Abstract 3814: Proteomics and overall mortality, imminent death, death at younger age, and cancer death

Circulating proteins can shed light on the biological mechanisms underlying mortality risk. We present findings from our proteomic study on overall mortality, imminent death (within one year), death at younger ages (under 60 years), and cancer death. Using SomaLogic® 7K panel, we assessed 6,412 proteins in 10,163 participants, with 6,441 deaths [including 2,551 cancer deaths], from a case-cohort study within the European Investigation into Cancer and Nutrition. Protein associations were identified after correcting for multiple testing and assessing potential for residual confounding. We identified 322 proteins [348 aptamers] linked to overall mortality, 315 proteins [329 aptamers] with imminent death, 185 proteins [190 aptamers] with death at younger ages, and 265 proteins [284 aptamers] with cancer death, using Prentice-weighted Cox models with age at recruitment as the primary time variable, adjusted for common confounders. GDF15 was associated with overall mortality (HR:1.46; -log10p:21.7), imminent death (HR:1.75; -log10p:5.7), younger age mortality (HR:1.39; -log10p:20.6), and death from cancer (HR:1.34; -log10p:14.8). TIMP1 (HR:1.96; -log10p:4.3) was specifically associated with imminent death, and MRC1 (HR:1.23; -log10p:7.5) with younger age mortality. Integrating information on receptor-ligand and transcription factor binding pairs into our results revealed that many of these protein-mortality associations reflect broader proteomic networks of death while complementary results from exome-sequencing analyses highlighted candidate causal markers of mortality driven by familiar pathways, such as differences in clotting. Individual proteins showed comparable risk stratification to common risk factors, like smoking, while multi-protein scores may improve risk stratification for death; we observed a 3-fold increased risk of death at younger age in ever smoking participants with a high protein score compared to low protein score never smokers and a 2-fold increased risk when compared to low protein score ever smokers. Our findings highlight the potential of blood proteomics to reveal cancer-specific and general mortality-driving processes and improve risk stratification beyond what is currently possible using established risk factors alone, such as smoking and lifestyle factors. Citation Format: Karl Smith-Byrne, Vivian Viallon, Antonio Agudo, Giovanna Masala, Domenico Pali, Salvatore Panico, Carlotta Sacerdote, Ruth Travis, Rosario Tumino, Roel C. Vermeulen, Monique Verschuren, Nicholas Wareham, Marc Gunter, Elio Riboli, David C. Muller, Pietro Ferrari. Proteomics and overall mortality, imminent death, death at younger age, and cancer death [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 3814.