Integrating plasma proteomic and genomic data to discover novel markers for colorectal cancer

Background The proteome stands as a pivotal source of therapeutic targets. We utilized Proteome-Wide Association Studies (PWAS) and Summary-data-based Mendelian randomization (SMR) analysis to uncover protein markers and potential therapeutic targets specific to colorectal cancer (CRC). Methods Utilizing protein prediction models (1,296 proteins) from the Atherosclerosis Risk in Communities (ARIC) study, we conducted PWAS on the CRC cohort of the FinnGen study (6,847 cases and 314,193 controls), with replicability of findings tested in the UK Biobank cohort (5,657 cases and 372,016 controls). For significant associations identified, SMR analysis was implemented across both cohorts to test the causality of candidate biomarkers on CRC. Further investigations, including functional enrichment analysis, single-cell type expression analysis, and molecular docking, were conducted to explore the biological functions of these proteins and predict drugs. Results We found that the abundance of seven plasma proteins was associated with CRC risk. Elevated levels of five proteins (GREM1, CHRDL, HHIP, IGFBP3, EPHA10) and decreased levels of two proteins (LRRC32, NTN4) were associated with an increased risk of CRC, among which four (GREM1, HHIP, CHRDL2, NTN4) were causal in CRC. These proteins were significantly enriched in the TGF-β, Hedgehog, and p53 signaling pathways, and involved in biological processes such as BMP binding, growth factor binding, and vascular endothelial growth factor receptor binding. GREM1, IGFBP3 specifically expressed in tissue stem cells, and LRRC32 in epithelial cells in tumor tissues. Molecular docking showed excellent binding for six drugs and proteins with available structural data. Conclusion Our investigation pinpointed seven plasma proteins linked to CRC risk, offering novel perspectives on CRC etiology and identifying potential targets for creating screening biomarkers and therapeutic agents for CRC.