Prospective Proteomic Study Identifies Potential Circulating Protein Biomarkers for Colorectal Cancer Risk

Simple Summary Studies on circulating protein for colorectal cancer risk in a prospective study design is lacking. The aim of the present study was to scan and identify the protein markers by using proteomics technologies in a two-stage case-control study nested within the Shanghai Women's Health Study (SWHS), a population-based prospective cohort study. In the discovery set, we found 27 circulating proteins with a nominally significant association. Six of them, including CD79B, DDR1, EFNA4, FLRT2, LTA4H, and NCR1, were validated in the validation phase of the study. This study is the first to evaluate over 1000 circulating proteins in prediagnostic blood samples for their associations with CRC risk in East Asians. Background: Proteomics-based technologies are emerging tools used for cancer biomarker discovery. Limited prospective studies have been conducted to evaluate the role of circulating proteins in colorectal cancer (CRC) development. Methods: A two-stage case-control proteomics study nested in the Shanghai Women's Health Study was conducted. A total of 1104 circulating proteins were measured in the discovery phase, consisting of 100 incident CRC cases and 100 individually matched controls. An additional 60 case-control pairs were selected for validation. Protein profiling at both stages was completed using the Olink platforms. Conditional logistic regression was used to evaluate the associations between circulating proteins and CRC risk. The elastic net method was employed to develop a protein score for CRC risk. Results: In the discovery set, 27 proteins showed a nominally significant association with CRC risk, among which 22 were positively and 5 were inversely associated. Six of the 27 protein markers were significantly associated with CRC risk in the validation set. In the analysis of pooled discovery and validation sets, odds ratios (ORs) per standard deviation (SD) increase in levels of these proteins were 1.54 (95% confidence interval (CI): 1.15-2.06) for CD79B; 1.71 (95% CI: 1.24-2.34) for DDR1; 2.04 (95% CI: 1.39-3.01) for EFNA4; 1.54 (95% CI: 1.16-2.02) for FLRT2; 2.09 (95% CI: 1.47-2.98) for LTA4H and 1.88 (95% CI: 1.35-2.62) for NCR1. Sensitivity analyses showed consistent associations for all proteins with the exclusion of cases diagnosed within the first two years after the cohort enrollment, except for CD79B. Furthermore, a five-protein score was developed based on the six proteins identified and showed significant associations with CRC risk in both discovery and validation sets (Discovery: OR1-SD = 2.46, 95% CI: 1.53-3.95; validation: OR1-SD = 4.16, 95% CI: 1.92-8.99). Conclusions: A panel of five protein markers was identified as potential biomarkers for CRC risk. Our findings provide novel insights into the etiology of CRC and may facilitate the risk assessment of the malignancy.