cell carcinoma (UCC) cases and 118 aggressive tumors. Prentice-weighted Cox regression models, with adjustment for smoking and other covariates, were conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), with false discovery rate correction. Covariates included smoking status (never; former; current: ≤15 cigarettes/day, occasional or cigar smoker; current: >15 cigarettes/day), alcohol consumption (mL/day), BMI (kg/m2), diabetes (yes, no), physical activity (inactive; moderately inactive; moderately active; active), education (primary/none, secondary, university degree). Results: Of 7,363 aptamers, we identified 31 significant associations with bladder cancer risk after false discovery rate correction. All HRs changed less than 15% when comparing the multivariable-adjusted to the minimally-adjusted model, and 11 proteins were also conventionally significant among never-smokers. Subgroup analyses identified nine proteins associated with UCC and 31 proteins associated with aggressive tumors. Twenty-five proteins were significant ≥10 years from blood collection. Notably, positive associations for I3L1E1 were observed for bladder cancer overall (HR: 1.23, 95% CI: 1.11-1.36), in never-smokers, and for cases diagnosed ≥10 years from blood collection, for WFIKKN1 in relation to UCC (HR: 1.33, 95% CI: 1.18-1.51), and for IRF4 in relation to aggressive tumors (HR: 1.29, 95% CI: 1.16-1.45). Conclusions: Evidence for several protein-cancer associations may suggest these could be used as novel biomarkers and provides insight into bladder cancer etiology. Citation Format: Alison Dillman, Zhe Huang, Joshua Atkins, Marc Gunter, Pietro Ferrari, Antonio Agudo, Carlotta Sacerdote, David C. Muller, Domenico Pali, Giovanna Masala, Monique Verschuren, Nicholas Wareham, Raul Zamora-Ros, Roel C. Zamora-Ros, Rosario Tumino, Salvatore Panico, Vivian Vallon, Elio Riboli, Karl Smith-Byrne, Ruth Travis. Prediagnostic circulating proteins and risk of bladder cancer in the European Prospective Investigation into Cancer and Nutrition (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 2337.