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Blood-Based microRNA Biomarker Signature of Early-Stage Pancreatic Ductal Adenocarcinoma with Lead-Time Trajectory in Pre-Diagnostic Samples

ABSTRACT: Background & Aims: Early detection biomarkers for pancreatic ductal adenocarcinoma (PDAC) are needed since the clinically validated biomarker, CA19-9, has limited sensitivity and specificity for early-stage disease. Circulating miRNAs in plasma associated with cancer relevant pathways were developed as early detection biomarkers. Methods: Whole transcriptome assay interrogated 2,083 miRNAs in 15 µl of plasma from multicenter diagnostic cohorts (N=203: controls, n=82; diagnosed PDAC cases: n=121) and a pre-diagnostic PLCO cohort (N=96; controls, n=48; pre-diagnosed cases, n=48). A three-miRNA biomarker signature was developed for early detection of PDAC. Results: The three-miRNA signature detected PDAC from healthy controls independently (AUC = 0.974) and in combination with CA19-9 (AUC = 0.995). It also discriminated from pancreatitis (AUC = 0.931), improving performance of CA19-9 alone (AUC = 0.749) in combination (AUC = 0.954). Blinded validation in pre-diagnostic PLCO cohort revealed lead-time trajectory increase in AUC to 0.702 tat twelve-months before PDAC diagnosis. Conclusions: Plasma miRNAs associated with oncogenic pathways may serve as PDAC early detection biomarkers, with model performance progressively increasing approximately twelve months before diagnosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE259327 | GEO | 2026/01/14

REPOSITORIES: GEO

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Project description:Pancreatic ductal adenocarcinoma (PDAC) suffers from lack of an effective diagnostic method, limiting improvement in patient survival. Although the FDA-approved biomarker CA19-9 has been used for detection and surveillance of PDAC, its clinical utility is generally regarded to be limited due to its suboptimal diagnostic performance. Liquid chromatography-mass spectrometry (LC-MS) has emerged as a burgeoning technology in clinical proteomics, and identified a plethora of protein biomarker candidates for PDAC. Yet few if any has successfully transitioned into clinical practice. This translational standstill is owed partly to the limited considerations of practical needs and perspectives of clinical implementation in the course of a biomarker pipeline, such as demonstrating analytical validity of proposed biomarkers, which is critical to turning research-grade assays to clinical-grade tests. Here, we developed a fit-for-purpose multi-marker panel for PDAC diagnosis by consolidating analytically robust biomarkers as well as employing a relatively simple LC-MS method. In the discovery phase, we systematically collected putative biomarkers from both in-house proteomics data and the large volume of literature documenting PDAC biomarkers. In the verification phase, we developed a multiple-reaction monitoring (MRM)-MS-based proteomic assay using surrogate peptides that passed stringent analytical validation criteria. Given the intended use of our panel (i.e., primary screening), we adopted a high-throughput protocol including short gradient (<10 min) and simple sample preparation (no depletion or enrichment steps). To further facilitate clinical implementation, we performed verification of our panel on serum samples, which are usually the preferred biospecimen available in clinical settings. We developed a stacking ensemble model based on our final panel of 12 protein biomarkers combined with CA19-9, which showed improved diagnostic performance compared to using CA19-9 alone (AUC 0.919 and 0.830, respectively). A large-scale clinical validation study is underway to demonstrate the clinical validity of our panel.

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Blood-Based microRNA Biomarker Signature of Early-Stage Pancreatic Ductal Adenocarcinoma with Lead-Time Trajectory in Pre-Diagnostic Samples

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