When LASSO with .632+ bootstrap was applied on the eleven protein biomarkers and additionally AREG measurements of PEA in the discovery set, a five-marker signature (AREG, MASP1, OPN, PON3, and TR) was obtained and improved AUCsBS of 0.87, 0.81, and 0.92 were observed for all, early, and late CRC detection. Here, SPP1 is linked to colorectal carcinoma.