Identification of prediagnostic proteomic biomarkers for colon and rectal cancer in 3 prospective cohorts
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 ChanAbstract
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 3 prospective cohorts with banked blood and cancer follow-up information (median = 7 years). In total, 851 incident CRC cases matched 1:1 to control cases, with 1801 prediagnostic plasma proteins from Olink panels.
Results
Twelve proteins showed statistically significant paired differences between CRC cases and control cases (false discovery rate < 0.1), with modest effect sizes. These proteins included previously implicated CRC biomarkers (eg, higher GDF15 and TFF2) as well as less established associations (eg, lower LEPR and BCAN). Paired protein differences are statistically significantly distinct in colon cancer vs rectal cancer pairs (P = .005), driven by genes enriched in leukocyte activation, cell activation, and extracellular components. In stratified analysis, for colon cancer, 11 of 12 proteins were lower in cases (false discovery rate < 0.1), including BCAN, with an odds ratio of 0.83 (95% CI = 0.74 to 0.94) per 1-unit increase in quantile-normalized Olink Normalized Protein eXpression level, with cross-cohort consistency (I2 < 0.01). For rectal cancer, 25 of 28 proteins were higher in cases, including HDGF (odds ratio = 1.75, 95% CI = 1.15 to 2.66; I2 < 0.01). HDGF could partially mediate body mass index–rectal cancer risk (25.0%, false discovery rate = 0.044). Overall, we found that prediagnostic plasma proteomics identified proteins and pathways with modest effect sizes and clear differences between future risk of CRC.
Conclusion
These findings provide insight for future mechanistic validation of prediagnostic plasma proteins as CRC biomarkers and motivate site-specific biomarker discovery that distinguishes colon cancer from rectal cancer.