Abstract 4507: Circulating plasma proteins and risk of multimorbidity of cancer and cardiometabolic diseases

Abstract Background: Cancer, type 2 diabetes (T2D), and cardiovascular diseases (CVD) are the leading causes of death worldwide. These chronic conditions can also co-occur within individuals, a phenomenon known as multimorbidity. Other than exposure to common risk factors, multimorbidity could be the result of shared biologic pathways. Leveraging large-scale proteomic data, we investigated whether specific patterns of circulating proteins were common to the occurrence of combinations of cancer, T2D, and CVD, as well as to multimorbidity of these conditions. Methods: In a case-cohort study of the European Prospective Investigation into Cancer and Nutrition (EPIC), participants from the sub-cohort (n=4, 063), as well as pre-selected cases of cancer (n=5, 577) were included. The SomaScan 7k Assay was used to acquire aptamer measurements on pre-diagnostic samples. Using Prentice-weighted multivariable-adjusted Cox regression, we assessed single aptamer associations with cancer, T2D, CVD, and multimorbidity. We also sought to showcase the potential of proteomic profiling to study exposure-disease associations by investigating a proteomics signature of weekly leisure-time physical activity and its association with disease outcomes. Results: Common patterns of aptamers across multiple diseases (3, 612 incident cancers, 435 T2D, 503 CVD, and 403 multimorbidity cases) are identified in ongoing statistical analyses. Weekly leisure-time physical activity was inversely associated with 6 proteins (e.g., sorbitol dehydrogenase and leptin) and positively with 10 proteins (e.g., COMP and laminin-2) after multiple-testing correction. After multivariable- and physical activity adjustment, the signature of those proteins per 1 SD increment was inversely associated with overall cancer (HR: 0.93, 95% CI: 0.86 to 0.99) and T2D (HR: 0.54, 95% CI: 0.45, 0.66), but not with CVD (HR: 0.91, 95% CI: 0.76, 1.09). Results of associations with multimorbidity will be presented. Conclusions: Candidate biological pathways common to cancer, T2D, and CVD as well as to multimorbidity, and their link with major lifestyle factors, will be comprehensively investigated in this large-scale proteomics dataset. Citation Format: Heinz Freisling, Michael Stein, Vivian Viallon, Karl Smith-Byrne, David C. Muller, Antonio Agudo, Giovanna Masala, Salvatore Panico, Carlotta Sacerdote, Ruth C. Travis, Rosario Tumino, Martijn Kolijn, Roel Vermeulen, Monique Verschuren, Adam Butterworth, Nicholas Wareham, Marc J. Gunter, Elio Riboli, Pietro Ferrari. Circulating plasma proteins and risk of multimorbidity of cancer and cardiometabolic diseases [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 4507.