Cyst fluid proteins stratify malignant risk of intraductal papillary mucinous neoplasm of the pancreas

Intraductal papillary mucinous neoplasm (IPMN) is the most common type of pancreatic cyst often incidentally detected in asymptomatic patients. The current consensus guidelines, largely based on imaging features, have high sensitivity but low specificity in differentiating benign from malignant IPMNs, leading to unnecessary surgeries. Discovering biomarkers is thus warranted to improve the preoperative risk stratification of IPMN. Pancreatic cyst fluid samples were obtained from patients with pathologically confirmed low-grade (n = 73) or high-grade/invasive (n = 18) IPMN. Global proteome quantitation was performed using liquid chromatography-tandem mass spectrometry. Differentially expressed proteins (DEPs) between the two groups were analyzed using Wilcoxon rank-sum test. 152 upregulated and 74 downregulated DEPs were discovered by comparing low-grade IPMN with high-grade/invasive IPMN (all p < 0.05). The enriched upstream regulators of these DEPs included let-7, miR-122, IL15, and FLT1 (p = 6.76 × 10⁻⁵ - 5.97 × 10⁻³). Five discriminatory biomarkers with the largest LASSO coefficients and each with AUCs of >0.75 (FAHD2A, TCEAL3, TWF1, MMUT, and NTPCR) were identified. The combined five-protein model achieved a bootstrap-corrected AUC of 0.94. A combined analysis of TCGA and GTEx databases showed TWF1 overexpression in pancreatic cancer (p = 2.22 × 10⁻¹⁶) that was associated with poor prognosis (p = 0.0063). The present study identified several cyst fluid proteins (particularly TWF1) that are predictive of malignant pancreatic cyst lesions. If validated in other patient populations, these biomarkers may enhance the accuracy of the preoperative detection of high-risk IPMN and thereby improve patient outcomes.