Abstract Background Carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19–9 are used in clinical practice as tumor markers to diagnose or monitor colorectal cancer (CRC) patients, However, their specificities and sensitivities are not ideal, and novel alternatives are needed. In this study, mass spectrometry was used to search for screening markers, focusing on glycan alterations of glycoproteins in the sera of CRC patients. Methods Glycopeptides were prepared from serum glycoproteins separated from blood samples of 80 CRC patients and 50 healthy volunteers, and their levels were measured by liquid chromatography time-of flight mass spectrometry (LC–TOF–MS). Results Leucine-rich alpha-2-glycoprotein-1 with fucosylated triantennary N-glycan (LRG–FTG) was identified as CRC marker after evaluating 30,000 candidate glycopeptide peaks. The average LRG–FTG level in CRC patients (1.25 ± 0.973 U/mL) was much higher than that in healthy volunteers (0.496 ± 0.433 U/mL, P < 10− 10), and its sensitivity and specificity exceeded those of CA19–9. The combination of CEA and LRG–FTG showed a complementary effect and had better sensitivity (84%), specificity (90%), and AUC (0.91 by ROC analysis) than each marker alone or any other previously reported marker. LRG–FTG alone or combined with CEA also corresponded well with patient response to treatment. Conclusions We identified LRG–FTG as a new CRC marker, with a sensitivity and specificity exceeding CA19–9. The combination of LRG–FTG and CEA showed much higher sensitivity and specificity than each marker alone. Further validation beyond this initial exploratory cohort is warranted.
