Proteomic markers of colorectal cancer risk: results from the European Prospective Investigation into Cancer and Nutrition

Background: Circulating proteins are promising biomarkers of colorectal cancer risk. Most studies combine colon and rectal cancer despite their biological differences. Objective: To identify proteins associated with colorectal, colon, and rectal cancer risk and triangulate findings using cross-cohort confirmation and Mendelian randomisation (MR). Design: We profiled 6,402 proteins, using the SomaScan 7K assay in a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC; 658 colon and 319 rectal cancers). Cox models identified proteins associated with cancer risk at a false discovery rate <5%. Findings were confirmed in the Atherosclerosis Risk in Communities study (ARIC; SomaScan; 235 colon, 36 rectal) and UK Biobank (Olink Explore; 321 colon, 164 rectal). MR and genetic colocalisation evaluated potential causality. Results: We identified 36 proteins associated with colorectal cancer, 50 with colon cancer, and 2 with rectal cancer; 20 of the 36 were also associated with colon cancer and none with rectal cancer, and no protein was associated with both sites. Seven of the 40 colon cancer proteins available in ARIC were confirmed, including COMP, MIC-1/GDF15, TFF3, and THIK. Of these, MIC-1/GDF15 and TFF3 were also confirmed in UK Biobank. COMP was inversely associated with colon cancer risk observationally and in MR analyses. Conclusion: Colon and rectal cancers have different pre-diagnostic proteomic profiles, underlining the need for site-specific analyses. COMP, MIC-1/GDF15, and TFF3 were the most robustly supported biomarkers of colon cancer risk. Future work should prioritise experimental validation of these associations and use of repeated measures to define timing.