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Identification of prediagnostic proteomic biomarkers for colon and rectal cancer in 3 prospective cohorts

Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Large-scale proteomics may reveal circulating biomarkers of colorectal cancer (CRC) years before diagnosis, yet cross-cohort reproducibility and anatomic site-specificity remain unclear. METHODS: We conducted nested case-control studies in three prospective cohorts with banked blood and cancer follow-up (median 7 years), totaling 851 incident CRC cases matched 1:1 to controls, with 1,801 pre-diagnostic plasma proteins from Olink panels. RESULTS: Twelve proteins showed significant paired differences between CRC cases and controls (FDR <0.1), with modest effect sizes. These included previously implicated CRC-biomarkers (e.g., higher GDF15 and TFF2) as well as less established associations (e.g., lower LEPR and BCAN). Paired protein differences are significantly distinct in colon vs. rectal cancer pairs (P = 0.005), driven by genes enriched in leukocyte activation, cell activation, and extracellular components. In stratified analysis, for colon cancer, 11 out of 12 proteins were lower in cases (FDR <0.1), including BCAN with 0.83 (0.74-0.94) odds ratio (OR, with 95% CI) per 1-unit increase in quantile-normalized NPX level, with cross-cohort consistency (I2 <0.01). For rectal cancer, 25 out of 28 proteins were higher in cases, including HDGF (OR 1.75 [1.15-2.66], I2 <0.01). HDGF could partially mediate BMI-rectal cancer risk (25.0%, FDR=0.044). Overall, we found that pre-diagnostic plasma proteomics identified proteins and pathways with modest effect sizes and clear differences between future risk of colon and rectal cancer. CONCLUSION: These findings provide insight for future mechanistic validation of pre-diagnostic plasma proteins as CRC biomarkers and motivate site-specific biomarker discovery that distinguishes colon from rectal cancer.
DOI: 10.1093/jnci/djag217
Authors: Xinyuan Zhang, Jonathan M Downie, David A Drew, Keming Yang, Suzanne G Orchard, John Zalcberg, Meir J Stampfer, Edward Giovannucci, Shuji Ogino, Robert E Gerszten, Jeffrey A Meyerhardt, Erica T Warner, Robyn L Woods, Rory Wolfe, Peter Gibbs, Mingyang Song, Yin Cao, Andrew T Chan
Institutions: Brigham and Women's Hospital, Harvard University, Massachusetts General Hospital, University of Pittsburgh Medical Center, Monash University, Broad Institute, Institute of Science Tokyo, Kobe University, Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute, Walter and Eliza Hall Institute of Medical Research, Western Health, Western Hospital, Washington University in St. Louis, Alvin J. Siteman Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Open Access status: hybrid
Estimated APC paid: $5,436
Funders: Bayer, Monash University, National Institutes of Health, Centers for Disease Control and Prevention, National Health and Medical Research Council, National Institute on Aging, National Cancer Institute
Awards: G1071680758, G1488872182, G1740950978, G2256521538, G2749632936, ASPirin in Reducing Events in the Elderly - eXTension, ASPirin in Reducing Events in the Elderly, ASPREE Completion Project, G6380345011, G7210608478, The role of aspirin in the prevention of colorectal cancer, Long Term Multidisciplinary Study of Cancer in Women: The Nurses Health Study, G8932330266, ASPirin in Reducing Events in the Elderly (ASPREE), The Gut Microbiome, Lifestyle, and Colorectal Neoplasia, Precision Prevention Research Program, Obesity, sedentary behaviors, and diet quality for prevention and early detection of early-onset colorectal neoplasia, Harnessing DNA methylation in peripheral blood for improved colorectal cancer prevention, Cancer Epidemiology Cohort in Male Health Professionals
OpenAlex ID: W7222926544
FWCI:
Cites: 29
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Related to: 10