Diagnostic Biomarkers for Pancreatic Ductal Adenocarcinoma Using Non-Targeted Metabolomic Analysis

TL;DR

This study identifies potential metabolic biomarkers in pancreatic juice that could help diagnose pancreatic cancer more effectively.

Contribution

The study introduces a non-targeted metabolomic approach to identify novel diagnostic biomarkers for pancreatic ductal adenocarcinoma.

Findings

56 metabolites were found to differentiate pancreatic cancer from other diseases, with 19 annotated.

Citric acid and other metabolites were significantly decreased in pancreatic cancer patients.

A logistic regression model using three metabolites showed moderate diagnostic performance for pancreatic cancer.

Abstract

Bodily fluids of cancer patients contain various tumor-derived molecules that can provide a broad overview of cancer status. This study analyzed pancreatic juice using non-targeted metabolomic profiling to identify characteristic metabolic changes associated with pancreatic ductal adenocarcinoma (pancreatic cancer) and to develop a provisional diagnostic model. We analyzed pancreatic juice from 11 patients with pancreatic cancer and 14 patients with other benign or malignant diseases, including chronic pancreatitis and non-pancreatic malignancies such as distal bile duct adenocarcinoma and ampullary adenocarcinoma, extracting 56 metabolites that differentiated the two groups. Of these, 19 were annotated. One metabolite was notably increased and 22 were relatively decreased in pancreatic cancer. Among the decreased metabolites were isocitric acid, citric acid, and oxidized fatty acids. Using annotated metabolites, we constructed a logistic regression diagnostic model that demonstrated moderate discriminatory ability. Citric acid was included in the final, three-metabolite model, suggesting its potential usefulness as a diagnostic marker. These findings indicate that metabolic signatures in pancreatic juice may enable development of new diagnostic approaches for pancreatic cancer.

Background: Liquid biopsy using bodily fluids enables noninvasive acquisition of diverse tumor-derived molecules for comprehensive characterization of tumor profiles. Metabolomic analysis, in particular, may accurately reflect disease pathogenesis and holds promise for clinical diagnostic applications. Objective: This study explored metabolic alterations associated with pancreatic ductal adenocarcinoma (PDAC) using non-targeted metabolomic analysis of pancreatic juice to construct a preliminary diagnostic model based on selected metabolites. Methods: Pancreatic juice samples were collected intraoperatively and postoperatively from patients undergoing pancreaticoduodenectomy for PDAC (n = 11) and from those who had non-PDAC diseases, including benign conditions such as chronic pancreatitis and non-pancreatic malignancies such as distal bile duct adenocarcinoma and ampullary adenocarcinoma (n = 14). Non-targeted metabolomic analysis was performed using LC-QTOF-MS. Data were processed using MS-DIAL and MetaboAnalyst, and components showing intergroup differences were selected via PLS-DA. A diagnostic model was constructed using logistic regression based on annotated metabolites. Results: PLS-DA identified 56 discriminative components, of which 19 were successfully annotated. One metabolite was notably increased and 22 were relatively decreased in pancreatic juice of patients with PDAC. Among known metabolites that tended to decrease were isocitric acid, citric acid, and several oxidized fatty acids. A tentative logistic regression-based diagnostic model using these selected metabolites showed moderate discriminative performance. Citric acid was included in the final three-variable model, suggesting its potential as a candidate marker for PDAC discrimination. Conclusions: Pancreatic juice reflects PDAC-associated metabolic changes and may contain candidate diagnostic biomarkers. Metabolites annotated in this study may have potential as novel markers, and further studies on unknown components could help advance PDAC diagnosis and treatment.

Figures