N-glycan biosignatures as a potential diagnostic biomarker for early-stage pancreatic cancer

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of less than 10%, owing to its late-stage diagnosis. Early detection of pancreatic cancer (PC) can significantly increase survival rates.

Aim: To identify the serum biomarker signatures associated with early-stage PDAC by serum N-glycan analysis.

Methods: An extensive patient cohort was used to determine a biomarker signature, including patients with PDAC that was well-defined at an early stage (stages I and II). The biomarker signature was derived from a case-control study using a case-cohort design consisting of 29 patients with stage I, 22 with stage II, 4 with stage III, 16 with stage IV PDAC, and 88 controls. We used multiparametric analysis to identify early-stage PDAC N-glycan signatures and developed an N-glycan signature-based diagnosis model called the "Glyco-model".

Results: The biomarker signature was created to discriminate samples derived from patients with PC from those of controls, with a receiver operating characteristic area under the curve of 0.86. In addition, the biomarker signature combined with cancer antigen 19-9 could discriminate patients with PDAC from controls, with a receiver operating characteristic area under the curve of 0.919. Glyco-model demonstrated favorable diagnostic performance in all stages of PC. The diagnostic sensitivity for stage I PDAC was 89.66%.

Conclusion: In a prospective validation study, this serum biomarker signature may offer a viable method for detecting early-stage PDAC.

Keywords: Biomarkers; Glycomics; N-glycans; Pancreatic cancer; Predictive modeling.

Figure 1

Overview of study design and patient cohort. PDAC: Pancreatic ductal adenocarcinoma.

Figure 2

N-glycome profile from desialylated serum. A: Typical desialylated N-glycan profiles from the total serum protein in patients with pancreatic ductal adenocarcinoma (PDAC), patients without PDAC, and healthy participants; B: Structure of nine N-glycan peaks (GPs). GP1 indicates an agalacto core α-1,6 fucosylated biantennary glycan (NGA2F), GP2 indicates an agalacto core α-1,6 fucosylated bisecting bian tennary glycan (NGA2FB), GP3 and GP4 indicate a single agalacto core α-1,6 fucosylated biantennary glycan (NG1A2F), GP5 indicates a bigalacto biantennary glycan (NA2), GP6 indicates a bigalacto core α-1,6 fucosylated biantennary glycan (NA2F), GP7 indicates a bigalacto core α-1,6 fucosylated bisecting biantennary glycan (NA2FB), GP8 indicates a triantennary glycan (NA3), and GP9 indicates a branching α-1,3 fucosylated triantennary glycan (NA3Fb); C: N-glycan analysis in the three groups of patients. ^aP < 0.05, ^bP < 0.01. GPs: Glycan peaks; PDAC: Pancreatic ductal adenocarcinoma.

Figure 3

Verification of N-glycan peaks for distinguishing malignant pancreatic cancer (pancreatic ductal adenocarcinoma) from non-pancreatic ductal adenocarcinoma cases. A: N-glycan analysis in pancreatic ductal adenocarcinoma (PDAC) and non-PDAC (intraductal papillary mucinous neoplasm, mucinous cyst neoplasm, pancreatic neuroendocrine tumor, serous cyst adenoma, solid pseudopapillary neoplasm) groups; B: Tumor markers analysis in PDAC and non-PDAC groups. ^aP < 0.05, ^bP < 0.01. GPs: Glycan peaks; PDAC: Pancreatic ductal adenocarcinoma; SPN: Solid pseudopapillary neoplasm; PNET: Pancreatic neuroendocrine tumor; SCN: Serous cyst adenoma; IPMN: Intraductal papillary mucinous neoplasm; MCN: Mucinous cyst neoplasm; AFP: Alpha fetoprotein; CEA: Carcinoembryonic antigen; CA19-9: Cancer antigen 19-9.

Figure 4

Comparative analysis of early-stage and advanced pancreatic ductal adenocarcinoma. A: Serum glycan peak (GP)2 and GP7 levels differ significantly between early (stage I and II) and advanced (stage III and IV) pancreatic ductal adenocarcinoma; B: Serum cancer antigen (CA)19-9 and CA242 levels differ significantly between early (stage I and II) and advanced (stage III and IV) pancreatic ductal adenocarcinoma. ^aP < 0.05, ^bP < 0.01. GPs: Glycan peaks; CA19-9: Cancer antigen 19-9.

Figure 5

Glyco-model for detecting patients with pancreatic ductal adenocarcinoma. A: Diagnostic model for detecting patients with pancreatic ductal adenocarcinoma (PDAC) using the 10-fold cross-validation diagnostic model; B: The diagnostic values for Glyco-model to distinguish patients with PDAC from those of non-PDAC. AUC: Area under the curve.