Abstract 7680: Pre-diagnostic plasma proteomic signatures associated with early-onset colorectal cancer in two large prospective cohorts

Abstract Objective: Early-onset colorectal cancer (EOCRC) has been rising globally, yet its molecular pathways and mechanisms have not been fully explored. Large-scale proteomic studies suggest circulating proteins can illuminate key biological pathways and early markers of carcinogenesis, but robust evidence on pre-diagnostic protein biomarkers specific to EOCRC is still scarce. Design: We measured 3,072 pre-diagnostic plasma proteins using the Olink Explore platform in EOCRC (age 55 at diagnosis) cases and matched controls, in two prospective studies, the Nurses’ Health Study II (NHSII, 1989-2015; 43 pairs; 98.8% White) and Southern Community Cohort Study (SCCS, 2002-2015; 109 pairs; 78.9% Black), as well as 59 pairs of advanced adenoma (age 50) in NHSII. Controls were matched on age and year at blood draw, sex, and race. Cohort-specific multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) per standard deviation (SD) increase by protein. Inverse variance-weighted fixed-effect meta-analyses estimated pooled ORs. We additionally generated plasma protein-based estimates of organ-specific biological aging to assess differences in accelerated aging between cases and controls. Results: The mean (SD) age at blood draw was 43.7 (4.7) years in NHSII and 45.5 (3.6) years in SCCS. Meta-analysis identified 13 proteins associated with EOCRC that met replication criteria (consistent effect direction, I2 ≤ 40%, FDR 0.25). Top replicated proteins implicate immune regulation (IL7 OR per SD increase: 1.67; 95% CI 1.25-2.25; ANK2 [1.35; 1.02-1.80; PTX3 1.33; 1.03-1.72), cellular structural pathways (PRSS53 1.31; 1.00-1.71; FSTL1 0.67; 0.50-0.92; MMP13 0.75; 0.56-0.99), and metabolic pathways (GHRL 1.33; 1.02-1.74; GIPR 0.73; 0.55-0.96). Cohort-specific analyses revealed additional distinct protein associations. In NHSII, TLR4, VEGFA, PGLYRP2, PXDNL, KRT17, and HRC were associated with EOCRC risk, implicating disrupted host-microbiome interactions, angiogenic signaling and altered epithelial biology as potential pathways. Some associations (KRT17 and HRC) were also observed in advanced adenoma compared with controls, highlighting their potential roles in initiation of precancerous changes. In SCCS, proteins positively associated with EOCRC risk suggested alterations in matrix and cytoskeletal remodeling (AFAP1, CORO6, ARAF) and immune activation (WAS). Organ-specific aging analyses suggested higher accelerated aging levels in EOCRC cases for multiple organs, including brain, the immune system, and intestine. Conclusion: In this prospective, multi-cohort proteomic profiling study, we identified pre-diagnostic circulating proteins associated with EOCRC risk, highlighting immune and inflammatory signaling, and metabolic dysregulation as key biological pathways. Citation Format: Mengyao Shi, Xiaoyu Zong, Ruiyi Tian, Daniel Hong, Xinyuan (Cindy) Zhang, Yichen Sun, A. Heather Eliassen, Edward L. Giovannucci, Gong Yang, Andrew T. Chan, Wei Zheng, Yin Cao. Pre-diagnostic plasma proteomic signatures associated with early-onset colorectal cancer in two large prospective cohorts abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7680.