Serum high mobility group box-1 is a powerful diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma

Abstract

Extracellular high mobility group box-1 (HMGB1) contributes to tumor growth and invasiveness. We evaluated the diagnostic and prognostic ability of serum HMGB1 for pancreatic ductal adenocarcinoma (PDAC). Serum HMGB1 measured by enzyme-linked immunosorbent assay (ELISA) were compared among normal, chronic pancreatitis, PDAC group in both training (n = 25, each group) and independent validation set (n = 45, each group). To determine the usability of serum HMGB1 as a diagnostic predictor of PDAC, receiver operating characteristic (ROC) curves with sensitivity/specificity and logistic regression were evaluated. To assess the HMGB1-associated prognosis of PDAC, Kaplan-Meier survival and Cox proportional-hazards regression were applied. Serum HMGB1 was correlated with presence and advanced-stage of PDAC. Logistic regression exhibited serum HMGB1 was a remarkable biomarker to predict PDAC as a single or multiple-markers; sensitivity/specificity of serum HMGB1 were superior to carbohydrate antigen (CA) 19-9 or carcinoembryonic antigen (CEA) in both training and independent datasets. Kaplan-Meier survival analysis showed PDAC patients with high serum HMGB1 levels (>30 ng/mL; median survival, 192 days) had a worse prognosis than patients with low HMGB1 levels (≤30 ng/mL; 514 days) by log-rank (P = 0.017). Cox proportional-hazards model showed the relative hazard ratios in high-serum HMGB1 group was 3.077 compared with the low-serum HMGB1 group. In conclusion, serum HMGB1 is a desirable diagnostic and prognostic biomarker for PDAC compared with pre-existing PDAC biomarkers, CA19-9 and CEA.

Figure 1

A flow diagram for validation process of serum high mobility group box‐1 as a tumor marker for pancreatic ductal adenocarcinoma throughout the study.

Figure 2

Receiver operator characteristic (ROC) curves and optimized sensitivity/specificity of high mobility group box‐1 (HMGB1), carbohydrate antigen (CA) 19‐9 or carcinoembryonic antigen (CEA) for screening of pancreatic ductal adenocarcinoma (PDAC) in training dataset (a) and in independent validation dataset (b). AUC, area under the receiver operating characteristic (ROC) curve.

Figure 3

Distribution of three tested biomarkers (high mobility group box‐1 [HMGB1], carbohydrate antigen [CA] 19‐9 or carcinoembryonic antigen [CEA]) at each stage of pancreatic ductal adenocarcinoma (PDAC). *P < 0.05.

Figure 4

Kaplan–Meier overall survival curves according to serum high mobility group box‐1 (HMGB1) levels. Patients with high serum HMGB1 (>30 ng/mL) have shorter survival than those with low serum‐HMGB1 (≤30 ng/mL) (Log‐rank, P = 0.017). CI, confidence interval; SD, standard deviation.