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

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.