Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome

Abstract Background: Proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) study to identify candidate protein markers and therapeutic targets for colorectal cancer (CRC). Methods: Protein quantitative trait loci (pQTL) were derived from seven published genome-wide association studies (GWAS) on plasma proteosome, and summary-level data were extracted for 4,853 circulating protein markers. Genetic associations with CRC were obtained from a large-scaled GWAS meta-analysis (16,871 cases and 26,328 controls), the FinnGen cohort (4,957 cases and 304,197 controls) and the UK Biobank (9,276 cases and 477,069 controls). Colocalization and summary-data-based MR (SMR) analyses were performed sequentially to verify the causal role of candidate proteins. Single cell-type expression analysis, protein-protein interaction (PPI), and druggability evaluation were further conducted to detect the specific cell type with enrichment expression and prioritize potential therapeutic targets. Results: Collectively, genetically predicted levels of 13 proteins were associated with CRC risk. Elevated levels of two proteins (GREM1, CHRDL2) and decreased levels of 11 proteins were associated with an increased risk of CRC, among which six (CLSTN3, POLR2F, ADPGK, CSAG1, STXBP6, FUT3) were novel protein markers. These protein-coding genes mainly expressed in tissue stem cells, epithelial cells, and monocytes in colon tumor tissue. Two interactive pairs of proteins (GREM1 and CHRDL2; MMP2 and TIMP2) were identified to be involved in osteoclast differentiation and tumorigenesis pathways; four proteins (POLR2F, CSF2RA, CD86, MMP2) have been targeted for drug development on autoimmune diseases and other cancers, with the potentials of being repurposed as therapeutic targets for CRC. Conclusion: This study identified several protein biomarkers to be associated with CRC risk and provided new insights into the etiology and promising targets for the development of screening biomarkers and therapeutic drugs for CRC.