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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.

SUBMITTER: Chung HW

PROVIDER: S-EPMC7659219 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Chung Hye Won HW Lim Jong-Baeck JB Jang Sunphil S Lee Kyong Joo KJ Park Kyung Hwa KH Song Si Young SY

Cancer science 20120730 9

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, ...[more]

PMID: 22703527

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Project description:Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal common cancer because of late diagnosis. Novel biomarkers for PDAC early detection are urgently needed. tRNA-derived small RNAs (tsRNAs) are novel small RNAs might serve as biomarkers for cancer diagnosis and participate in diverse physiological and pathological process. We investigated whether the expression of tsRNAs in serum could be a noninvasive method in the early detection of PDAC. Blood sample of PDAC patients and healthy controls were collected from Ruijin Hospital, Shanghai, China. Tumor and adjacent normal pancreas tissues were collected from 51 patients with PDAC undergoing therapeutic surgery. The testing cohort comprised 6 PDAC patients and 6 healthy controls and the expression of small RNAs in serum was analyzed by small RNA sequence. We verified the diagnostic performance of serum tsRNAs by qPCR in validation cohort including 110 PDAC patients and 100 healthy controls. Expression level of tsRNAs in tissue was also verified in another independent cohort including 51 tumor and 51 adjacent normal pancreas tissues. Unpaired t-test and paired t-test are used for comparing depending on whether the samples are paired. The predictive performance of tsRNAs was evaluated by Kaplan-Meier survival and receiver operating characteristic (ROC) curve. There were 45 tsRNAs expressed at remarkably higher levels, 6 tsRNAs expressed at lower levels in PDAC patients, respectively, compared with healthy volunteers. tsRNA-ValTAC-41, tsRNA-MetCAT-37 and tsRNA-ThrTGT-23 expressed significant highly (P < 0.05) in serum of PDAC patients in validation cohort. tsRNA-ValTAC-41 or tsRNA-MetCAT-37 combined with CA19-9 could increase the AUC of PDAC prediction (AUC = 0.947 and 0.949 respectively), relative to CA19-9 test alone. Besides, patients with higher serum tsRNA-ValTAC-41 level showed shorter overall survival (OS). tsRNA-ValTAC-41 also expressed at remarkably higher level in tumor tissue, and it was obviously associated with tumor staging both in serum and tissue. We provide tsRNAs profiles observed by small RNA sequencing. The diagnostic accuracy of tsRNA-ValTAC-41 and tsRNA-MetCAT-37 in serum of PDAC patients were verified. Further studies for tsRNA-ValTAC-41 are needed to confirm the findings. These tsRNAs may be promising and effective candidates in the development of highly sensitive, noninvasive biomarkers for PDAC diagnosis.

Project description:ObjectivePancreatic ductal adenocarcinoma (PDAC) is a highly malignant neoplasm with rising incidence worldwide. Gremlin 1 (GREM1), a regulator of bone morphogenetic protein (BMP) signaling, fine-tunes extensive biological processes, including organ morphology, cellular metabolism, and multiple pathological developments. The roles of GREM1 in PDAC remain unknown.MethodsVarieties of public databases and online software were employed to analyze the expressions at transcription and protein levels of GREM1 in multiple malignant neoplasms including PDAC, and in addition, its potential pro-tumoral functions in PDAC were further evaluated. A total of 340 serum samples of pancreatic disease, including PDAC, low-grade malignant pancreatic neoplasm, benign pancreatic neoplasm, pancreatitis, and 132 healthy controls, were collected to detect GREM1. The roles of serum GREM1 in the diagnosis and prediction of survival of PDAC after radical resection were also analyzed.ResultsBioinformatics analyses revealed that GREM1 was overexpressed in PDAC and predicted a poorer survival in PDAC. A higher protein level of GREM1 in PDAC correlated with stroma formation and immunosuppression by recruiting varieties of immunosuppressive cells, including T regulatory cells (Tregs), M2 macrophages, myeloid-derived suppressor cells (MDSCs), and exhaustion T cells into the tumor microenvironment. A higher level of serum GREM1 was observed in PDAC patients, compared to healthy control (p < 0.001). Serum GREM1 had a good diagnostic value (area under the curve (AUC) = 0.718, p < 0.001), and its combination with carbohydrate antigen 199 (CA199) achieved a better diagnostic efficacy (AUC = 0.914, p < 0.001), compared to CA199 alone. The cutoff value was calculated by receiver operating characteristic (ROC) analysis, and PDAC patients were divided into two groups of low and high GREM1. Logistic analyses showed serum GREM1 positively correlated with tumor size (hazard ratio (HR) = 7.097, p = 0.032) and histopathological grades (HR = 2.898, p = 0.014). High-level serum GREM1 (1,117.8 pg/ml) showed a shorter postoperative survival (p = 0.0394).ConclusionHigher intra-tumoral expression of GREM1 in PDAC contributes to tumor stroma and immunosuppressive tumor microenvironment, presenting its therapeutic potential. High-level serum GREM1 predicts poorer survival after resection. A combination of serum CA199 and GREM1 shows a stronger diagnostic efficacy in PDAC.

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

Publications

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

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