Carcinoembryonic Antigen Glycosylation: Revealing Novel Features of Human Glycosylation and Cancer Origin Specificity

Carcinoembryonic Antigen (CEA) is a biomarker strongly associated with tumour progression and metastasis. Even though N-glycans make up »50% of the entire CEA molecule, current knowledge on CEA specific glycosylation in health and disease is scarce. We show for the first time in an indepth glycomics and glycoproteomics study that the over 270 different N-glycans identified exhibited antenna fucosylation and sialylation features that allowed a clear CEA body origin assignment. Colon-derived CEA carried a hitherto not described, hexosylated bisected GlcNAc glycoepitope. All analysed CEAs contained a 29th site of N-glycosylation on Asn71, located within a non-canonical 71N-R-Q73 sequence motif critical for CD8a binding. Correlation analyses of CEA and glycosyltransferase genes across the TGCA dataset revealed that CEACAM5 and B4GALNT3 expression levels were indicative for survival prediction. Our results open novel opportunities to understand CEA function, its role as a cancer marker but also reveal hitherto unknown aspects of glycobiology