IDENTIFICATION AND ASSESSMENT OF NEW BIOMARKERS FOR COLORECTAL CANCER WITH SERUM N-GLYCAN PROFILING

摘要

Objectives: This study aimed to identify and validate the diagnostic values of N-glycan markers for colorectal cancer (CRC) and to uncover the underlying molecular mechanism. Methods: A total of 347 subjects including CRC, colorectal adenoma and healthy controls were randomly divided into training (n=287) and retrospective validation groups (n=60). Serum Nglycan profiling was analyzed by DNA sequencerassisted flurophore-assisted carbohydrate electrophoresis (DSA-FACE). Two diagnostic models were constructed based on the N-glycan profiling with logistic step-wise regression. Their diagnostic performances were further assessed in retrospective, prospective (n=43) and follow-up (n=46) cohorts. Lectin blot and RT-PCR were used to analyze the total core-fucosylated residues and molecular expression involved in core-fucosylation modifications in CRC. Results: Two diagnostic models nominated as CRCglycoA and CRCglycoB were constructed to differentiate CRC from normal and adenoma respectively. The areas under the receiver operating characteristic curves of both CRCglycoA and CRCglycoB were higher than that of CEA (CRCglycoA: 0.92 vs. 0.81; CRCglycoB: 0.81 vs. 0.73). The sensitivity and accuracy of CRCglycoA was improved 21.7-25% and 11.63-18% in training, retrospective and prospective cohorts compared to that of CEA. The sensitivity of CRCglycoB was improved 20-28.23%. Both the altered N-glycans and results of diagnostic models were reversed after curative surgery. The level of total core fucose residues and fucosyltransferase (Fut8) were decreased significantly in CRC. Conclusions: The N-glycan markers based diagnostic models are new valuable non-invasive alternatives for CRC identification. Decreased Fut8 might be responsible for the decreased level of total core-fucosylated modification in both tissue and serum of CRC.