Background: Obesity is a well-established risk factor for colorectal cancer, however, the biological mechanisms underlying this association are not fully understood. Circulating proteins and how they relate to obesity and colorectal cancer may help to explain these pathways.
Objectives: Here we aimed to identify a proteomic signature of obesity and then to investigate its association with colorectal cancer risk. We also explored the theoretical effect of semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist approved for weight management, on the association of the obesity signature and colorectal cancer risk.
Methods: Data on 7,596 aptamers measured using the SomaScan 7k platform (SomaLogic) in a case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were used to identify proteins robustly associated with body mass index (BMI) using stability selection methods in a random sub-cohort of 3,826 participants. We then examined whether these proteins were associated with colon and rectal cancer based on 574 and 277 cases, respectively, using weighted Cox proportional hazards models adjusted for lifestyle and demographic covariates, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Published data on the effect of semaglutide treatment on circulating SomaScan 7k proteins was used to predict the anticipated effect of semaglutide on the identified obesity signature and colorectal cancer risk (1).
Results: Stability selection identified 21 proteins strongly associated with BMI, some of which have previously been linked to obesity, while others may represent novel markers. Five of these proteins were also associated with colon cancer, including LEP, CHAD, SFTPD, HS6ST3, and LSAMP. For rectal cancer, associations were observed only for LMOD1 and SEMA4G. A combined proteomic signature of obesity derived from these 21 proteins showed a strong association with colon cancer risk per 1-SD increase (HR?=?1.20, 95% CI?=?1.08 –1.34, p?=9.35 × 10??), but not with rectal cancer (HR?= 1.03, 95% CI?=?0.90 –1.17, p?=?0.672). Semaglutide impacted most of the BMI-related proteins associated with colon cancer in a direction that would be consistent with a reduced colorectal cancer risk.  
Conclusion: This study identified obesity-related proteins that may also contribute to colorectal cancer development and suggests that treatment by semaglutide could lower risk. The findings highlight the value of proteomic signatures in capturing information across multiple obesity-related proteins, thereby improving understanding of the biological pathways through which obesity may affect colorectal cancer risk.

References:
1. Maretty L, Gill D, Simonsen L, Soh K, Zagkos L, Galanakis M, et al. Proteomic changes upon treatment with semaglutide in individuals with obesity. Nature Medicine. 2025;31(1):267-77.