Longitudinal Changes of Serum N-Glycan Levels for Earlier Detection of Pancreatic Cancer in High-Risk Individuals

Abstract

Background: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. Alternatively, individuals with lesions progressing to malignancy can be recognized by molecular biomarkers. We aimed to identify changes in serum protein glycosylation levels over time to earlier detect PDAC in high-risk individuals undergoing surveillance. \n \nMethods: Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs and we included those of which at least two consecutive serum samples were available. Mass spectrometry analysis was performed to determine total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis (PDAC cases versus controls) and relative abundances were calculated for each glycosylation feature. \n \nFindings: 165 individuals (“FPC-cohort” N=119; Leiden cohort N=46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (estimated >10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected.Ten individuals (6%) developed PDAC during 35 months of follow-up. Upon comparison of these patients with all other individuals, several glycosylation characteristics were increased, namely fucosylation, tri- and tetra-antennary structures, and specific sialic linkage types. Other glycosylation characteristics decreased, such as complex-type diantennary and bisected glycans. The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%. \n \nInterpretation: This study explores the applicability of serum N-glycan longitudinal monitoring for early detection in a pancreas surveillance program. \n \nFunding: The current study was supported by ZonNW project number 531002011 and Genootschap Bollenstreek – Bollenstreekfonds, Lisse-Hillegom, The Netherlands. \n \nDeclaration of Interest: F.P. Vleggaar: Boston Scientific (Consultant) H.F., M.J Bruno: Boston Scientific (Consultant, support for industry and investigator-initiated studies), Cook Medical (Consultant, support for industry and investigator-initiated studies), Pentax Medical (Consultant, support for investigator-initiated studies), Mylan (Support for investigator-initiated studies), ChiRoStim (Support for investigator-initiated studies), all other authors have nothing to declare. \n \nEthical Approval: The institutional ethical review boards of participating centers (2007_024, Amsterdam University Medical Center; MEC-2021-448 EMC; MEC P00.107 LUMC) have approved the study